Kenneth H. Mayer

Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death.As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01).The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57).Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.

The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of infection.In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations.We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 [81%] vs 809/1084 [75%], p=0·003) and having serological evidence of herpes (612/791 [77%] vs 613/812 [75%] p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26-1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31-0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes.PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit.US National Institutes of Health.

MethodsA double-blind, randomized trial of a recombinant HIV-1 envelope glycoprotein subunit (rgp120) vaccine was conducted among men who have sex with men and among women at high risk for heterosexual transmission of HIV-1. Volunteers received 7 injections of either vaccine or placebo (ratio, 2:1) over 30 months. The primary end point was HIV-1 seroconversion over 36 months

Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.

We describe the emergence of lesbian, gay, bisexual, and transgender (LGBT) health as a key area of study and practice for clinicians and public health professionals. We discuss the specific needs of LGBT populations on the basis of the most recent epidemiological and clinical investigations, methods for defining and measuring LGBT populations, and the barriers they face in obtaining appropriate care and services. We then discuss how clinicians and public health professionals can improve research methods, clinical outcomes, and service delivery for lesbian, gay, bisexual, and transgender people.

Objectives: Risk factors for HIV acquisition were examined in a recent cohort of men who have sex with men (MSM). Design: A longitudinal analysis of 4295 HIV-negative MSM enrolled in a randomized behavioral intervention trial conducted in six US cities. Methods: MSM were enrolled and assessed for HIV infection and risk behaviors semi-annually, up to 48 months. Results: In multivariate analysis, men reporting four or more male sex partners, unprotected receptive anal intercourse with any HIV serostatus partners and unprotected insertive anal intercourse with HIV-positive partners were at increased risk of HIV infection, as were those reporting amphetamine or heavy alcohol use and alcohol or drug use before sex. Some depression symptoms and occurrence of gonorrhea also were independently associated with HIV infection. The attributable fractions of high number of male partners, use of alcohol or drugs before sex, and unprotected receptive anal intercourse with unknown status partners and the same with presumed negative partners accounted for 32.3, 29.0, 28.4 and 21.6% of infections, respectively. Conclusions: The challenge is to develop strategies to identify men in need. Interventions are needed to help men reduce their number of sexual partners, occurrences of unprotected anal intercourse, alcohol or drug use before sex and address other mental health issues.

Inspired by unprecedented improvements in human health and development in recent decades, our world has embarked on a quest that only a generation ago would have been considered unreachable—achieving sustainable health and development for all. Improving the health and wellbeing of the world's people is at the core of the Sustainable Development Goals (SDGs), reflected in targets that call for ending the epidemics of AIDS, tuberculosis, and malaria; achieving enormous improvements in maternal and child health; and tackling the growing burden of non-communicable diseases (NCDs). Attaining universal health coverage is the means by which these ambitious health targets are to be achieved. Although on their face, the SDGs reflect an unprecedented level of global solidarity and resolve, the trends that increasingly define our world in 2018 are inconsistent with both the sentiments that underlie the SDGs and the ethos that generated such striking health and development gains in recent years. Democracy is in retreat, and in many countries the space for civil society is declining and the human rights environment deteriorating. Official development assistance for health has stalled, as an inward-looking nationalism has in many places supplanted recognition of the need for global collaboration to address shared challenges. The loss of momentum on global health ignores the urgent need to strengthen health systems to address the steady growth of NCDs, which now account for seven of ten deaths worldwide. Recent trends in the HIV response are especially concerning. Although the number of new HIV infections and AIDS-related deaths have markedly decreased since the epidemic peaked, little progress has been made in reducing new infections in the past decade. Without further reductions in HIV incidence, a resurgence of the epidemic is inevitable, as the largest ever generation of young people age into adolescence and adulthood. Yet where vigilance and renewed efforts are needed, there are disturbing indications that the world's commitment is waning. Allowing the HIV epidemic to rebound would be catastrophic for the communities most affected by HIV and for the broader field of global health. If the world cannot follow through on HIV, which prompted such an extraordinary global mobilisation, hopes for achieving the ambitious health aims outlined in the SDGs will inevitably dim. At this moment of uncertainty for the future of the HIV response and for global health generally, the International AIDS Society and The Lancet convened an international Commission of global experts and stakeholders to assess the future of the HIV response in the context of a more integrated approach to health. A central finding of the Commission is that the HIV epidemic is not on track to end and that existing tools are insufficient. Although antiretroviral therapy (ART) has transformed the HIV response by averting deaths, improving quality of life, and preventing new HIV infections, HIV treatment alone will not end the epidemic. The UNAIDS 90-90-90 approach must be accompanied by a similarly robust commitment to scaled-up primary HIV prevention and to the development of a preventive vaccine and a functional cure for HIV. Ironically, the diminishing energy on HIV is occurring at the moment when lessons learned during the HIV response could serve as pathfinders in the quest for sustainable health for all. Key messages•The HIV pandemic is not on track to end, and the prevailing discourse on ending AIDS has bred a dangerous complacency and may have hastened the weakening of global resolve to combat HIV•Existing HIV tools and strategies are insufficient, and although dramatic gains can be made through maximizing existing prevention and treatment strategies, the HIV pandemic is likely to remain a major global challenge for the foreseeable future•Tens of millions of people will require sustained access to antiretroviral therapy for decades to come, vigilance will be needed to prevent a resurgence of the epidemic as the largest-ever generation of young people age into adolescence and young adulthood, and intensified efforts are required to address HIV among populations and settings that are being left behind•Allowing the pandemic to rebound after achieving such remarkable progress would not only increase the human and financial costs of HIV, but it would potentially demoralise the global health field and diminish support for similarly ambitious global health undertakings•A rejuvenated global effort on HIV is essential; to renew and strengthen the global HIV response, the world's impressive commitment to the scaling up of HIV treatment services must be matched by a similarly robust commitment to expanded access to HIV prevention•The HIV response must make common cause with the broader global health field to herald a new era of global solidarity for health, and specific action is urgently needed to respond to the rapidly rising health toll associated with non-communicable diseases, including taking health into account in the development of public policies of all kinds. HIV services should, where feasible, be integrated with broader health services, in co-located sites where possible, with the aim of improving both HIV-related and non-HIV-specific health outcomes; greater integration of HIV and global health must preserve and build on key attributes of the HIV response, including participatory community and civil society engagement and an ironclad commitment to human rights, gender equality, and equitable access to health and social justice•The new era of global health solidarity should focus on the development of robust, flexible, people-centred health systems to end communicable diseases, develop effective measures to address the steady rise of non-communicable diseases, achieve universal health coverage, provide coordinated services tailored to the needs of health service users, and effectively address the social and structural determinants of health •The HIV pandemic is not on track to end, and the prevailing discourse on ending AIDS has bred a dangerous complacency and may have hastened the weakening of global resolve to combat HIV•Existing HIV tools and strategies are insufficient, and although dramatic gains can be made through maximizing existing prevention and treatment strategies, the HIV pandemic is likely to remain a major global challenge for the foreseeable future•Tens of millions of people will require sustained access to antiretroviral therapy for decades to come, vigilance will be needed to prevent a resurgence of the epidemic as the largest-ever generation of young people age into adolescence and young adulthood, and intensified efforts are required to address HIV among populations and settings that are being left behind•Allowing the pandemic to rebound after achieving such remarkable progress would not only increase the human and financial costs of HIV, but it would potentially demoralise the global health field and diminish support for similarly ambitious global health undertakings•A rejuvenated global effort on HIV is essential; to renew and strengthen the global HIV response, the world's impressive commitment to the scaling up of HIV treatment services must be matched by a similarly robust commitment to expanded access to HIV prevention•The HIV response must make common cause with the broader global health field to herald a new era of global solidarity for health, and specific action is urgently needed to respond to the rapidly rising health toll associated with non-communicable diseases, including taking health into account in the development of public policies of all kinds. HIV services should, where feasible, be integrated with broader health services, in co-located sites where possible, with the aim of improving both HIV-related and non-HIV-specific health outcomes; greater integration of HIV and global health must preserve and build on key attributes of the HIV response, including participatory community and civil society engagement and an ironclad commitment to human rights, gender equality, and equitable access to health and social justice•The new era of global health solidarity should focus on the development of robust, flexible, people-centred health systems to end communicable diseases, develop effective measures to address the steady rise of non-communicable diseases, achieve universal health coverage, provide coordinated services tailored to the needs of health service users, and effectively address the social and structural determinants of health From its inception, the HIV response was a unique undertaking, apart from the broader health system. Although elements of a disease-specific approach will and should be retained, the future of the HIV response will also depend on finding opportunities for integrating HIV services more closely within health systems. Wholesale abandonment of vertical HIV funding would involve considerable risks, as the laser-like focus on a single disease accounts in large measure for the HIV response's successes. Unique attributes that have defined the HIV response (including its multisectoral and inclusive approach, engagement of civil society, emphasis on equity and human rights, galvanisation of scientific innovation, and foundation of global collaboration and problem solving) must be preserved and mainstreamed across global health practice. Whether to integrate HIV within broader health systems is not an either–or choice, and optimal paths will differ between settings, populations, and services. To be effective, more integrated approaches must yield improvements both to HIV-related and non-HIV-related health outcomes. In most cases, approaches to integration will and should be incremental, allowing learning by doing. To assess the health and financial benefits of such win-win scenarios, the Commission engaged modellers to examine different scenarios for incremental integration of HIV-related and non-HIV-related services. These include: models in South Africa and Kenya for screening of HIV alongside screening for diabetes, hypertension, and other NCDs; integration of HIV in reproductive health services in Nigeria; integrated management of HIV and sexually transmitted infections in India; and integration of harm reduction and overdose services and ART for people who use drugs in Russia. In each of these scenarios, integrated approaches generated concrete improvements in HIV and broader health outcomes. With one exception (antiretroviral pre-exposure prophylaxis [PrEP] in India), integrated models were consistently found to be cost-effective. The HIV community must make common cause with the global health field— to make universal health coverage a reality, to substantially increase the share of resources devoted to health, and to build worldwide recognition of health as key to progress across the breadth of the SDGs. The global health field must take a leading role in resisting the turn towards authoritarianism, xenophobia, and austerity with respect to essential public health investments. In a time of fragmentation and uncertainty, the global health field can aid in reminding all of us of our common humanity. Health systems must be designed to meet the needs of the people they serve, including having the capacity to address multiple health problems simultaneously. No one can be left behind in our efforts to achieve sustainable health. Recognising health as an investment, major new resources (from national governments, the international community, and the private sector, involving innovative financing mechanisms) must be mobilised to support stronger, sustainable, and people-centred health systems. The SDGs sharply elevate global health and development aspirations, contemplating a world that is far more prosperous, secure, healthy, and equitable, where human rights and dignity are universally respected, and where human development unfolds in a manner that preserves the natural environment. Yet, the 3 years that have passed since the SDGs were agreed have dimmed prospects for achieving many of these visionary aims. By contrast with the international solidarity, shared commitment, and increased investments that characterised the era of the Millennium Development Goals (MDGs), much of the world has, since 2015, turned inward and toward authoritarianism, repression, a diminished role for civil society, a policy of austerity for public investments, and suspicion of international cooperation. As a result of civil conflicts that have yet to elicit an appropriate international response, more people than ever have been forced from their homes and countries. At a time when the fruits of scientific advances are so evident, denial in many quarters of the role of humankind in the degradation of our environment threatens the very health and wellbeing of our planet and our civilisations. Among the reasons why the world opted for such an ambitious agenda for the SDGs was the success of the HIV response. As a result of a worldwide mobilisation, the incidence of HIV infections peaked and began to decrease in all parts of the world, and AIDS-related mortality decreased from 1·9 million in 2005 to 1·0 million in 2016.1AIDSInfoJoint United Nations Programme on HIV/AIDS.http://aidsinfo.unaids.orgDate accessed: June 14, 2018Google Scholar The HIV response has not been an unalloyed story of achievement, as the world's capacity to respond effectively to the epidemic has been undermined by 15 years of relative inaction in the epidemic's early stages, an approach to epidemic management that has undervalued primary prevention, and the enduring stigma associated with HIV. The broader global health community, facing both historic opportunities and profound challenges, could potentially benefit from lessons learned from the successes and failures of the global HIV response. With its multisectoral and inclusive approach, mobilisation of political commitment, engagement of civil society at every level, emphasis on equity and human rights, galvanisation of scientific innovation, and foundation of global collaboration and problem solving, the HIV response has properly been cited as a model for the future of global health.2Piot P Quinn TC Response to the AIDS pandemic—a global health model.N Engl J Med. 2013; 368: 2210-2218Crossref PubMed Scopus (85) Google Scholar The global health challenge remains immense, with millions of people in low-income and middle-income countries (LMICs) dying each year from causes that have either been largely eradicated or are decreasing in prevalence in high-income countries (figure 1).3GBD 2016 Causes of Death CollaboratorsGlobal, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2017; 390: 1151-1210Summary Full Text Full Text PDF PubMed Scopus (662) Google Scholar Whether the world is prepared to meet these challenges is unclear. Although the incidence of communicable, maternal, neonatal, and nutritional diseases have decreased worldwide since 1980,3GBD 2016 Causes of Death CollaboratorsGlobal, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2017; 390: 1151-1210Summary Full Text Full Text PDF PubMed Scopus (662) Google Scholar the most recent projections indicate that financial resources available for health programmes in LMICs are likely to fall far short of amounts needed to reach the health targets set forth in the SDGs.4Global Burden of Disease Health Financing Collaborator NetworkFuture and potential spending on health 2015–40: development assistance for health, and government, prepaid private, and out-of-pocket health spending in 184 countries.Lancet. 2017; 389: 2005-2030Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Persistent weaknesses of health systems undermine prospects for progress in addressing the full panoply of health challenges. At the very moment when HIV could serve as a pathfinder for global health, there are signs that global commitment to build on the gains achieved against HIV thus far is waning. From 2013 to 2016, international HIV assistance was reduced by roughly 20%, from almost US$10 billion to US$8·1 billion.5UNEnding AIDS. Progress towards the 90–90–90 targets. Joint United Nations Programme on HIV/AIDS, Geneva2017Google Scholar Relinquishing the fight against HIV before it is over would have disastrous consequences, both for people affected by HIV and for the broader global health community. Unless further investments are made to accelerate expansion of HIV prevention and treatment programmes, the HIV epidemic is likely to rebound and grow far more serious in the coming years, especially as the world's largest-ever cohort of young people age into adolescence and young adulthood.6Piot P Abdool Karim SS Hecht R et al.the UNAIDS–Lancet CommissionDefeating AIDS—advancing global health.Lancet. 2015; 386: 171-218Summary Full Text Full Text PDF PubMed Google Scholar Notwithstanding the enormous progress that has been made in the HIV response, HIV remains "the epidemic of our time".7Corey L Gray GE Preventing acquisition of HIV is the only path to an AIDS-free generation.Proc Natl Acad Sci USA. 2017; 114: 3798-3800Crossref PubMed Scopus (4) Google Scholar In 2015–16, an estimated 36·7–38·8 million people were living with HIV worldwide, including 1·9–2·5 million newly infected in 2015.1AIDSInfoJoint United Nations Programme on HIV/AIDS.http://aidsinfo.unaids.orgDate accessed: June 14, 2018Google Scholar, 8GBD 2015 HIV CollaboratorsEstimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015.Lancet HIV. 2016; 3: e361-e387Summary Full Text Full Text PDF PubMed Scopus (218) Google Scholar More than 35 million people have died of AIDS-related causes; 1·0 million of these deaths were in 2016.9WHOGlobal Health Observatory (GHO) data.http://www.who.int/gho/hiv/en/Date accessed: June 14, 2018Google Scholar A refusal to follow through to achieve long-term control of the epidemic would merely repeat a longstanding pattern in global health, when failure to sustain a surge in global interest in combating particular health threats allows these epidemics to return in force. The history of malaria elimination efforts is a case in point, as the failure to sustain malaria-related control programmes, funding, and research investments led to an abandonment of the global malaria elimination campaign in 1969 and subsequent increases in the global malaria burden.10Nájera JA González-Silva M Alonso PL Some lessons for the future from the Global Malaria Eradication Programme (1955-1969).PLoS Med. 2011; 8: e1000412Crossref PubMed Scopus (0) Google Scholar At a moment when the means to improve human health are greater than ever, allowing a resurgence of HIV through neglect and apathy could deal a blow from which the broader cause of global health could need decades to recover. The relationship between the HIV response and the broader global health field is multilayered and bidirectional. Even as the HIV response offers important lessons from which global health can learn, it is also clear that controlling the HIV epidemic will depend in large measure on the broader global health and development fields. However, the exceptionalist approach to the HIV epidemic, in which the HIV response has often unfolded as a vertical undertaking, distinct from other health programmes, has achieved historic results and should not be jettisoned lightly. Both the HIV response and the broader global health field share a commitment to the development of health systems that are capable of addressing several health challenges at the same time. In many settings, robust, if still flawed, service systems have been developed for certain populations (eg, pregnant women, children) or for priority health conditions (eg, maternal and child health, HIV, and other communicable diseases). However, health systems as a whole are largely unprepared for providing care that is holistic, universal, and well coordinated. In the still-early years of the SDG era, the gap between reality and the vision of sustainable health remains gaping. In the midst of uncertainty about the long-term feasibility of an exceptionalist HIV approach and the prospects for achieving the lofty health targets in the SDGs, the International AIDS Society (IAS)-Lancet Commission on the Future of Global Health and the HIV Response was established in 2016 to critically examine future prospects for global health and the HIV response. The Commission was tasked with assessing the future of the HIV response in a more integrated global health and development agenda, with the aim of advising how best to achieve global control of the HIV pandemic in an era in which health and development priorities are proliferating. The Commission studied the history of the HIV response to discern how experience in responding to HIV might inform and strengthen global health more broadly. Modelling exercises were undertaken to assess the effect of various approaches to improve integration of HIV and non-HIV-related services. The most salient threats to global health and to the goal of universal health coverage were identified. With this report, we summarise the findings of the Commission, and we seek to articulate a vision for the future of the HIV response and global health that builds common cause across health and development movements and sectors. Rather than despair over the trends and patterns of the past several years, we must instead look to the extraordinary achievements of the past two decades to embolden us and reinforce our resolve to rejuvenate the HIV response and strengthen the broader cause of global health. By taking on board the lessons of the HIV response, the global health field can be made fit for the purpose of realising the vision of sustainable health for all. Global health can serve as a driving force to repudiate and discredit the continuing retreat from international solidarity, human rights, reason, scientific evidence, and open societies. Global health can serve as a pioneer in a re-engineering of the development project, from one based on charity from the high-income countries to one that tackles the central determinants of global health inequities. Just as the HIV response has demonstrated that global problems demand global solutions, the future health and wellbeing of our planet relies on us to recognise, celebrate, and build on our common humanity. With respect to the flagging response to HIV, the Commission hopes that this report serves as a wake-up call. Without a thorough rejuvenation of the HIV response and a change of course, we are likely to see a resurgence of the epidemic. After such history-making successes from unprecedented global solidarity and collaboration, the world can and must do better. To realise the vision of sustainable health for all, we must ensure that health systems are equipped to bring communicable diseases under control and to respond effectively to the growing burden of NCDs. A focused response and categorical HIV funding will remain crucial to avoid a resurgence of HIV and to bring the global pandemic under control. However, immediate and incremental steps are needed to strategically integrate HIV services into co-located primary care platforms and toward the longer-term goal of creating fully integrated, co-located, and patient-centred health-service systems. The Agenda for Sustainable Development envisages "a world free from poverty, hunger, disease and want, where all life can thrive."11UNResolution adopted by the General Assembly on 25 September 2015. Transforming our world: the 2030 Agenda for Sustainable Development (A/Res/70/1). United Nations General Assembly, New York2015Google Scholar SDG 3 calls for concerted action to ensure healthy lives and promote wellbeing for all at all ages.11UNResolution adopted by the General Assembly on 25 September 2015. Transforming our world: the 2030 Agenda for Sustainable Development (A/Res/70/1). United Nations General Assembly, New York2015Google Scholar SDG 3 also calls for ending the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases; eliminating preventable deaths in children younger than 5 years; and reducing by a third the number of deaths from NCDs.11UNResolution adopted by the General Assembly on 25 September 2015. Transforming our world: the 2030 Agenda for Sustainable Development (A/Res/70/1). United Nations General Assembly, New York2015Google Scholar Under the Agenda for Sustainable Development, universal health coverage serves as the primary vehicle for continuing and fully leveraging the momentum on health.11UNResolution adopted by the General Assembly on 25 September 2015. Transforming our world: the 2030 Agenda for Sustainable Development (A/Res/70/1). United Nations General Assembly, New York2015Google Scholar The health targets of SDG 3 build on historic gains made under the MDGs (panel 1).12UNThe Millennium Development Goals Report 2015. United Nations, New York2015Google Scholar The health gains during the MDG era coincided with, and were enabled by, advances across the broader development agenda. Whereas nearly half of the population in LMICs lived on less than $1·25 per day in 1990, this proportion had fallen to 14% by 2015.12UNThe Millennium Development Goals Report 2015. United Nations, New York2015Google Scholar Primary school attendance worldwide increased between 2000 and 2015, and differences in secondary school attendance between boys and girls diminished or disappeared altogether in some regions.12UNThe Millennium Development Goals Report 2015. United Nations, New York2015Google ScholarPanel 1Health targets for Sustainable Development Goal 3•By 2030, reduce the global maternal mortality ratio to less than 70 deaths per 100 000 livebirths•By 2030, end preventable deaths of newborn babies and children younger than 5 years, with all countries aiming to reduce neonatal mortality to at least as low as 12 deaths per 1000 livebirths and under-5 mortality to at least as low as 25 deaths per 1000 livebirths•By 2030, end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases and combat hepatitis, water-borne diseases, and other communicable diseases•By 2030, reduce by a third premature mortality from non-communicable diseases through prevention and treatment, and promote mental health and wellbeing•Strengthen the prevention and treatment of substance abuse, including narcotic drug abuse and harmful use of alcohol•By 2020, halve the number of deaths and injuries from road traffic accidents globally•By 2030, ensure universal access to sexual and reproductive health-care services, including for family planning, information, and education and ensure the integration of reproductive health into national strategies and programmes•Achieve universal health coverage, including financial risk protection, access to quality and essential health-care services, and access to safe, effective, quality, and affordable essential medicines and vaccines for all•By 2030, substantially reduce the number of deaths and illnesses from hazardous chemicals and air, water, and soil pollution and contamination•Strengthen the implementation of the WHO Framework Convention on Tobacco Control in all countries, as appropriate•Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries, provide access to affordable essential medicines and vaccines, in accordance with the Doha Declaration on the TRIPS Agreement and Public Health, which affirms the right of developing countries to use to the full the provisions in the Agreement on Trade-Related Aspects of Intellectual Property Rights regarding flexibilities to protect public health, and, in particular, provide access to medicines for all•Substantially increase health financing and the recruitment, development, training, and retention of the health workforce in developing countries, especially in least developed countries and small-island developing states•Strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction, and management of national and global health risks •By 2030, reduce the global maternal mortality ratio to less than 70 deaths per 100 000 livebirths•By 2030, end preventable deaths of newborn babies and children younger than 5 years, with all countries aiming to reduce neonatal mortality to at least as low as 12 deaths per 1000 livebirths and under-5 mortality to at least as low as 25 deaths per 1000 livebirths•By 2030, end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases and combat hepatitis, water-borne diseases, and other communicable diseases•By 2030, reduce by a third premature mortality from non-communicable diseases through prevention and treatment, and promote mental health and wellbeing•Strengthen the prevention and treatment of substance abuse, including narcotic drug abuse and harmful use of alcohol•By 2020, halve the number of deaths and injuries from road traffic accidents globally•By 2030, ensure universal access to sexual and reproductive health-care services, including for family planning, information, and education and ensure the integration of reproductive health into national strategies and programmes•Achieve universal health coverage, including financial risk protection, access to quality and essential health-care services, and access to safe, effective, quality, and affordable essential medicines and vaccines for all•By 2030, substantially reduc

Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581.1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.US National Institute of Allergy and Infectious Diseases.

Epidemiologic description of long-term adverse health effects of childhood sexual abuse is lacking, despite estimates that perhaps 30 percent of adults have experienced sexual assault in childhood.In an adult cohort enrolled to investigate causes of transmission of human immunodeficiency virus, we identified current behaviors affecting risk of infection that were associated with a history of early sexual abuse. One hundred and eighty-six individuals provided information on the occurrence of abuse and subsequent sexual and drug using activities.Approximately half of the women and one-fifth of the men reported a history of rape during childhood or adulthood. Twenty-eight percent of the women and 15 percent of the men recalled that they had been sexually assaulted during childhood. People who reported childhood rape compared with people who did not were four times more likely to be working as prostitutes (90 percent confidence interval = 2.0, 8.0). Women were nearly three times more likely to become pregnant before the age of 18 (90% CI = 1.6, 4.1). Men who reported a history of sexual abuse had a twofold increase in prevalence of HIV infection relative to unabused men (90% CI = 1.0, 3.9).The disturbing prevalence of early sexual abuse and its possible health-related consequences call for prompt and routine investigation of sexual abuse histories. Identification of sexual victimization may be an important component for management of risk factors for human immunodeficiency virus.

Background: Infection with multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus (MRSA) has been reported but seems to be isolated. Objective: To determine the incidence of a multidrug-resistant MRSA clone (USA300) in San Francisco, and to determine risk factors for the infection. Design: Population-based survey and cross-sectional study using chart review. Setting: 9 hospitals in San Francisco (population-based survey) and 2 outpatient clinics in San Francisco and Boston (cross-sectional study). Patients: Persons with culture-proven MRSA infections in 2004 to 2006. Measurements: Annual incidence, spatial clustering, and risk factors for multidrug-resistant USA300 infection. Pulsed-field gel electrophoresis, polymerase chain reaction assays, and DNA sequencing were used to characterize MRSA isolates. Results: The overall incidence of multidrug-resistant USA300 infection in San Francisco was 26 cases per 100 000 persons (95% CI, 16 to 36 cases per 100 000 persons); the incidence was higher in 8 contiguous ZIP codes with a higher proportion of male same-sex couples. Male–male sex was a risk factor for multidrug-resistant USA300 infection (relative risk, 13.2 [CI, 1.7 to 101.6]; P < 0.001) independent of past MRSA infection (relative risk, 2.1 [CI, 1.2 to 3.7]; P = 0.007) or clindamycin use (relative risk, 2.1 [1.2 to 3.6]; P = 0.007). The risk seemed to be independent of HIV infection. In San Francisco, multidrug-resistant USA300 manifested most often as infection of the buttocks, genitals, or perineum. In Boston, the infection was recovered exclusively from men who had sex with men. Limitations: The study was retrospective, and sexual risk behavior was not assessed. Conclusion: Infection with multidrug-resistant USA300 MRSA is common among men who have sex with men, and multidrug-resistant MRSA infection might be sexually transmitted in this population. Further research is needed to determine whether existing efforts to control epidemics of other sexually transmitted infections can control spread of community-associated, multidrug-resistant MRSA.

To evaluate cognitive-behavioral therapy to enhance medication adherence and reduce depression (CBT-AD) in individuals with HIV.A two arm, randomized, controlled, cross-over trial comparing CBT-AD to enhanced treatment as usual only (ETAU). ETAU, which both groups received, included a single-session intervention for adherence and a letter to the patient's provider documenting her or his continued depression. The intervention group also received 10 to 12 sessions of CBT-AD.Adherence to antiretroviral therapy as assessed by Medication Event Monitoring Systems (MEMs) and depression as assessed by blinded structured evaluation.At the acute outcome assessment (3-months), those who received CBT-AD evidenced significantly greater improvements in medication adherence and depression relative to the comparison group. Those who were originally assigned to the comparison group who chose to cross over to CBT-AD showed similar improvements in both depression and adherence outcomes. Treatment gains for those in the intervention group were generally maintained at 6- and 12-month follow-up assessments. By the end of the follow-up period, those originally assigned CBT-AD demonstrated improvements in plasma HIV RNA concentrations, though these differences did not emerge before the cross-over, and hence there were not between-groups differences.CBT-AD is a potentially efficacious approach for individuals with HIV struggling with depression and adherence. Replication and extension in larger efficacy trials are needed.

Little is known about how adolescents and young adults contribute to the declines in the cascade of care from HIV-1 diagnosis to viral suppression. We reviewed published literature from the Unites States reporting primary data for youth (13–29 years of age) at each stage of the HIV cascade of care. Approximately 41% of HIV-infected youth in the United States are aware of their diagnosis, while only 62% of those diagnosed engage medical care within 12 months of diagnosis. Of the youth who initiate antiretroviral therapy, only 54% achieve viral suppression and a further 57% are not retained in care. We estimate less than 6% of HIV-infected youth in the United States remain virally suppressed. We explore the cascade of care from HIV diagnosis through viral suppression for HIV-infected adolescents and young adults in the United States to highlight areas for improvement in the poor engagement of the infected youth population.

Heterosexual transmission by vaginal intercourse accounts for most transmission of human immunodeficiency virus-type 1 (HIV-1) in Africa and Asia but is less important in the HIV-1 epidemics of the United States and Western Europe. Epithelial Langerhans' cells (LCs) represent a possible source of initial cell contact for vaginal infection. Fifteen primary isolates of HIV-1 from U.S. homosexuals and 18 HIV-1 isolates from Thailand heterosexuals were evaluated for growth in LCs of U.S. origin. All the viruses from the Thai heterosexuals, which were subtype E, grew more efficiently in the LCs than any of the viruses from the U.S. homosexuals, which are subtype B. These results suggest that LC tropism is associated with the efficiency of heterosexual transmission of HIV.

In this work, we estimate the proportions of transmissions occurring in main vs. casual partnerships, and by the sexual role, infection stage, and testing and treatment history of the infected partner, for men who have sex with men (MSM) in the US and Peru. We use dynamic, stochastic models based in exponential random graph models (ERGMs), obtaining inputs from multiple large-scale MSM surveys. Parallel main partnership and casual sexual networks are simulated. Each man is characterized by age, race, circumcision status, sexual role behavior, and propensity for unprotected anal intercourse (UAI); his history is modeled from entry into the adult population, with potential transitions including HIV infection, detection, treatment, AIDS diagnosis, and death. We implemented two model variants differing in assumptions about acute infectiousness, and assessed sensitivity to other key inputs. Our two models suggested that only 4-5% (Model 1) or 22-29% (Model 2) of HIV transmission results from contacts with acute-stage partners; the plurality (80-81% and 49%, respectively) stem from chronic-stage partners and the remainder (14-16% and 27-35%, respectively) from AIDS-stage partners. Similar proportions of infections stem from partners whose infection is undiagnosed (24-31%), diagnosed but untreated (36-46%), and currently being treated (30-36%). Roughly one-third of infections (32-39%) occur within main partnerships. Results by country were qualitatively similar, despite key behavioral differences; one exception was that transmission from the receptive to insertive partner appears more important in Peru (34%) than the US (21%). The broad balance in transmission contexts suggests that education about risk, careful assessment, pre-exposure prophylaxis, more frequent testing, earlier treatment, and risk-reduction, disclosure, and adherence counseling may all contribute substantially to reducing the HIV incidence among MSM in the US and Peru.

Gay and bisexual men and other men who have sex with men (MSM) account for more than two thirds of new HIV infections in the U.S., with Black MSM experiencing the greatest burden. Antiretroviral pre-exposure prophylaxis (PrEP) can reduce MSM’s vulnerability to HIV infection. Uptake of PrEP has been limited, particularly among racial and ethnic minority MSM. Four semi-structured focus groups with gay and bisexual men and other MSM at risk for HIV infection were convened in Boston and Jackson in late 2013. The analysis plan utilized a within-case, across-case approach to code and analyze emerging themes, and to compare results across the two cities. Participants recruited in Jackson were primarily Black gay men, while Boston participants were mostly non-Hispanic White gay men. Participants in both sites shared concerns about medication side effects and culturally insensitive health care for gay men. Jackson participants described stronger medical mistrust, and more frequently described experiences of anti-gay and HIV related stigma. Multiple addressable barriers to PrEP uptake were described. Information about side effects should be explicitly addressed in PrEP education campaigns. Providers and health departments should address medical mistrust, especially among Black gay and bisexual men and other MSM, in part by training providers in how to provide affirming, culturally competent care. Medicaid should be expanded in Mississippi to cover low-income young Black gay and bisexual men and other MSM.

Epidemics of HIV in MSM continue to expand in most low, middle, and upper income countries in 2013 and rates of new infection have been consistently high among young MSM. Current prevention and treatment strategies are insufficient for this next wave of HIV spread. We conducted a series of comprehensive reviews of HIV prevalence and incidence, risks for HIV, prevention and care, stigma and discrimination, and policy and advocacy options. The high per act transmission probability of receptive anal intercourse, sex role versatility among MSM, network level effects, and social and structural determinants play central roles in disproportionate disease burdens. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiologic data show marked clustering of HIV in MSM networks, and high proportions of infections due to transmission from recent infections. Prevention strategies that lower biological risks, including those using antiretrovirals, offer promise for epidemic control, but are limited by structural factors including, discrimination, criminalization, and barriers to healthcare. Subepidemics, including among racial and ethnic minority MSM in the United States and UK, are particularly severe and will require culturally tailored efforts. For the promise of new and combined bio-behavioral interventions to be realized, clinically competent healthcare is necessary and community leadership, engagement, and empowerment are likely to be key. Addressing the expanding epidemics of HIV in MSM will require continued research, increased resources, political will, policy change, structural reform, community engagement, and strategic planning and programming, but it can and must be done.

To estimate the duration and frequency of the period of HIV infection without detectable antibody, modelling techniques were applied to results of detection of HIV DNA by means of the polymerase chain reaction (PCR) and to data from cases in published reports. PCR was carried out with gag and env region primers on samples from 27 homosexual and 12 haemophilic men for whom stored samples were available from before and after seroconversion; serum was also tested for p24 antigen by antigen-capture enzyme immunoassay. HIV DNA was detectable before seroconversion in 4 men; in all 4 PCR was positive only in the seronegative sample taken closest to the time of seroconversion. In 3 men antigen was detected before seroconversion; in each case HIV DNA was also detected. By a Markov model, the time from infection with HIV (as assessed by detection of HIV DNA) to first detection of HIV antibody was estimated to be 2.4 (SE 2.1) months for the median individual. Modelling of cases of HIV infection with known exposure in published reports gave a median estimate of 2.1 (0.1) months from exposure to antibody detection, and 95% of cases would be expected to seroconvert within 5.8 (0.6) months. HIV infection for longer than 6 months without detectable antibody seems uncommon.

Oral pre-exposure prophylaxis (PrEP) can reduce HIV incidence among at-risk persons. However, for PrEP to have an impact in decreasing HIV incidence, clinicians will need to be willing to prescribe PrEP. HIV specialists are experienced in using antiretroviral medications, and could readily provide PrEP, but may not care for HIV-uninfected patients. Six focus groups with 39 Boston area HIV care providers were conducted (May–June 2012) to assess perceived barriers and facilitators to prescribing PrEP. Participants articulated logistical and theoretical barriers, such as concerns about PrEP effectiveness in real-world settings, potential unintended consequences (e.g., risk disinhibition and medication toxicity), and a belief that PrEP provision would be more feasible in primary care clinics. They identified several facilitators to prescribing PrEP, including patient motivation and normative guidelines. Overall, participants reported limited prescribing intentions. Without interventions to address HIV providers’ concerns, implementation of PrEP in HIV clinics may be limited.

Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention.This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting.Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints.Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate.Gilead Sciences.

Objectives. We sought to determine whether health care use and expenditures among gay and bisexual men were reduced following the enactment of same-sex marriage laws in Massachusetts in 2003. Methods. We used quasi-experimental, prospective data from 1211 sexual minority male patients in a community-based health center in Massachusetts. Results. In the 12 months after the legalization of same-sex marriage, sexual minority men had a statistically significant decrease in medical care visits (mean = 5.00 vs mean = 4.67; P = .05; Cohen's d = 0.17), mental health care visits (mean = 24.72 vs mean = 22.20; P = .03; Cohen's d = 0.35), and mental health care costs (mean = $2442.28 vs mean = $2137.38; P = .01; Cohen's d = 0.41), compared with the 12 months before the law change. These effects were not modified by partnership status, indicating that the health effect of same-sex marriage laws was similar for partnered and nonpartnered men. Conclusions. Policies that confer protections to same-sex couples may be effective in reducing health care use and costs among sexual minority men.

Pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy. There is little scientific consensus about how to measure PrEP program implementation progress. We draw on several years of experience in implementing PrEP programs and propose a PrEP continuum of care that includes: (1) identifying individuals at highest risk for contracting HIV, (2) increasing HIV risk awareness among those individuals, (3) enhancing PrEP awareness, (4) facilitating PrEP access, (5) linking to PrEP care, (6) prescribing PrEP, (7) initiating PrEP, (8) adhering to PrEP, and (9) retaining individuals in PrEP care. We also propose four distinct categories of PrEP retention in care that include being: (1) indicated for PrEP and retained in PrEP care, (2) indicated for PrEP and not retained in PrEP care, (3) no longer indicated for PrEP, and (4) lost to follow-up for PrEP care. This continuum of PrEP care creates a framework that researchers and practitioners can use to measure PrEP awareness, uptake, adherence, and retention. Understanding each point along the proposed continuum of PrEP care is critical for developing effective PrEP interventions and for measuring public health progress in PrEP program implementation.

Where surveillance has been done, it has shown that men (MSM) who have sex with men bear a disproportionate burden of HIV. Yet they continue to be excluded, sometimes systematically, from HIV services because of stigma, discrimination, and criminalisation. This situation must change if global control of the HIV epidemic is to be achieved. On both public health and human rights grounds, expansion of HIV prevention, treatment, and care to MSM is an urgent imperative. Effective combination prevention and treatment approaches are feasible, and culturally competent care can be developed, even in rights-challenged environments. Condom and lubricant access for MSM globally is highly cost effective. Antiretroviral-based prevention, and antiretroviral access for MSM globally, would also be cost effective, but would probably require substantial reductions in drug costs in high-income countries to be feasible. To address HIV in MSM will take continued research, political will, structural reform, community engagement, and strategic planning and programming, but it can and must be done.

Background: Previous studies have found high rates of childhood sexual abuse (CSA) among US men who have sex with men (MSM). CSA history has been associated with a variety of negative effects later in life including behaviors that place MSM at greater risk for HIV acquisition and transmission. The present analysis is the first to examine the longitudinal association between CSA and HIV infection, unprotected anal sex, and serodiscordant unprotected anal sex, as well as mediators of these relationships among a large sample of HIV-uninfected MSM. Methods: The EXPLORE Study was a behavioral intervention trial conducted in 6 US cities over 48 months with HIV infection as the primary efficacy outcome. Behavioral assessments were done every 6 months via confidential computerized assessments. Longitudinal regression models were constructed, adjusting for randomization arm, geographical location of study site, age at enrollment, education, and race/ethnicity. Results: Of the 4295 participants enrolled, 39.7% had a history of CSA. Participants with a history of CSA [adjusted hazards ratio = 1.30, 95% confidence interval (CI): 1.02 to 1.69] were at increased risk for HIV infection over study follow-up. A significant association was seen between history of CSA and unprotected anal sex (adjusted odds ratio = 1.24, 95% CI: 1.12 to 1.36) and serodiscordant unprotected anal sex (adjusted odds ratio = 1.30, 95% CI: 1.18 to 1.43). Among participants reporting CSA, the EXPLORE intervention had no effect in reducing HIV infection rates. Participants reporting CSA were significantly more likely to have symptoms of depression and use nonprescription drugs. Conclusions: A predictive relationship between a history of CSA and subsequent HIV infection was observed among this large sample of HIV-uninfected MSM. Findings indicate that HIV-uninfected MSM with CSA histories are at greater risk for HIV infection, report higher rates of HIV sexual risk behavior, and may derive less benefit from prevention programs. Future HIV prevention interventions should address the specific mental health concerns of MSM with a history of CSA.

Background: Young men who have sex with men (YMSM) are a key population for implementation of preexposure prophylaxis (PrEP) interventions. This open-label study examined adherence to PrEP and assessed sexual behavior among a diverse sample of YMSM in 12 US cities. Methods: Eligible participants were 18- to 22-year-old HIV-uninfected MSM who reported HIV transmission risk behavior in the previous 6 months. Participants were provided daily tenofovir disoproxil fumarate/emtricitabine (Truvada). Study visits occurred at baseline, monthly through week 12, and then quarterly through week 48. Dried blood spots were serially collected for the quantification of tenofovir diphosphate (TFV-DP). Results: Between March and September 2013, 2186 individuals were approached and 400 were found to be preliminarily eligible. Of those 400, 277 were scheduled for an in-person screening visit and 200 were enrolled (mean age = 20.2; 54.5% black, 26.5% Latino). Diagnosis of sexually transmitted infections, including urethral and rectal chlamydial/gonococcal infection and syphilis, at baseline was 22% and remained high across visits. At week 4, 56% of participants had TFV-DP levels consistent with ≥4 pills per week. By week 48, 34% of participants had TFV-DP levels consistent with ≥4 pills per week, with a noticeable drop-off occurring at week 24. Four HIV seroconversions occurred on study (3.29/100 person-years). Condomless sex was reported by &gt;80% of participants, and condomless anal sex with last partner was associated with higher TFV-DP levels. Conclusions: Acceptability of PrEP was high, and most participants achieved protective drug levels during monthly visits. As visit frequency decreased, so did adherence. YMSM in the United States may need PrEP access in youth-friendly settings with tailored adherence support and potentially augmented visit schedules.

Background In 2010, the iPrEx trial demonstrated that oral antiretroviral pre-exposure prophylaxis (PrEP) reduced the risk of HIV acquisition among high-risk men who have sex with men (MSM). The impact of iPrEx on PrEP knowledge and actual use among at-risk MSM is unknown. Online surveys were conducted to assess PrEP awareness, interest and experience among at-risk MSM before and after iPrEx, and to determine demographic and behavioral factors associated with these measures. Methods and Findings Cross-sectional, national, internet-based surveys were administered to U.S. based members of the most popular American MSM social networking site 2 months before (n = 398) and 1 month after (n = 4 558) publication of iPrEx results. Comparisons were made between these samples with regards to PrEP knowledge, interest, and experience. Data were collected on demographics, sexual risk, and experience with post-exposure prophylaxis (PEP). Regression analyses were performed to identify factors associated with PrEP awareness, interest, and experience post-iPrEx. Most participants were white, educated, and indicated high-risk sexual behaviors. Awareness of PrEP was limited pre- and post-iPrEx (13% vs. 19%), whereas interest levels after being provided with a description of PrEP remained high (76% vs. 79%). PrEP use remained uncommon (0.7% vs. 0.9%). PrEP use was associated with PEP awareness (OR 7.46; CI 1.52–36.6) and PEP experience (OR 34.2; CI 13.3–88.4). PrEP interest was associated with older age (OR 1.01; CI 1.00–1.02), unprotected anal intercourse with ≥1 male partner in the prior 3 months (OR 1.40; CI 1.10–1.77), and perceiving oneself at increased risk for HIV acquisition (OR 1.20; CI 1.13–1.27). Conclusions Among MSM engaged in online networking, awareness of PrEP was limited 1 month after the iPrEx data were released. Utilization was low, although some MSM who reported high-risk behaviors were interested in using PrEP. Studies are needed to understand barriers to PrEP utilization by at-risk MSM.

The Institute of Medicine and The Joint Commission have recommended asking sexual orientation and gender identity (SOGI) questions in clinical settings and including such data in Electronic Health Records (EHRs). This is increasingly viewed as a critical step toward systematically documenting and addressing health disparities affecting lesbian, gay, bisexual, and transgender (LGBT) people. The U.S. government is currently considering whether to include SOGI data collection in the Stage 3 guidelines for the incentive program promoting meaningful use of EHR. However, some have questioned whether acceptable standard measures to collect SOGI data in clinical settings exist.In order to better understand how a diverse group of patients would respond if SOGI questions were asked in primary care settings, 301 randomly selected patients receiving primary care at four health centers across the U.S. were asked SOGI questions and then asked follow-up questions. This sample was mainly heterosexual, racially diverse, and geographically and regionally broad.There was a strong consensus among patients surveyed about the importance of asking SOGI questions. Most of the LGBT respondents thought that the questions presented on the survey allowed them to accurately document their SOGI. Most respondents--heterosexual and LGBT--answered the questions, and said that they would answer such questions in the future. While there were some age-related differences, respondents of all ages overwhelmingly expressed support for asking SOGI questions and understood the importance of providers' knowing their patients' SOGI.Given current deliberations within national health care regulatory bodies and the government's increased attention to LGBT health disparities, the finding that patients can and will answer SOGI questions has important implications for public policy. This study provides evidence that integrating SOGI data collection into the meaningful use requirements is both acceptable to diverse samples of patients, including heterosexuals, and feasible.

About 40 000 Americans and 2 million people worldwide are newly infected with HIV each year. The combination antiretroviral regimen, tenofovir disoproxil fumarate (TDF)/emtricitabine, taken as a single pill once daily, has been shown to prevent HIV transmission but is used by fewer than 20% of people who could benefit in the United States.PubMed was searched on February 15, 2018, using the search terms pre-exposure, prophylaxis, HIV, and PrEP to identify English-language articles published between 2010 and 2018. Four placebo-controlled randomized clinical trials have demonstrated that preexposure prophylaxis (PrEP) with daily dosing of TDF/emtricitabine significantly reduces HIV acquisition in men who have sex with men, high-risk heterosexuals, and injection drug users who share injection equipment. The efficacy of daily TDF/emtricitabine exceeds 90% but is highly correlated with degree of adherence. TDF/emtricitabine is safe and well-tolerated. Only 2% of people discontinue PrEP because of adverse effects. Sexually transmitted infections are common among those using PrEP. Resistance to TDF/emtricitabine when used for PrEP is rare (<0.1%) and usually occurs when PrEP is inadvertently prescribed to individuals with undiagnosed acute HIV infection who have false-negative findings on HIV antibody/antigen testing due to HIV infection acquired within 7 to 10 days of testing. Effective methods are needed to identify individuals at high risk for acquiring HIV, ensure their access to PrEP, and maximize medication adherence.TDF/emtricitabine is an effective and safe therapy for preventing HIV transmission. Increasing prescription of TDF/emtricitabine for patients at risk of acquiring HIV has the potential to reduce new HIV infections.

Preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced HIV acquisition in the iPrEx trial among men who have sex with men and transgender women. Self-reported sexual risk behavior decreased overall, but may be affected by reporting bias. We evaluated potential risk compensation using biomarkers of sexual risk behavior.Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and PrEP efficacy beliefs were assessed at 12 weeks. Among participants with ≥1 follow-up behavioral assessment, sexual behavior, syphilis, and HIV infection were compared by perceived treatment assignment, actual treatment assignment, and perceived PrEP efficacy.Overall, acute HIV infection and syphilis decreased during follow-up. Compared with participants believing they were receiving placebo, participants believing they were receiving FTC/TDF reported more receptive anal intercourse partners prior to initiating drug (12.8 vs. 7.7, P = 0.04). Belief in receiving FTC/TDF was not associated with an increase in receptive anal intercourse with no condom (ncRAI) from baseline through follow-up (risk ratio [RR] 0.9, 95% confidence interval [CI]: 0.6-1.4; P = 0.75), nor with a decrease after stopping study drug (RR 0.8, 95% CI: 0.5-1.3; P = 0.46). In the placebo arm, there were trends toward lower HIV incidence among participants believing they were receiving FTC/TDF (incidence rate ratio [IRR] 0.8, 95% CI: 0.4-1.8; P = 0.26) and also believing it was highly effective (IRR 0.5, 95% CI: 0.1-1.7; P = 0.12).There was no evidence of sexual risk compensation in iPrEx. Participants believing they were receiving FTC/TDF had more partners prior to initiating drug, suggesting that risk behavior was not a consequence of PrEP use.

Background India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions. Methods and Findings The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014–2015), one WHO dataset (2015), and three RNTCP reports (2014–2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000–2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB—including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000–3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775–1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India. Conclusions Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India.

Antiretroviral pre-exposure prophylaxis (PrEP) to prevent HIV transmission was first approved by the US Food and Drug Administration in 2012. Despite correlations of decreases in new HIV infections being greatest where PrEP has been deployed, the uptake of PrEP is lagging, particularly among populations with disproportionate HIV burden. This narrative review seeks to identify individual and systemic barriers to PrEP usage in the USA. A comprehensive search of recent literature uncovered a complex array of structural, social, clinical, and behavioral barriers, including knowledge/awareness of PrEP, perception of HIV risk, stigma from healthcare providers or family/partners/friends, distrust of healthcare providers/systems, access to PrEP, costs of PrEP, and concerns around PrEP side effects/medication interactions. Importantly, these barriers may have different effects on specific populations at risk. The full potential of PrEP for HIV prevention will not be realized until these issues are addressed. Strategies to achieve this goal should include educational interventions, innovative approaches to delivery of HIV care, financial support, and destigmatization of PrEP and PrEP users. Until then, PrEP uptake will continue to be suboptimal, particularly among those who need it most.Pre-exposure prophylaxis (PrEP) is a way of preventing HIV. By taking a daily pill, which contains two medicines, HIV can be stopped before it causes an infection. PrEP is prescribed for people at risk of HIV infection. However, many people who are at risk do not use PrEP. We explored the reasons for this. We found that many individuals at risk had not heard of PrEP, so would be unable to ask their doctors for it. Even among healthcare providers themselves, some were not aware of PrEP or how it should be used. For individuals who have heard of PrEP, unfortunately a stigma remains around HIV that deters some people from seeking the treatment. Furthermore, many individuals at risk have experienced bias at the hands of healthcare providers, deepening distrust of the medical establishment. Many individuals at risk also experience poverty and although there are multiple financial assistance options for PrEP, these can be difficult to access without support. Public education and training of healthcare providers may address many of the barriers we found, but deep-rooted issues such as racism and bias will require significant changes within the healthcare system.

Introduction Despite the efficacy of pre‐exposure prophylaxis (PrEP) in preventing HIV transmission, few studies have evaluated PrEP use and retention in care outcomes in real‐world settings outside of clinical trials. Methods Data were collected from PrEP clinical care programmes in three mid‐size US cities: Providence, Rhode Island (RI); Jackson, Mississippi (MS); and St. Louis, Missouri (MO). We assessed the demographic and social characteristics of patients prescribed PrEP and documented their insurance and copayment experiences. We assessed retention in PrEP care at three and six months. Multivariate analyses were used to predict retention in care among men who have sex with men (MSM). HIV acquisition among the cohort was also assessed. Results A total of 267 (RI: 117; MS: 88; MO: 62) patients were prescribed PrEP; 81% filled prescriptions (RI: 73%; MS: 82%; MO: 94%; p &lt;0.001). Patients in MS and MO were more commonly African American than in RI (72% and 26% vs. 7%, respectively), but less frequently Latino (2% and 3% vs. 24%, respectively). More patients reported living below the federal poverty line in MS (52%) compared to MO (23%) and RI (26%). Most patients were MSM (RI: 92%; MS: 88%; MO: 84%). The majority of MSM reported recent condomless anal sex (RI: 70%; MS: 65%; MO: 75%). Among 171 patients prescribed PrEP at least six months beforehand, 72% were retained in care at three months (RI: 68%; MS: 70%; MO: 87%; p =0.12) and 57% were retained in PrEP care at six months (RI: 53%: MS: 61%; MO: 63%; p =0.51). Insurance status and medication costs were not found to be significant barriers for obtaining PrEP. Three patients became infected with HIV during the six‐month period after being prescribed PrEP (1.1%; 3/267), including one in RI (suspected acute HIV infection), one in MO (confirmed poor adherence) and one in MS (seroconverted just prior to initiation). Conclusions PrEP initiation and retention in care differed across these distinct settings. In contrast, retention in PrEP care was consistently suboptimal across sites. Further research is needed to identify the individual, social and structural factors that may impede or enhance retention in PrEP care

Objectives. The purpose of this study was to better understand substance use behaviors and deleterious health consequences among individuals with HIV. Methods. We examined a multicenter cohort of HIV-infected patients (n = 3413) receiving care in 4 US cities (Seattle, Birmingham, San Diego, Boston) between December 2005 and April 2010 in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We used generalized estimating equations to model specific substance use outcomes. Results. Overall, 24% of patients reported recent use of marijuana; 9% reported amphetamine use, 9% reported crack–cocaine use, 2% reported opiate use, 3.8% reported injection drug use, and 10.3% reported polydrug use. In adjusted multivariable models, those who reported unprotected anal sex had higher odds of marijuana, amphetamine, injection drug, and polydrug use. An increased number of distinct vaginal sexual partners was associated with polydrug and crack–cocaine use. Nonadherence to antiretroviral therapy was associated with the use of all substances other than marijuana. Conclusions. The co-occurrence of substance use, unprotected intercourse, and medication nonadherence could attenuate the public health benefits of test, treat, and link to care strategies. Prevention programs are needed that address these coprevalent conditions.

Gay, bisexual, and other men who have sex with men (MSM) continue to have disproportionately high burdens of HIV infection in countries of low, middle, and high income in 2016. 4 years after publication of a Lancet Series on MSM and HIV, progress on reducing HIV incidence, expanding sustained access to treatment, and realising human rights gains for MSM remains markedly uneven and fraught with challenges. Incidence densities in MSM are unacceptably high in countries as diverse as China, Kenya, Thailand, the UK, and the USA, with substantial disparities observed in specific communities of MSM including young and minority populations. Although some settings have achieved sufficient coverage of treatment, pre-exposure prophylaxis (PrEP), and human rights protections for sexual and gender minorities to change the trajectory of the HIV epidemic in MSM, these are exceptions. The roll-out of PrEP has been notably slow and coverage nowhere near what will be required for full use of this new preventive approach. Despite progress on issues such as marriage equality and decriminalisation of same-sex behaviour in some countries, there has been a marked increase in anti-gay legislation in many countries, including Nigeria, Russia, and The Gambia. The global epidemic of HIV in MSM is ongoing, and global efforts to address it remain insufficient. This must change if we are ever to truly achieve an AIDS-free generation.

Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237-0·385), 0·331 μg/mL (0·253-0·435), and 0·387 μg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.ViiV Healthcare.

Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts.From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition.Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men ≤30 years old (95% CI: 3.6, 9.1%). Men ≤30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age ≤30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition.In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates.

Adolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults.To examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM).Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP.All participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks.The main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC.Among 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively.Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence.clinicaltrials.gov Identifier: NCT01769456.

Poor medication adherence may increase rates of loss to follow-up, disease relapse and drug resistance for individuals with active tuberculosis (TB). While TB programmes have historically used directly observed therapy (DOT) to address adherence, concerns have been raised about the patient burden, ethical limitations, effectiveness in improving treatment outcomes and long-term feasibility of DOT for health systems. Digital adherence technologies (DATs)-which include feature phone-based and smartphone-based technologies, digital pillboxes and ingestible sensors-may facilitate more patient-centric approaches for monitoring adherence, though available data are limited. Depending on the specific technology, DATs may help to remind patients to take their medications, facilitate digital observation of pill-taking, compile dosing histories and triage patients based on their level of adherence, which can facilitate provision of individualised care by TB programmes to patients with varied levels of risk. Research is needed to understand whether DATs are acceptable to patients and healthcare providers, accurate for measuring adherence, effective in improving treatment outcomes and impactful in improving health system efficiency. In this article, we describe the landscape of DATs that are being used in research or clinical practice by TB programmes and highlight priorities for research.

This report describes the evolution of a Boston community health center's multidisciplinary model of transgender healthcare, research, education, and dissemination of best practices. This process began with the development of a community-based approach to care that has been refined over almost 20 years where transgender patients have received tailored services through the Transgender Health Program. The program began as a response to unmet clinical needs and has grown through recognition that our local culturally responsive approach that links clinical care with biobehavioral and health services research, education, training, and advocacy promotes social justice and health equity for transgender people. Fenway Health's holistic public health efforts recognize the key role of gender affirmation in the care and well-being of transgender people worldwide.

Cross-sectional studies have suggested that co-occurring epidemics or "syndemics" of psychosocial health problems may accelerate HIV transmission among men who have sex with men (MSM) in the United States. We aimed to assess how 5 syndemic conditions (depressive symptoms, heavy alcohol use, stimulant use, polydrug use, and childhood sexual abuse) affected HIV incidence and sexual risk behavior over time.Eligible men in a large prospective cohort of sexually active HIV-uninfected MSM completed HIV testing and behavioral surveys at baseline and every 6 months for 48 months. We examined interrelationships between psychosocial problems and whether these interactions increased the odds of HIV risk behaviors and risk of seroconversion over study follow-up.Among 4295 men, prevalence of psychosocial conditions was substantial at baseline and was positively associated with each other. We identified a statistically significant positive dose-response relationship between numbers of syndemic conditions and HIV seroconversion for all comparisons (with the greatest hazard among those with 4-5 conditions, adjusted hazard ratio = 8.69; 95% confidence interval: 4.78 to 15.44). The number of syndemic conditions also predicted increased HIV-related risk behaviors over time, which mediated the syndemic-HIV seroconversion association.The accumulation of syndemic psychosocial problems predicted HIV-related sexual risk behaviors and seroconversion in a large sample of US MSM. Given the high prevalence of syndemic conditions among MSM and the moderate effect sizes attained by traditional brief behavioral interventions to date, the HIV prevention agenda requires a shift toward improved assessment of psychosocial comorbidities and stronger integration with mental health and substance abuse treatment services.

The FDA approval of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) in 2012 has raised questions about the delivery of PrEP in a real-world setting. iPad-based questionnaires were given to providers at conferences in California and New York to assess knowledge, experience and attitudes regarding PrEP in HIV and non-HIV providers. HIV provider status was defined either by self-identification or by having greater than 5 years of HIV care experience. Knowledge scores were the sum of correct answers from five PrEP knowledge questions. Univariate analyses used t-test to compare knowledge scores and Fisher’s exact test for past or future PrEP prescription between HIV and non-HIV providers. Multivariable linear or logistic regression models were used to assess factors associated with the outcomes. Of 233 respondents, the mean age was 40 years, 59 % were White, 59 % were physicians and 52 % were HIV providers. In univariate analysis, mean PrEP knowledge scores (max 5) were significantly higher for HIV providers (2.8 versus 2.2; p < 0.001), age > 41 (mean 2.8 versus 2.3; p = 0.004), White race (2.7 versus 2.2; p = 0.026) and participants in the New York region (3.0 versus 2.3; p < 0.001). In a multivariable model of knowledge scores, all but age remained significant. Among 201 potential prescribers, the rate of prior PrEP prescription was higher among HIV providers than non-HIV providers (34 versus 9 %; p < 0.001) and by knowledge score, but the association with provider status was no longer significant in multivariable analysis that controlled for knowledge. Intent to prescribe PrEP in the future was high for all provider types (64 %) and was associated with knowledge scores in multivariable analysis. The most common concerns about PrEP (>40 % of providers) were drug toxicities, development of resistance and patient adherence to follow-up; 32 % identified risk compensation as a concern. HIV providers had significantly greater PrEP knowledge than non-HIV providers, but differences by provider type in past PrEP prescription were largely dependent on knowledge. Future PrEP prescription was also associated with knowledge, though all providers expressed greater future use. Education of potential PrEP providers will be a key component of successful PrEP implementation.

Prior efforts to estimate U.S. prevalence of substance use disorders (SUDs) in HIV care have been undermined by caveats common to single-site trials. The current work reports on a cohort of 10,652 HIV-positive adults linked to care at seven sites, with available patient data including geography, demography, and risk factor indices, and with substance-specific SUDs identified via self-report instruments with validated diagnostic thresholds. Generalized estimating equations also tested patient indices as SUD predictors. Findings were: (1) a 48 % SUD prevalence rate (between-site range of 21–71 %), with 20 % of the sample evidencing polysubstance use disorder; (2) substance-specific SUD rates of 31 % for marijuana, 19 % alcohol, 13 % methamphetamine, 11 % cocaine, and 4 % opiate; and (3) emergence of younger age and male gender as robust SUD predictors. Findings suggest high rates at which SUDs occur among patients at these urban HIV care sites, detail substance-specific SUD rates, and identify at-risk patient subgroups.

<h2>Summary</h2> The HIV epidemic in the USA began as a bicoastal epidemic focused in large cities but, over nearly four decades, the epidemiology of HIV has changed. Public health surveillance data can inform an understanding of the evolution of the HIV epidemic in terms of the populations and geographical areas most affected. We analysed publicly available HIV surveillance data and census data to describe: current HIV prevalence and new HIV diagnoses by region, race or ethnicity, and age; trends in HIV diagnoses over time by HIV acquisition risk and age; and the distribution of HIV prevalence by geographical area. We reviewed published literature to explore the reasons for the current distribution of HIV cases and important disparities in HIV prevalence. We identified opportunities to improve public health surveillance systems and uses of data for planning and monitoring public health responses. The current US HIV epidemic is marked by geographical concentration in the US South and profound disparities between regions and by race or ethnicity. Rural areas vary in HIV prevalence; rural areas in the South are more likely to have a high HIV prevalence than rural areas in other US Census regions. Ongoing disparities in HIV in the South are probably driven by the restricted expansion of Medicaid, health-care provider shortages, low health literacy, and HIV stigma. HIV diagnoses overall declined in 2009–18, but HIV diagnoses among individuals aged 25–34 years increased during the same period. HIV diagnoses decreased for all risk groups in 2009–18; among men who have sex with men (MSM), new diagnoses decreased overall and for White MSM, remained stable for Black MSM, and increased for Hispanic or Latino MSM. Surveillance data indicate profound and ongoing disparities in HIV cases, with disproportionate impact among people in the South, racial or ethnic minorities, and MSM.

Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4(+) TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes.

Cardiac complications, particularly myocarditis and pericarditis, have been associated with SARS-CoV-2 (the virus that causes COVID-19) infection (1-3) and mRNA COVID-19 vaccination (2-5). Multisystem inflammatory syndrome (MIS) is a rare but serious complication of SARS-CoV-2 infection with frequent cardiac involvement (6). Using electronic health record (EHR) data from 40 U.S. health care systems during January 1, 2021-January 31, 2022, investigators calculated incidences of cardiac outcomes (myocarditis; myocarditis or pericarditis; and myocarditis, pericarditis, or MIS) among persons aged ≥5 years who had SARS-CoV-2 infection, stratified by sex (male or female) and age group (5-11, 12-17, 18-29, and ≥30 years). Incidences of myocarditis and myocarditis or pericarditis were calculated after first, second, unspecified, or any (first, second, or unspecified) dose of mRNA COVID-19 (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) vaccines, stratified by sex and age group. Risk ratios (RR) were calculated to compare risk for cardiac outcomes after SARS-CoV-2 infection to that after mRNA COVID-19 vaccination. The incidence of cardiac outcomes after mRNA COVID-19 vaccination was highest for males aged 12-17 years after the second vaccine dose; however, within this demographic group, the risk for cardiac outcomes was 1.8-5.6 times as high after SARS-CoV-2 infection than after the second vaccine dose. The risk for cardiac outcomes was likewise significantly higher after SARS-CoV-2 infection than after first, second, or unspecified dose of mRNA COVID-19 vaccination for all other groups by sex and age (RR 2.2-115.2). These findings support continued use of mRNA COVID-19 vaccines among all eligible persons aged ≥5 years.

COVID-19 vaccine development has advanced at lighting speed. Research that would normally require years has been completed in months. As a result of this unprecedented effort, two vaccine candidates, mRNA-1273 (Moderna, Cambridge, MA) and BNT162b2 (Pfizer, New York, NY), have been found to be safe and more than 90% effective in preventing symptomatic COVID-19 shortly after vaccination. These vaccines are extremely promising and will eventually be distributed widely. Unfortunately, as the science of vaccine development has swiftly progressed, the equally important science of community engagement, which should guide the establishment of mutually beneficial partnerships and promote eventual vaccine uptake, has lagged behind. Research methods focused on the development of effective public health interventions place communities-groups with shared culture, norms, beliefs, or language-at their core and emphasize the primacy of community ownership as essential for uptake and sustainability.1 Yet, communities of color (i.e., Black, Latinx, and Indigenous communities), who remain at highest risk for infection, have been peripheral, not central actors in the pursuit of COVID-19 vaccines. Instead, the tripartite relationship between industry, government, and academia has dominated the research enterprise related to COVID-19. (Am J Public Health. Published online ahead of print December 10, 2020: 1-3. https://doi.org/10.2105/AJPH.2020.306087).

During the COVID-19 pandemic, men who have sex with men (MSM) in the USA have reported similar or fewer sexual partners and reduced HIV testing and care access compared with before the pandemic. Pre-exposure prophylaxis (PrEP) use has also declined. We aimed to quantify the potential effect of COVID-19 on HIV incidence and HIV-related mortality among US MSM.We used a calibrated, deterministic, compartmental HIV transmission model for MSM in Baltimore (MD, USA) and available data on COVID-19-related disruptions to HIV services to predict effects of reductions in sexual partners (0%, 25%, 50%), condom use (5%), HIV testing (20%), viral suppression (10%), PrEP initiations (72%), PrEP adherence (9%), and antiretroviral therapy (ART) initiations (50%). In our main analysis, we modelled disruptions due to COVID-19 starting Jan 1, 2020, and lasting 6 months. We estimated the median change in cumulative new HIV infections and HIV-related deaths among MSM over 1 and 5 years, compared with a base case scenario without COVID-19-related disruptions.A 25% reduction in sexual partners for 6 months among MSM in Baltimore, without HIV service changes, could reduce new HIV infections by median 12·2% (95% credible interval 11·7 to 12·8) over 1 year and median 3·0% (2·6 to 3·4) over 5 years. In the absence of changes in sexual behaviour, the 6-month estimated reductions in condom use, HIV testing, viral suppression, PrEP initiations, PrEP adherence, and ART initiations combined are predicted to increase new HIV infections by median 10·5% (5·8 to 16·5) over 1 year, and by median 3·5% (2·1 to 5·4) over 5 years. Disruptions to ART initiations and viral suppression are estimated to substantially increase HIV-related deaths (ART initiations by median 1·7% [0·8 to 3·2], viral suppression by median 9·5% [5·2 to 15·9]) over 1 year, with smaller proportional increases over 5 years. The other individual disruptions (to HIV testing, PrEP and condom use, PrEP initiation, and partner numbers) were estimated to have little effect on HIV-related deaths (<1% change over 1 or 5 years). A 25% reduction in sexual partnerships is estimated to offset the effect of the combined service disruptions on new HIV infections (change over 1 year: median -3·9% [-7·4 to 1·0]; over 5 years: median 0·0% [-0·9 to 1·4]), but not on HIV deaths (change over 1 year: 11·0% [6·2 to 17·7]; over 5 years: 2·6% [1·5 to 4·3]).Maintaining access to ART and adherence support is of the utmost importance to maintain viral suppression and minimise excess HIV-related mortality due to COVID-19 restrictions in the USA, even if disruptions to services are accompanied by reductions in sexual partnerships.National Institutes of Health.

We describe the prevalence of risk behaviors at baseline among men who have sex with men (MSM) who were enrolled in a randomized behavioral intervention trial conducted in 6 US cities.Data analyses involved MSM who were negative for HIV antibodies and who reported having engaged in anal sex with 1 or more partners in the previous year.Among 4295 men, 48.0% and 54.9%, respectively, reported unprotected receptive and insertive anal sex in the previous 6 months. Unprotected sex was significantly more likely with 1 primary partner or multiple partners than with 1 nonprimary partner. Drug and alcohol use were significantly associated with unprotected anal sex.Our findings support the continued need for effective intervention strategies for MSM that address relationship status, serostatus of partners, and drug and alcohol use.

Advances in the medical treatment of HIV have made it clear that adherence to highly active antiretroviral treatment is a crucial feature for treatment success. The present paper had two goals: (1) to examine psychosocial predictors of adherence in persons receiving HIV antiretroviral therapy; (2) to compared two minimal-treatment interventions to increase HIV medication adherence in a subset of persons who self-reported less than perfect adherence. One of the interventions, Life-Steps, is a single-session intervention utilizing cognitive-behavioral, motivational interviewing, and problem-solving techniques. The other intervention, self-monitoring, utilizes a pill-diary and an adherence questionnaire alone. Significant correlates of adherence included depression, social support, adherence self-efficacy, and punishment beliefs about HIV. Depression was a significant unique predictor of adherence over and above the other variables. Both interventions yielded improvement in adherence from baseline, and the Life-Steps intervention showed faster improvements in adherence for persons with extant adherence problems.

The cellular fraction of semen contains spermatozoa, immature germ cells, leukocytes, and epithelial cells. Recent evidence implicates seminal cells as a major source of sexually transmitted human immunodeficiency virus (HIV) in semen, but the identity and infectious potential of infected cells remains poorly understood. HIV provirus was found in 75% of viable semen cell samples by polymerase chain reaction and in 88% of paired blood cell samples from HIV-seropositive men. When semen cell subpopulations were isolated by an immunomagnetic bead technique, T cells were found to be most commonly HIV-infected (75% of samples), followed by macrophages (38% of samples). Viral DNA was never detected in motile spermatozoa or immature germ cell populations. Semen leukocytes proliferated in response to mitogenic and antigenic challenge and produced p24 following stimulation with irradiated allogeneic cells. These data provide evidence that both T cells and macrophages, but not germ cells, are cellular vectors of HIV transmission in semen.

Infection with human papillomavirus (HPV) is causally linked to the development of anal and cervical cancer. In the United States, the incidence of anal cancer among men who have sex with men (MSM) is higher than the incidence of cervical cancer among women. Anal squamous intraepithelial lesions (ASILs) are anal cancer precursors comprising low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). The prevalence of cervical cancer precursor lesions peaks at around 30 years of age. The age-related prevalence of ASILs in HIV-negative MSM is unknown.We conducted a cross-sectional analysis of the prevalence and determinants of ASILs in 1262 HIV-negative MSM aged 18-89 years recruited from four U.S. cities. Anal cytology and behavioral data were obtained. Anal HPV infection status was assessed by polymerase chain reaction. Independent predictors of ASILs were identified using logistic regression. All statistical tests were two-sided.The prevalences of LSILs and HSILs were 15% and 5%, respectively, and did not change with age. In a multivariable analysis, the risk of LSILs was associated with having more than five male receptive anal sex partners (P = .03), any use of poppers (alkyl nitrites) in the previous 6 months [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.1 to 2.5; P = .03] or use of injection drugs two or more times per month during the previous 6 months [OR = 19, 95% CI = 1.3 to 277; P = .03], older age at first receptive anal intercourse (P = .004), and infection with a greater number of HPV types (P < .001 for linear trend). The risk of HSILs was associated with any anal HPV infection (OR = 3.2, 95% CI = 1.1 to 9.4; P = .039) and infection with an increasing number of HPV types (P < .001 for linear trend).Sexually active HIV-negative MSM in all age groups have a high prevalence of ASILs, possibly reflecting their ongoing sexual exposure to HPV.

Men who have sex with men (MSM) continue to account for the largest number of new HIV infections in the United States, but limited data exist on independent risk factors for infection beyond the early 1990s. The HIV Network for Prevention Trials Vaccine Preparedness Study enrolled 3257 MSM in 6 US cities from 1995 to 1997. HIV seroincidence was 1.55 per 100 person-years (95% confidence interval: 1.23-1.95) over 18 months of follow-up. On multi-variable analysis using time-dependent covariates, independent risk factors for HIV seroconversion were increased number of reported HIV-negative male sex partners (adjusted odds ratio (AOR) = 1.14 per partner, population attributable risk (PAR) = 28%), nitrite inhalant use (AOR = 2.2, PAR = 28%), unprotected receptive anal sex with an HIV unknown serostatus partner (AOR = 2.7, PAR = 15%) or HIV-positive partner (AOR = 3.4, PAR = 12%), protected receptive anal sex with an HIV-positive partner (AOR = 2.2, PAR = 11%), lack of circumcision (AOR = 2.0, PAR = 10%), and receptive oral sex to ejaculation with an HIV-positive partner (AOR = 3.8, PAR = 7%). Having a large number of male sex partners, nitrite inhalant use, and engaging in receptive anal sex explained the majority of infections in this cohort and should be targeted in prevention strategies for MSM.

Background: Preexposure prophylaxis (PrEP) could protect individuals engaging in repeated high-risk behaviors from HIV infection. Understanding the demographic and behavioral predictors of intent-to-use PrEP may prove useful to identify clinical trial participants. Methods: In 2007, 227 HIV-uninfected men who report having sex with men (MSM) recruited through modified respondent-driven sampling completed an interviewer-administered survey assessing prior PrEP use and awareness, future intent-to-use PrEP, demographics, sexual risk, psychosocial variables, and drug/alcohol use. Bivariate and multivariable logistic regression procedures examined predictors of intent-to-use PrEP. Results: Mean age of participants was 41 (SD = 9.1); 54% were nonwhite. One participant reported prior off-label PrEP use (medication obtained from his HIV-infected brother). Nineteen percent had previously heard of PrEP, whereas 74% reported intent-to-use PrEP if available after being educated about its potential. In multivariable analysis controlling for age and race/ethnicity, significant predictors of intent-to-use PrEP included the following: less education [odds ratio (OR) = 7.7; P = 0.04], moderate income (OR = 13.0; P = 0.04), no perceived side effects from taking PrEP (OR = 3.5; P = 0.001), and not having to pay for PrEP (OR = 4.2; P = 0.05). Discussion: Many New England MSM indicated an interest in using PrEP after learning about its potential, particularly if they could obtain PrEP at no expense and if PrEP had no side effects. Less educated MSM and those who knew less about PrEP and antiretroviral therapy before entering the study were more open to using antiretroviral therapy for prevention once they had received some information suggesting its potential value. Findings suggest that careful educational messages are necessary to ensure appropriate PrEP use if clinical trials reveal partial efficacy.

purpose: Candida is the most common cause of opportunistic mucosal infections in human immunodeficiency virus (HIV)-positive women. We had observed an apparent correlation between the severity of immunodeficiency and the site of mucosal candida infection. The current study was designed to determine whether significant correlations existed between the sites of mucosal candida infection and the degree of immunodeficiency, as determined by subsets of lymphocyte populations. patients and methods: The subjects in this study are 66 HIV-seropositive women evaluated by members of the Brown University Acquired Immunodeficiency Syndrome (AIDS) Program during the 3-year period, September 1, 1986, through August 30, 1989. All patients had thorough clinical evaluations and relevant laboratory studies at defined intervals. All patients with CD4 lymphocyte counts below 0.2 × 109/L received zidovudine therapy as soon as it became available. After July 1988, all patients with CD4 counts below 0.2 × 109/L received prophylaxis against Pneumocystis carinii pneumonia. All patients were counseled about HIV infection, its modes of transmission, and the early symptoms of opportunistic infections. results: The longitudinal data demonstrated that candida often infected vaginal mucosa when there was no significant reduction in CD4 lymphocyte counts. Candida infection of the oropharyngeal mucosa was associated with highly significant reductions in CD4 lymphocyte counts. Esophageal candidiasis occurred only with advanced immunodeficiency associated with CD4 counts below 0.1 × 109/L. conclusions: Candida mucosal infections occur in a hierarchical pattern in women with HIV infection. Determination of the basis for the differences in susceptibility to candida of the vaginal, oropharyngeal, and esophageal mucosal surfaces will require further studies.

Antiretroviral therapy (ART) for HIV is increasingly being introduced and utilized in diverse areas of the world. However, little research exists on adherence to ART in different cultural settings, particularly in developing countries such as India. This formative qualitative study examined barriers and facilitators of ART adherence among 60 (49 men, 11 women; 33 taking ART, 27 not currently taking ART) patients receiving HIV primary care at YRG CARE, a nongovernmental organization, in Chennai, India. The average participant reported becoming HIV infected through heterosexual transmission, was between 31 and 40 years old, had over ninth class standard education, was married, and generally had access to medical care; however, we obtained some qualitative data from various other risk categories. Trained ethnographers at the study site conducted in-depth interviews in the local language. These interviews were analyzed for content and ethnographic data. Almost all of the participants discussed the cost of ART as a barrier, with many reporting extended drug holidays, turning to family and/or friends, or taking drastic measures (i.e., selling family jewels, property) for financial assistance. Other barriers centered on privacy and stigma issues, such as disclosure of HIV inhibiting pill-taking and social support. Frequently discussed facilitators of adherence included perceived benefits of ART and proper adherence, perceptions about the consequences of nonadherence, and social support, if available. These data highlight the importance of reducing the cost of antiretroviral medications, involving family members in HIV care, and addressing privacy issues and stigma in counseling interventions in this setting.

To determine the potential for secondary HIV transmission among newly HIV-infected men who have sex with men (MSM) during their HIV antibody seroconversion period, and for the 12 months after seroconversion.A cohort study.Risk assessment questionnaires administered before receipt of the first positive HIV antibody result, plasma and seminal viral load measurements, and risk assessments one month and quarterly after receipt of the first HIV-positive test, and generalized estimating equation modelling techniques to analyse behavioral trends.Of 66 seroconverters, more than half reported unprotected anal intercourse (UAI) with HIV-negative or unknown-serostatus partners during seroconversion, with 27% reporting insertive UAI with an HIV-negative partner. The initial median plasma viral load was 4.6 log/ml, the median seminal viral load was 2.7 log/ml, suggesting a high level of infectiousness. Compared with risk behavior during seroconversion, UAI with HIV-negative or unknown-serostatus partners was reduced after the receipt of positive antibody results; however, a substantial proportion of participants reported high-risk behaviors for transmission for 12 months of follow-up. After learning of their HIV infection, recent seroconverters did not reduce the risk of secondary transmission by engaging in proportionally more high-risk practices with HIV-infected partners (compared with HIV-negative or unknown-serostatus partners), or engaging in proportionally more receptive compared with insertive UAI.Substantial potential exists for secondary HIV transmission during and for one year after HIV seroconversion. Receipt of an HIV-positive test is associated with a significant reduction in risk behavior, reinforcing the need to identify and counsel recently HIV-infected MSM.

A retrospective study was conducted on 134 HIV-infected females evaluated at an HIV/AIDS centre in south India to characterize their sociodemographics, HIV risk factors and initial clinical presentations. The mean age was 29 years; 81% were housewives; 95% were currently or previously married; 89% reported heterosexual sex as their only HIV risk factor; and 88% reported a history of monogamy. The majority were of reproductive age, thus the potential for vertical transmission of HIV and devastating impacts on families is alarming. Nearly half of these women initially presented asymptomatically implying that partner recruitment can enable early HIV detection. Single partner heterosexual sex with their husband was the only HIV risk factor for the majority of women. HIV prevention and intervention strategies need to focus on married, monogamous Indian women whose self-perception of HIV risk may be low, but whose risk is inextricably linked to the behaviour of their husbands.

Despite enormous improvements achieved through the use of antiretroviral therapies (ARTs), the risk for eventual human immunodeficiency virus (HIV) disease progression remains high. Agents that enhance the immunologic mechanism for viral recognition might reduce disease progression.To determine whether the addition of HIV-1 Immunogen would confer added clinical efficacy to that achievable by ARTs.Multicenter, double-blind, placebo-controlled, randomized trial beginning March 1996 and ending May 1999 conducted at 77 centers in the United States providing primary care or referral care for persons infected with HIV.Adults infected with HIV who have baseline CD4 cell counts between 300 x 10(6)/L and 549 x 10(6)/L without prior acquired immunodeficiency syndrome-defining conditions receiving stable ART (or no therapy) were screened and 2527 were randomized.Ten units of HIV-1 Immunogen, derived from a Zairian HIV isolate, inactivated and formulated with incomplete Freund adjuvant, was administered intramuscularly every 12 weeks. The placebo was incomplete Freund adjuvant. Changes in ARTs were allowed.HIV progression-free survival; secondary end points included overall survival, changes in HIV RNA, CD4 cell counts, CD4 percentage, body weight, and immunogenicity.The overall event rate was 1.8 per 100 person-years of follow-up. Fifty-three subjects developed clinical progression in each treatment group (relative risk [RR], 0.97; 95% confidence interval [CI], 0.66-1.42; P =.89). There were 19 and 23 deaths in the placebo and HIV-1 Immunogen groups, respectively (RR, 0.81; 95% CI, 0.44-1. 48; P =.49). There were no statistically significant differences between the groups with respect to changes in HIV RNA (P =.59), CD4 percentage (P =.63), or body weight (P =.89). Subjects in the HIV-1 Immunogen group had an increase in average CD4 cell count of approximately 10 x 10(6)/L greater than the placebo group (P =.02).HIV-1 Immunogen with unrestricted ART failed to demonstrate an increase in HIV progression-free survival. JAMA. 2000;284:2193-2202.

There are few reports of the natural history of human immunodeficiency virus (HIV) infection from Asia. In a retrospective analysis of 594 patients (72.9% male; baseline CD4 cell count, 216 cells/μL) receiving care at YRG Center for AIDS Research and Education, a tertiary HIV referral center in southern India, the mean duration of survival from serodiagnosis was 92 months. Ninety-three percent of the patients acquired infection through heterosexual contact. The most common acquired immune deficiency syndrome–defining illnesses were pulmonary tuberculosis (49%; median duration of survival, 45 months), Pneumocystis carinii pneumonia (6%; median duration of survival, 24 months), cryptococcal meningitis (5%; median duration of survival, 22 months), and central nervous system toxoplasmosis (3%; median duration of survival, 28 months). Persons with a CD4 lymphocyte count of <200 cells/μL were 19 times (95% confidence interval [CI], 5.56–64.77) more likely to die than were those with CD4 cell count of >350 cells/μL. Patients who had ⩾1 opportunistic infection were 2.6 times more likely to die (95% CI, 0.95–7.09) than were those who did not have an opportunistic infection. Antiretroviral therapy for patients with low CD4 lymphocyte counts improved the odds of survival (odds ratio, 5.37; 95% CI, 1.82–15.83).

This study was designed to gain a deeper understanding of the barriers and facilitators related to sexually transmitted diseases (STDs) and HIV screening among at-risk Boston men who have sex with men (MSM).The cohort was recruited by a modified respondent-driven sampling technique and used one-on-one semistructured interviews and a quantitative survey to examine participants' understanding of STDs and HIV, perceptions of risk for disease, reasons for getting (or not getting) tested, and experiences with testing.The study found that although most of the MSM knew the signs and symptoms of HIV, they were less familiar with STDs. MSM were most likely to be screened if they had symptoms or were told by a partner of a recent exposure. However, many barriers to STD/HIV screening among MSM still exist, including lack of awareness of symptoms, misperceptions about the ways STDs are transmitted, and perceived impediments from the healthcare system, including misgivings about provider sensitivity.To decrease current increases in HIV/STDs among MSM, new strategies that include community and provider education are needed.

In Brief Background: Asymptomatic Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) infections pose diagnostic and control problems in developing countries. Methods: Participants in China, India, Peru, Russia, and Zimbabwe were screened for C. trachomatis and N. gonorrhoeae infections and symptoms. Results: A total of 18,014 participants were evaluated at baseline, 15,054 at 12 months, and 14,243 at 24 months. The incidence of chlamydia in men was 2.0 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 4.6 from baseline to 12 months and 3.6 from 12 to 24 months; a range of 31.2% to 100% reported no symptoms across the 5 countries. The incidence of gonorrhea in men was 0.3 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 1.4 from baseline to 12 months and 1.1 from 12 to 24 months; a range of 66.7% to 100% reported no symptoms. Being female, aged 18 to 24 years, and having more than 1 partner were associated with both the infections. In addition, being divorced, separated, or widowed was associated with gonorrhea. Being male, having 6+ years of education, and reporting only 1 partner were associated with having no symptoms among those infected with chlamydia. No variables correlated with asymptomatic gonorrhea among those infected. Conclusion: A high prevalence and incidence of asymptomatic sexually transmitted infections was identified among men and women in a wide variety of settings. More effective programs are needed to identify and treat chlamydia and gonorrhea infections, especially among women, young adults, those with multiple partners, those repeatedly infected, and particularly those at risk without symptoms. The risk of transmission from persons with no symptoms requires further study. In 5 developing countries, incidence of chlamydia was 2 of 100 py in men and 4.1 in women, and gonorrhea was 0.3 of 100 person years in men and 1.3 in women. Over 80% of infected individuals reported no symptoms.

Objectives: To establish the highest practical dose and frequency (HPDF) of 0.3% or 1% tenofovir vaginal gel applied once or twice daily by sexually abstinent HIV-uninfected women, and to evaluate the safety, tolerability and systemic pharmacokinetics of the HPDF in abstinent and sexually active HIV-negative and HIV-infected women. Methods: Eighty-four women, enrolled in sequential cohorts, used the study product for 14 consecutive intermenstrual days. Safety laboratory assessments and pelvic examinations were carried out during five study visits, with colposcopy at enrollment and on day 14. Samples for pharmacokinetics were collected before and after the initial tenofovir gel use and at day 13. Results: The 1% tenofovir gel used twice daily was as well tolerated as other regimens used by the 48 HIV-negative sexually abstinent women, establishing the HPDF. Although 92% of the women reported at least one adverse event, the majority were mild (87%) and involved the genitourinary tract (70%). One possibly product-related severe adverse event involving lower abdominal cramping was reported by a sexually abstinent woman who used 0.3% gel twice daily. Serum tenofovir levels were low but detectable in 14 of the 25 women. No new HIV RNA resistance mutations were detected after 2 weeks of tenofovir gel in the 24 HIV-infected participants. No significant systemic toxicity was detected. Conclusion: A 2-week course of 1% tenofovir vaginal gel used twice daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV-positive women. Systemic tenofovir absorption occurred. Expanded safety and effectiveness testing is warranted.

We assessed the effect of lower genital tract infections on human immunodeficiency virus type 1 (HIV-1) RNA shedding in the female genital tract. Bacterial vaginosis was significantly associated with HIV-1 RNA expression in the female genital tract of HIV-infected women.

The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1beta and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1beta and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by Kruskal-Wallis analysis of variance with Dunn's multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences ( P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1beta determinations were lower in both saline and phosphate-buffered saline as compared to vaginal fluid matrix, with no significant effect of pH. The (electro)chemiluminescence-based assays were most discriminative and consistently detected <2-fold differences within each matrix type. The Luminex-based assays were less discriminative with lower reproducibility between laboratories. These results suggest the need for uniform vaginal sampling techniques and a better understanding of immunoassay platform differences and cross-validation before the biological significance of cytokine variations can be validated in clinical trials. This investigation provides the first standardized analytic approach for assessing differences in mucosal cytokine levels and may improve strategies for monitoring immune responses at the vaginal mucosal interface.

This commentary presents the content and results of a recent symposium held to discuss how resiliencies among gay and bisexual men, and other men who have sex with men, could inform HIV prevention interventions. We outline the argument for including resiliencies in prevention work and present a critique of the deficit-based approached to public health research as it applies to this line of inquiry. The commentary makes the case that HIV prevention work would be more efficacious if it were designed to incorporate naturally occurring resiliencies that manifest among gay male communities rather than primarily using interventions that address vulnerabilities among men who continue to reside in high risk contexts. The commentary concludes by listing a set of resiliency variables and constructs proposed at the meeting that could be tested in theoretically-based investigations to raise resiliencies among gay and bisexual men thereby lowering HIV risks in this population.

To evaluate the clinical safety of daily tenofovir disoproxil fumarate (TDF) among HIV-negative men who have sex with men.Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to immediate or delayed study drug (TDF, 300 mg orally per day, or placebo).Four hundred healthy HIV-uninfected men who have sex with men reporting anal sex with another man within the previous 12 months enrolled in Atlanta, Boston, and San Francisco. HIV serostatus, clinical and laboratory adverse events (AEs), adherence (pill count, Medication Event Monitoring System, and self-report), and sexual and other sociobehavioral data were assessed at 3-month intervals for 24 months. Primary outcomes were clinical safety, assessed by incidence of AEs and laboratory abnormalities.Study drug was initiated by 373 (93%) participants (186 TDF and 187 placebo), of whom 325 (87%) completed the final study visit. Of 2428 AEs reported among 334 (90%) participants, 2366 (97%) were mild or moderate in severity. Frequencies of commonly reported AEs did not differ significantly between TDF and placebo arms. In multivariable analyses, back pain was more likely among TDF recipients (P = 0.04); these reports were not associated with documented fractures or other objective findings. There were no grade ≥3 creatinine elevations; grades 1 and 2 creatinine increases were not associated with TDF receipt. Estimated percentage of study drug doses taken was 92% by pill count and 77% by Medication Event Monitoring System. Seven seroconversions occurred: 4 on placebo and 3 among delayed arm participants not yet on study drug.Daily oral TDF was well tolerated, with reasonable adherence. No significant renal concerns were identified.

The high prevalence of bone demineralization among human immunodeficiency virus (HIV)-infected patients in the current therapeutic era has been described in multiple studies, sounding the alarm that we may expect an epidemic of fragility fractures in the future. However, despite noting high overall prevalences of osteopenia and osteoporosis, recent longitudinal studies that we review here have generally not observed accelerated bone loss during antiretroviral therapy beyond the initial period after treatment initiation. We discuss the continued progress toward understanding the mechanisms of HIV-associated bone loss, particularly the effects of HIV infection, antiretroviral therapy, and host immune factors on bone turnover. We summarize results of clinical trials published in the past year that studied the safety and efficacy of treatment of bone loss in HIV-infected patients and provide provisional opinions about who should be considered for bone disease screening and treatment.

This study assesses the effects of HIV (human immunodeficiency virus) antibody testing on subsequent (one year) sexual behavior among 270 homosexual men at a Boston community health center, 21 per cent of whom were unaware of their test result. Except for the number of steady partners, the levels of all sexual activities of all groups of study participants declined over time. No effects of test awareness of antibody status were found on protective behavior for receptive anogenital contact. Elimination of unprotected insertive anogenital contact (by elimination of the practice or by condom use) was reported somewhat more often among seropositive men who became aware of their test result. Increased negative emotional reactions were reported by HIV seropositive men who were aware of their test result. These results suggest some behavioral impact of HIV antibody test knowledge in this cohort, but may not be generalizable to other populations.

Men who have sex with men (MSM) have unique health-care needs, not only because of biological factors such as an increased susceptibility to infection with HIV and sexually transmitted infections associated with their sexual behaviour, but also because of internalisation of societal stigma related to homosexuality and gender non-conformity, resulting in depression, anxiety, substance use, and other adverse outcomes. Successful responses to the global HIV/AIDS epidemic will require the development of culturally sensitive clinical care programmes for MSM that address these health disparities and root causes of maladaptive behaviour (eg, societal homophobia). Health-care providers need to become familiar with local outreach agencies, hotlines, and media that can connect MSM with positive role models and social opportunities. Research is needed to understand how many MSM lead resilient and productive lives in the face of discrimination to develop assets-based interventions that build on community support. Optimum clinical care for sexual and gender minorities is a fundamental human right. MSM deserve to be treated with respect, and health-care providers need to interact with them in ways that promote disclosure of actionable health information.

This study examined the association of appointment nonadherence to markers of disease severity using one year of demographic and health information on 995 individuals with HIV in primary care at an urban community health centre. At the latest visit, 106 of 946 valid cases (11.2%) had a CD4 less than or equal to 200, and 454 of 936 valid cases (48.5%) had detectable plasma HIV RNA (greater than 50 copies/ml). Using logistic regression, appointment nonadherence (number of missed appointments) was a significant predictor (p < .03) of having an AIDS-defining CD4 count over and above the effects of number of kept appointments (p < .0001), and whether or not the patient was taking HAART (p < .002). Appointment nonadherence was also a significant predictor (p < .05) of having a detectable viral load over and above the effects of number of kept appointments (p < .003), HAART (p < .0001) and age (p < .004). Looking only at individuals with a detectable viral load at the earliest visit, the only significant unique predictor of improvement to an undetectable viral load at the latest visit was being on HAART (p < .05). Looking at those only with an undetectable viral load at the earliest visit, the only predictor of declining to a detectable viral load was number of kept appointments (p < 003), and being on HAART (p < .05).

Background Pre-exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir-disoproxil fumarate (TDF) for HIV prevention. We determined the baseline prevalence of low bone mineral density (BMD) and the effect of TDF on BMD in men who have sex with men (MSM) in a PrEP trial in San Francisco. Methods/Findings We evaluated 1) the prevalence of low BMD using Dual Energy X-ray Absorptiometry (DEXA) in a baseline cohort of 210 HIV-uninfected MSM who screened for a randomized clinical trial of daily TDF vs. placebo, and 2) the effects of TDF on BMD in a longitudinal cohort of 184 enrolled men. Half began study drug after a 9-month delay to evaluate changes in risk behavior associated with pill-use. At baseline, 20 participants (10%) had low BMD (Z score≤−2.0 at the L2–L4 spine, total hip, or femoral neck). Low BMD was associated with amphetamine (OR = 5.86, 95% CI 1.70–20.20) and inhalant (OR = 4.57, 95% CI 1.32–15.81) use; men taking multivitamins, calcium, or vitamin D were less likely to have low BMD at baseline (OR = 0.26, 95% CI 0.10–0.71). In the longitudinal analysis, there was a 1.1% net decrease in mean BMD in the TDF vs. the pre-treatment/placebo group at the femoral neck (95% CI 0.4–1.9%), 0.8% net decline at the total hip (95% CI 0.3–1.3%), and 0.7% at the L2–L4 spine (95% CI −0.1–1.5%). At 24 months, 13% vs. 6% of participants experienced >5% BMD loss at the femoral neck in the TDF vs. placebo groups (p = 0.13). Conclusions Ten percent of HIV-negative MSM had low BMD at baseline. TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck. Larger studies with longer follow-up are needed to determine the trajectory of BMD changes and any association with clinical fractures. Trial Registration ClinicalTrials.gov: NCT00131677

Over the past decade, limited attention has been paid to the human immunodeficiency virus (HIV) epidemic in the United States. The global epidemic — particularly the epidemic in sub-Saharan Africa, where approximately two thirds of the world's population living with AIDS resides — has rightfully received most of the focus. Meanwhile, however, the prevalence of HIV infection within some U.S. populations now rivals that in some sub-Saharan African countries (see graph). For example, more than 1 in 30 adults in Washington, D.C., are HIV-infected — a prevalence higher than that reported in Ethiopia, Nigeria, or Rwanda.1 Certain U.S. subpopulations are . . .

ABSTRACT Individual or multiple resistance to clindamycin, tetracycline, erythromycin, levofloxacin, or mupirocin was detected in a large proportion of methicillin-resistant Staphylococcus aureus pulsed-field type USA300 isolates collected at an ambulatory health center in Boston. The clindamycin, tetracycline, and mupirocin resistance genes identified in these isolates are commonly associated with plasmids.

Background: Stigmatizing social environments (of which ‘structural stigma’ is one component) negatively affect health-related outcomes. However, few studies have examined structural stigma related to sexual minority status as a risk factor for HIV outcomes among MSM. Methods: In August 2013, members of a large MSM social and sexual networking site in the United States completed a survey about HIV-prevention practices. A previously validated composite index provided values for state-level structural stigma, including density of same-sex couples, proportion of public high schools with Gay-Straight Alliances, state laws protecting sexual minorities, and public opinion toward homosexuality. Multivariable logistic generalized estimating equations assessed the relationship between structural stigma and condomless anal intercourse, use and awareness of antiretroviral-based HIV-prevention strategies (i.e. pre and postexposure prophylaxis, or PEP and PrEP), and comfort discussing male–male sex with primary care providers. Results: Among the 4098 HIV-uninfected MSM, lower state-level structural stigma was associated with decreased odds of condomless anal intercourse [adjusted odds ratio (aOR) 0.97 per one unit increase in structural stigma score, 95% confidence interval (CI) 0.94–0.99], increased odds of awareness of PEP (aOR 1.06, 95% CI 1.02–1.09), and PrEP (aOR 1.06, 95% CI 1.02–1.10), having taken PEP (aOR 1.15, 95% CI 1.05–1.26) and PrEP (aOR 1.21, 95% CI 1.01–1.44), and comfort discussing male–male sex with providers (aOR 1.08, 95% CI 1.05–1.11), after adjusting for social and state-level confounders. Conclusion: MSM living in more stigmatizing environments had decreased use of antiretroviral-based HIV-prevention strategies compared to those in less stigmatizing environments. Legal reforms protecting sexual minorities should be evaluated as structural interventions that could reduce HIV risk among MSM.

Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks. Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD. Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection. Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.

Missed HIV care visits have independent prognostic value for clinical events beyond core indicators of retention in care. As this information is readily available and immediately actionable, missed HIV care visits should be incorporated into clinical, programmatic, and policy initiatives. Background. The continuum of care is at the forefront of the domestic human immunodeficiency virus (HIV) agenda, with the Institute of Medicine (IOM) and Department of Health and Human Services (DHHS) recently releasing clinical core indicators. Core indicators for retention in care are calculated based on attended HIV care clinic visits. Beyond these retention core indicators, we evaluated the additional prognostic value of missed clinic visits for all-cause mortality. Methods. We conducted a multisite cohort study of 3672 antiretroviral-naive patients initiating antiretroviral therapy (ART) during 2000–2010. Retention in care was measured by the IOM and DHHS core indicators (2 attended visits at defined intervals per 12-month period), and also as a count of missed primary HIV care visits (no show) during a 24-month measurement period following ART initiation. All-cause mortality was ascertained by query of the Social Security Death Index and/or National Death Index, with adjusted survival analyses starting at 24 months after ART initiation. Results. Among participants, 64% and 59% met the IOM and DHHS retention core indicators, respectively, at 24 months. Subsequently, 332 patients died during 16 102 person-years of follow-up. Failure to achieve the IOM and DHHS indicators through 24 months following ART initiation increased mortality (hazard ratio [HR] = 2.23; 95% confidence interval [CI], 1.79–2.80 and HR = 2.36; 95% CI, 1.89–2.96, respectively). Among patients classified as retained by the IOM or DHHS clinical core indicators, >2 missed visits further increased mortality risk (HR = 3.61; 95% CI, 2.35–5.55 and HR = 3.62; 95% CI, 2.30–5.68, respectively). Conclusions. Beyond HIV retention core indicators, missed clinic visits were independently associated with all-cause mortality. Caution is warranted in relying solely upon retention in care core indicators for policy, clinical, and programmatic purposes.

High rates of depression have been observed among men who have sex with men (MSM) relative to the general adult male population; however, a dearth of research has explored depression among Black MSM. Black MSM (n = 197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered quantitative assessment and voluntary HIV counseling and testing. Bivariate and multivariable logistic regression procedures examined the associations of demographics, behavioral HIV risk factors, and psychosocial variables with depressive symptoms by severity, using the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Adjusting for demographic and behavioral variables, significant factors associated with (1) clinically significant depressive symptoms (33%; CES-D score > or = 16): being publicly insured by Medicaid, having serodiscordant anal sex with a casual male partner, and being diagnosed with an STD in the prior 12 months; (2) moderate depressive symptoms (19%; CES-D score 16-26): having serodiscordant unprotected anal sex with a casual male partner and being diagnosed with an STD in the prior 12 months; (3) severe depressive symptoms (14%; CES-D score 27+): being publicly insured by Medicaid and reporting difficulty accessing healthcare in the past 12 months. Moderately depressed Black MSM may be more likely to engage in behaviors that place them at increased risk for HIV and other STDs. HIV prevention interventions for Black MSM may benefit from incorporating screening and/or treatment for depression, allowing MSM who are depressed to respond more effectively to behavioral change approaches.

Chronic hepatitis C virus (HCV) infection has become a major threat to the survival of human immunodeficiency virus (HIV)–infected persons in areas where antiretroviral therapy is available. In coinfection, viral eradication has been difficult to attain, and HCV therapy is underused. Novel therapies may be particularly beneficial for this population, yet studies lag behind those for HCV monoinfection. Increasingly, incident HCV among HIV-infected men who have sex with men is associated with sexual risk behavior further research should be performed to refine understanding of the causal mechanism of this association. The phenomenon of aggressive hepatic fibrogenesis when HIV infection precedes HCV acquisition requires longer-term observation to ensure optimal timing of HCV therapy. Medical management in coinfection will be improved by enhancing HCV detection, with annual serologic testing, screening with HCV RNA to detect acute infection, and HIV testing of HCV-infected individuals; by addressing HCV earlier in coinfected persons; and by universal consideration for HCV therapy. HCV drug trials in individuals coinfected with HIV should be expedited. HIV/HCV coinfection remains a growing and evolving epidemic; new developments in therapeutics and improved care models offer promise.

Human papillomavirus (HPV) is a common sexually transmitted agent that causes anogenital cancer and precancer lesions that have an inflammatory infiltrate, may be friable and bleed. Our aim was to determine the association between anal HPV infection and HIV acquisition.A prospective cohort study.We recruited 1409 HIV-negative men who have sex with men from a community-based setting in Boston, Denver, New York and San Francisco. We used Cox proportional hazards regression modeling and assessed the independent association of HPV infection with the rate of acquisition of HIV infection.Of 1409 participants contributing 4375 person-years of follow-up, 51 HIV-seroconverted. The median number of HPV types in HPV-infected HIV-seroconverters was 2 (interquartile range 1-3) at the time of HIV seroconversion. After adjustment for sexual activity, substance use, occurrence of other sexually transmitted infections and demographic variables, there was evidence (P = 0.002) for the effect of infection with at least two HPV types (hazard ratio 3.5, 95% confidence interval 1.2-10.6) in HIV seroconversion.Anal HPV infection is independently associated with HIV acquisition. Studies that incorporate high-resolution anoscopy to more accurately identify HPV-associated disease are needed to determine the relationship between HPV-associated disease and HIV seroconversion.

The vast majority of research on HIV-related stigma has been cross sectional, and few studies have examined whether experiencing stigma is associated with sexual risk behaviors.The purpose of this study is to examine the prospective relationships between experiencing HIV-related stigma and symptoms of anxiety and depression, as well as sexual transmission risk behavior.The sample included HIV-infected men who have sex with men (n = 314) who participated in a secondary HIV-prevention study at their primary care site. Participants were assessed at baseline, and then completed follow-up assessments at 3, 6, 9, and 12 months.Experiencing HIV-related stigma was prospectively associated with symptoms of depression (β = 0.16, p < .001), panic (β = 0.11, p = .01), and generalized anxiety (β = 0.05, p = .05). In addition, perceiving HIV-related stigma was prospectively associated with transmission risk behaviors, including unprotected receptive or insertive anal intercourse with HIV-seronegative or status unknown partners (β = 0.06, p = .047).Experiencing HIV-related stigma may increase risk for sexual transmission risk behavior and mental health problems.

More than 3 decades since its emergence in the United States, HIV continues to spread and disproportionately affect socially marginalized groups. Preexposure prophylaxis (PrEP), a highly effective prevention strategy federally approved since 2012, could fundamentally alter the course of the epidemic. However, PrEP’s potential has not been fully realized, in part because health care providers have been slow to adopt PrEP in clinical practice and have been selective in their discussion of PrEP with patients. This nonstandardized approach has constrained PrEP access. PrEP access has not only been inadequate but also inequitable, with several groups in high need showing lower rates of uptake than do their socially privileged counterparts. Recognizing these early warning signs that current approaches to PrEP implementation could exacerbate existing HIV disparities, we call on health professionals to integrate PrEP into routine preventive health care for adult patients—particularly in primary care, reproductive health, and behavioral health settings. Drawing on the empirical literature, we present 4 arguments for why doing so would improve access and access equity, and we conclude that the benefits clearly outweigh the challenges.

Syphilis infection may potentiate transmission of human immunodeficiency virus (HIV). We sought to determine the extent to which HIV acquisition was associated with syphilis infection within an HIV preexposure prophylaxis (PrEP) trial and whether emtricitabine/tenofovir (FTC/TDF) modified that association.The Preexposure Prophylaxis Initiative (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily FTC/TDF or placebo. Syphilis prevalence at screening and incidence during follow-up were measured. Hazard ratios for the effect of incident syphilis on HIV acquisition were calculated. The effect of FTC/TDF on incident syphilis and HIV acquisition was assessed.Of 2499 individuals, 360 (14.4%) had a positive rapid plasma reagin test at screening; 333 (92.5%) had a positive confirmatory test, which did not differ between the arms (FTC/TDF vs placebo, P = .81). The overall syphilis incidence during the trial was 7.3 cases per 100 person-years. There was no difference in syphilis incidence between the study arms (7.8 cases per 100 person-years for FTC/TDF vs 6.8 cases per 100 person-years for placebo, P = .304). HIV incidence varied by incident syphilis (2.8 cases per 100 person-years for no syphilis vs 8.0 cases per 100 person-years for incident syphilis), reflecting a hazard ratio of 2.6 (95% confidence interval, 1.6-4.4; P < .001). There was no evidence for interaction between randomization to the FTC/TDF arm and incident syphilis on HIV incidence.In HIV-seronegative MSM, syphilis infection was associated with HIV acquisition in this PrEP trial; a syphilis diagnosis should prompt providers to offer PrEP unless otherwise contraindicated.

For maximum effect pre-exposure prophylaxis should be targeted to the subpopulations that account for the largest proportion of infections (population-attributable fraction [PAF]) and for whom the number needed to treat (NNT) to prevent infection is lowest. We aimed to estimate the PAF and NNT of participants in the iPrEx (Pre-Exposure Prophylaxis Initiative) trial.The iPrEx study was a randomised controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2499 men who have sex with men (MSM) and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the USA. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. We calculated the association between demographic and risk behaviour during screening and subsequent seroconversion among placebo recipients using a Poisson model, and we calculated the PAF and NNT for risk behaviour subgroups. The iPrEx trial is registered with ClinicalTrials.gov, NCT00458393.Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, 2010. Of the 2499 MSM and transgender women in the iPrEx trial, 1251 were assigned to pre-exposure prophylaxis and 1248 to placebo. 83 of 1248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom (adjusted hazard ratio [AHR] 5·11, 95% CI 1·55-16·79). The overall PAF for MSM and transgender women reporting receptive anal intercourse without a condom was 64% (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus (PAF 53%, prevalence 54%, AHR 4·76, 95% CI 1·44-15·71); by contrast, the PAF for receptive anal intercourse without a condom with an HIV-positive partner was 1% (prevalence 1%, AHR 7·11, 95% CI 0·70-72·75). The overall NNT per year for the cohort was 62 (95% CI 44-147). NNTs were lowest for MSM and transgender women self-reporting receptive anal intercourse without a condom (NNT 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest NNTs (100 and 77, respectively).Pre-exposure prophylaxis may be most effective at a population level if targeted toward MSM and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for STIs should also inform individual decisions to start pre-exposure prophylaxis. Consideration of the PAF and NNT can aid in discussion of the benefits and risks of pre-exposure prophylaxis with MSM and transgender women.National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation.

Age-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup. This cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy–exposed PLWH receiving clinical care (ie, ≥1 CD4 count) in the United States during 2000–2009. Multimorbidity was irreversible, defined as having ≥2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non–AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures. Among 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34–46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77–.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01–1.34). Hypertension and hypercholesterolemia most commonly co-occurred. Multimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care.

The EXPLORE study evaluated a behavioral intervention to prevent HIV infection among MSM. We examined depressive symptoms, utilization of mental health care, substance use and HIV risk taking behaviors in YMSM aged 16–25 years compared with their older counterparts. YMSM were more likely to report depressive symptoms (OR = 1.55) and less likely to report use of counseling (OR = 0.39) or medication (OR = 0.20) for psychiatric conditions. YMSM were more likely to report heavy alcohol and drug use. YMSM more often reported engaging in unprotected insertive (OR = 1.60) and receptive (OR = 2.07) anal intercourse with presumed HIV-uninfected partners, and unprotected receptive (OR = 1.72) anal intercourse with partners of unknown-HIV status. These findings suggest the need for more appropriate and accessible mental health care and substance use services for YMSM. Additionally, HIV prevention work with this population should provide comprehensive education about HIV testing and risk reduction counseling that focuses on communication about serostatus and safety in sexual situations.

To evaluate for changes in sexual behaviors associated with daily pill use among men who have sex with men (MSM) participating in a preexposure prophylaxis trial.Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to receive tenofovir disoproxil fumarate or placebo at enrollment or after a 9-month delay and followed for 24 months.Four hundred HIV-negative MSM reporting anal sex with a man in the past 12 months and meeting other eligibility criteria enrolled in San Francisco, Atlanta, and Boston. Sexual risk was assessed at baseline and quarterly visits using Audio Computer-Assisted Self-Interview. The association of pill taking with sexual behavior was evaluated using logistic and negative-binomial regressions for repeated measures.Overall indices of behavioral risk declined or remained stable during follow-up. Mean number of partners and proportion reporting unprotected anal sex declined during follow-up (P < 0.05), and mean unprotected anal sex episodes remained stable. During the initial 9 months, changes in risk practices were similar in the group that began pills immediately vs. those in the delayed arm. These indices of risk did not differ significantly after initiation of pill use in the delayed arm or continuation of study medication in the immediate arm. Use of poppers, amphetamines, and sexual performance-enhancing drugs were independently associated with one or more indices of sexual risk.There was no evidence of risk compensation among HIV-uninfected MSM in this clinical trial. Monitoring for risk compensation should continue now that preexposure prophylaxis has been shown to be efficacious in MSM and other populations and will be provided in open-label trials and other contexts.

Background American Black men who have sex with men (MSM) are disproportionately affected by HIV, but the factors associated with this concentrated epidemic are not fully understood. Methods Black MSM were enrolled in 6 US cities to evaluate a multi-component prevention intervention, with the current analysis focusing on the correlates of being newly diagnosed with HIV compared to being HIV-uninfected or previously diagnosed with HIV. Results HPTN 061 enrolled 1553 Black MSM whose median age was 40; 30% self-identified exclusively as gay or homosexual, 29% exclusively as bisexual, and 3% as transgender. About 1/6th (16.2%) were previously diagnosed with HIV (PD); of 1263 participants without a prior HIV diagnosis 7.6% were newly diagnosed (ND). Compared to PD, ND Black MSM were younger (p<0.001); less likely to be living with a primary partner (p<0.001); more likely to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.011) or chlamydia (p = 0.020). Compared to HIV-uninfected Black MSM, ND were more likely to report unprotected receptive anal intercourse (URAI) with a male partner in the last 6 months (p<0.001); and to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.004), and urethral (p = 0.025) or rectal chlamydia (p<0.001). They were less likely to report female (p = 0.002) or transgender partners (p = 0.018). Multivariate logistic regression analyses found that ND Black MSM were significantly more likely than HIV-uninfected peers to be unemployed; have STIs, and engage in URAI. Almost half the men in each group were poor, had depressive symptoms, and expressed internalized homophobia. Conclusions ND HIV-infected Black MSM were more likely to be unemployed, have bacterial STIs and engage in URAI than other Black MSM. Culturally-tailored programs that address economic disenfranchisement, increase engagement in care, screen for STIs, in conjunction with safer sex prevention interventions, may help to decrease further transmission in this heavily affected community.

Introduction ….is sure design’d, by fraud or force: trust not their presents, nor admit the horse. Virgil, Aeneid Human immunodeficiency virus type 1 (HIV-1), the lymphotropic virus that causes AIDS, has infected more than 60 million people worldwide since its clinical appearance in 1981. Despite intensive prevention efforts, the HIV/AIDS epidemic continues to spread, particularly in developing countries in sub-Saharan Africa, southeast Asia and the Caribbean, as well as the developed world [1]. Although HIV can be transmitted very efficiently parenterally, the advent of routine blood screening prior to transfusion and harm reduction programs for injection drug users, have made this mode of transmission much less common than mucosal transmission. Most new HIV infections are attributable to mucosal transmission: through genital and rectal mucosae in the case of sexual transmission and through oral or gastrointestinal mucosae in the case of mother-to-child transmission [2]. Much has been learned about HIV pathogenesis and infection mechanisms at the molecular level, but the scientific community has yet to develop an effective vaccine or microbicide for HIV prevention. Many unanswered questions remain concerning HIV-1 sexual transmission. In 1983, barely 2 years into the AIDS epidemic, we hypothesized that the agent that was subsequently identified as HIV-1 may be sexually transmitted by infected ‘Trojan Horse’ leukocytes in semen [3]. This hypothesis was based on our knowledge at the time that human semen contains substantial numbers of T lymphocytes and macrophages, which could host a T-cell tropic virus, and the following assumptions: intracellular virus would be better protected than free virus from adverse effects of antiviral factors in the genital environment such as antiviral antibodies likely to be present in genital secretions of the virus-infected transmitter, as well as antimicrobial peptides that play an important role in genital innate immune defense; and virus-infected allogeneic cells could also escape early detection by major histocompatibility complex (MHC)-restricted cytotoxic T cells in a new host. Over the intervening 25+ years, others have also championed this cause [4,5], and convincing evidence has emerged from clinical research as well as in-vitro and animal studies that infected leukocytes indeed play a role in HIV transmission. Yet, most recent research on sexual HIV transmission has focused on cell-free HIV in genital secretions because of the wide availability of HIV RNA quantification assays. Furthermore, the majority of HIV vaccines and microbicides have been designed to block transmission of cell-free virus and have been tested in animal and in-vitro models that use cell-free virus as the only infectious inoculum. As the molecular events underlying cell-associated HIV transmission differ from those underlying cell-free virus transmission, many of the current vaccine and microbicide candidates might not be expected to protect against cell-associated HIV transmission. The failure of several recent vaccine and microbicide clinical trials may be due in part to this oversight. It should be possible to design strategies that block cell-associated HIV transmission as well as cell-free HIV transmission. In this article, we present an overview of research that has been conducted on cell-associated HIV mucosal transmission and recommendations for future research. We focus on sexual HIV transmission, but this review also has relevance for mother-to-child HIV transmission, which may occur through mucosal transmission of cell-associated HIV from maternal genital or mammary gland secretions [6–8]. We review published reports that describe and enumerate HIV-infected cells in genital secretions, and compelling evidence from clinical, animal and in-vitro studies demonstrating that such cells can transmit HIV across genital tract epithelial surfaces; potential molecular mechanisms underlying cell-associated HIV transmission that could be specifically targeted by future HIV prevention strategies; and in-vitro and animal cell-associated HIV transmission models currently used for studies on cell-associated HIV transmission mechanisms and for testing vaccine and microbicide candidates. Using this information as a foundation, we discuss the evidence and probability that various current microbicide and vaccine approaches prevent cell-associated HIV transmission, and suggest additional microbicide and vaccine concepts and experiments that will move this field forward. Putative cellular vectors of HIV mucosal transmission Seminal leukocytes Cell populations The principal cell types in human semen are spermatozoa, immature germ cells, and white blood cells (WBCs) (Fig. 1). WBCs enter semen from various sites along the reproductive tract, including the rete testis, epididymis, prostate, and urethra, where they play an immunosurveillance role [9]. WBCs in semen have been enumerated and characterized by immunohistology and FACS analysis. Most of these studies indicate that semen from healthy non-HIV-infected men contains on the order of 105 WBCs/ml, the majority of which are polymorphonuclear leukocytes, although substantial numbers of macrophages and CD4+ T cells are also present [10–14]. Macrophages usually outnumber CD4+ T cells in semen. This is especially the case in HIV-infected men in whom seminal CD4+ lymphocytes are depleted; in one study of 98 antiretroviral therapy (ART)-naive HIV-positive men, the median ratio of macrophages to CD4+ lymphocytes in semen was 22: 1 [15] (Table 1). These data indicate that macrophages are the most abundant HIV-susceptible host cell in semen and a likely principal mediator of cell-associated HIV transmission.Fig. 1: Leukocytes in human genital secretions, identified by immunohistochemistry. (a) CD4+ T cell in semen. (b) CD68+ macrophages in semen. (c) CD45+ leukocytes in semen from a man with leukocytospermia. (d) CD68+ macrophages in cervicovaginal secretions. Magnification ×400.Table 1: White blood cell concentrations in semen.Concentrations of WBCs in semen are highly variable. Leukocytospermia, an asymptomatic genital inflammatory condition characterized by more than 106 WBCs/ml semen [16,17] occurs in approximately 5–10% of healthy non-HIV-infected men [18–20] and as many as 24% of HIV-infected men [21]. Leukocytospermic semen contains substantially elevated concentrations of macrophages and CD4+ T cells [22]. In some HIV-positive leukocytospermic men, the seminal macrophage cell count has exceeded 107 cells/ml and the CD4+ T-cell count exceeded 2 × 106 cells/ml (these cases are described in more detail below). HIV-infected cells have also been detected in pre-ejaculatory fluid, a urethral secretion secreted from the glands of Littre and Cowper glands during sexual stimulation, and these may also facilitate the sexual transmission of HIV [23,24]. Other important HIV-susceptible host cells such as dendritic and Langerhans cells have not been detected in semen, although it is possible that some viable HIV-infected Langerhans cells from penile skin, especially the inner foreskin [25–27], are shed in the vagina or rectum during intercourse. Prevalence and quantity of HIV-infected leukocytes in semen Most quantitative studies of HIV in semen have used commercially available HIV RNA assays to measure copy numbers of cell-free virions in seminal plasma; only a few have used HIV DNA PCR assays to assess the prevalence or number of HIV-infected cells in semen. In these studies, the prevalence of HIV proviral DNA in semen samples has ranged from 21 to 65% and the amount of HIV DNA has ranged from not detectable to 80 000 copies/ml (Table 2) [28–38]. Interestingly, in two of the larger studies that assessed both HIV RNA and DNA copy numbers in semen, these two parameters were not correlated [34,35]. Elevated proviral HIV DNA levels in semen have been associated with reduced peripheral CD4 cell counts [32], acute HIV infection [39], leukocytospermia and recent sexually transmitted infection (STI) [32,40], and vasectomy [34]. After initiation of HAART, levels of both HIV RNA and DNA are reduced in semen, although HIV proviral DNA-bearing cells can persist in semen for several months [35,37] and have been shown to be infectious in vitro[33].Table 2: Studies on HIV DNA in semen.The percentage of HIV-infected WBCs in semen has not been previously determined. To perform this calculation, we returned to a database that was used in a publication on factors associated with elevated HIV proviral DNA levels in semen [32]. Semen from 38 HIV-positive men from this study had measurable levels of both HIV DNA and HIV-susceptible host cells (macrophages and CD4+ T cells, quantified by immunohistology); making assumptions that only a single HIV DNA copy was present in each infected cell and that only macrophages and CD4+ T cells were infected, the median infection rate of this seminal HIV-susceptible host cell population was 0.2% (range 0.002–16%). Infectiousness of semen cells Since the pioneering discovery in 1983 that HIV-1 could be cultured from seminal cells [41], a number of laboratories have cultured HIV from both seminal cells and cell-free seminal plasma (Table 3) [42–53]. Overall, the recovery rate of infectious HIV from seminal cells has been much higher (median 20%, range 4–55%) than that from seminal plasma (median 5.9%, range 3–11%, P < 0.0001). The relatively low HIV recovery rate from seminal plasma contrasts with quantitative PCR data indicating that HIV prevalence rates and viral copy numbers are higher in seminal plasma than in the semen cell fraction [14,34–36]. This discrepancy suggests that much of the cell-free HIV in semen is replication incompetent or inactivated. A number of factors have been identified in seminal plasma that may inactivate HIV, including anti-HIV antibodies [54,55], X4/R5 chemokines [20], SLPI, lactoferrin, and defensins [56]. The low culture rate could also reflect the toxicity of seminal plasma to peripheral blood mononuclear cell (PBMC) target cells used for culturing HIV [57–61].Table 3: HIV culture rate from semen fractionsa.Factors that affect the abundance and infectiousness of HIV-infected leukocytes in semen Although WBCs can be detected in semen from virtually all men, several factors may affect the types, abundance, and infectiousness of WBCs in semen. Symptomatic bacterial genital tract infections and inflammation are often associated with increased urethral/seminal WBC numbers [62,63]. However, chronic asymptomatic genital viral infections do not generally produce elevated seminal WBC counts [64,65], and as mentioned above, HIV infection appears to deplete CD4+ and CD8+ lymphocytes in semen [15,66], an effect partially reversed by antiretroviral therapy [15]. Epidemiologic studies indicate that STIs substantially enhance HIV transmission [67,68]. Urethritis caused by Neisseria gonorrhoeae was associated with a 10-fold increase in HIV RNA copy numbers in semen, which declined following successful antibiotic treatment [69]. Other studies have demonstrated increased HIV RNA shedding from genital ulcers caused by various STI pathogens [70–72]. Most of these studies have only measured cell-free HIV RNA, but because symptomatic infections and inflammation are associated with elevated WBC levels in semen, it is probable that the number of HIV-infected cells in semen is also increased. One study to date has shown that both HIV RNA and proviral DNA levels were elevated in semen from men with a recent STI [40]. Elevated polymorphonuclear leukocyte (PMN) counts and leukocytospermia have also been associated with increased levels of both cell-free and cell-associated HIV in semen [32,45,73], as well as increased levels of IL-1β, TNF-α, IL-6, and other proinflammatory cytokines that could activate HIV replication in infected cells [20,65,74]. Some men may be particularly contagious due to abnormally elevated seminal leukocyte counts. In one study from our laboratory, semen samples from two HIV-positive persons without STI symptoms contained 15–25 million macrophages and 2–6 million CD4+ T cells per ml (the average human ejaculate comprises 2.5 million per ml). In addition, their semen was highly infectious when cultured with PBMC target cells [15]. Both of these men had advanced HIV disease in the pre-HAART era and had high peripheral blood viral loads. Cases such as these may play an important role in the HIV epidemic. Men with acute HIV infection also have high levels of HIV RNA in semen, and epidemiologic studies indicate that they are highly infectious [75,76]. Only one study thus far has measured HIV proviral DNA levels in semen of acutely infected men; 10 out of 13 samples from three HIV-infected men within 80 days of initial infection tested positive for HIV DNA [39]. More research is needed to determine whether HIV-infected WBCs in semen contribute to the highly contagious profile of this group. HIV transmission by spermatozoa The question of whether spermatozoa transmit HIV infection has been controversial for several years [77–79]. HIV and simian immunodeficiency viruses (SIV) apparently infect testicular germ cells [80–82], and early electron microscopy and in-situ hybridization studies provided evidence that human spermatozoa may contain HIV viral particles or RNA [83–85]. However, these findings have not been confirmed [78,86], and most recent studies using PCR techniques have not detected HIV infection of viable spermatozoa [79,87]. Viable, motile spermatozoa from HIV-infected men, separated from other cell types in semen by density gradient centrifugation and/or swim-up techniques, rarely contain detectable amounts of HIV DNA or RNA [31,36,79,86,88–96]. Occasional positive results may be due to contamination of the sperm pellet with infected leukocytes or false-positive PCR reactions, or could indicate that HIV infection of sperm occurs but is exceedingly rare. We measured HIV DNA in isolated cell populations from semen of HIV-infected men and detected HIV DNA in immunobead-purified macrophage and CD4+ T-cell populations, but not in motile sperm [31]. In the same study, we also compared the relative infectiousness of cell populations from semen of HIV-positive men and found that isolated CD4+ T cells and macrophages were highly infectious when cultured with PBMC target cells in vitro, whereas motile sperm from the same participants were not infectious [31]. Reports from Assisted Reproduction Clinics that have used isolated motile sperm from HIV-infected men to inseminate HIV-uninfected partners provide further evidence that motile sperm are not infectious. Over 4500 inseminations have been performed with processed sperm from HIV-infected men without infection of the seronegative partners [96–105]. However, even in light of substantial data to the contrary, one cannot conclude that sperm never transmit HIV following natural intercourse. As mentioned above, occasional detection of HIV DNA in purified sperm preparations could indicate rare HIV infection of sperm. Furthermore, several groups have reported that HIV virions can bind to sperm through mannose or glycolipid receptors [85,106–111]. This interaction may be missed with processed sperm, as loosely-attached HIV may be stripped-off by gradient separation protocols, but this association could be relevant following normal intercourse as sperm could transport HIV to host cells in the lower as well as upper urogenital tract. In a recent study [112], abnormal/immotile ejaculated sperm from HIV-infected men were found to contain HIV DNA, suggesting that HIV-infected testicular germ cells produce immotile/nonviable sperm. These defective sperm could potentially introduce HIV to phagocytic macrophages or other cells in the female genital tract after intercourse [105,113]. Leukocytes in female genital secretions Cell populations Several studies have documented HIV-susceptible host cells in vaginal and cervical tissue (described below), but few have quantified or characterized these cell populations in human vaginal and cervical secretions. Macrophages and CD4+ T cells are often detectable but not numerous in cervicovaginal secretions from healthy uninfected [114,115] or HIV-infected women [116] (Table 4) [117]. The viability of lymphocytes in vaginal secretions from healthy women is usually poor, probably due to the toxic effects of low pH conditions commonly found in the human vagina [118].Table 4: WBC concentrations in cervicovaginal secretions.Leukocyte counts are elevated in cervicovaginal secretions of women with certain STIs. Neisseria gonorrhoeae and Chlamydia trachomatis infections can induce massive inflammatory infiltrates [119]. In contrast, bacterial vaginosis appears to have little or no effect on vaginal leukocyte counts [119–121], but these cells could have improved viability and higher infectiousness due to near neutral pH associated with this condition. Prevalence and quantity of HIV-infected leukocytes in female genital secretions Several studies on HIV in vaginal secretions have used qualitative HIV DNA assessment as an endpoint. An increased prevalence of HIV DNA in vaginal secretions has been associated with cervicitis, candidiasis, and STIs [122–133], hormonal contraception [129,134], and vitamin A or selenium deficiency [129,135–137]. The prevalence of HIV-infected cells in vaginal secretions is reduced in women on antiretroviral therapy [138,139]. Only a few studies have quantified HIV DNA in cells from cervicovaginal secretions [7,131,140–145] (Table 5). In these studies, maximum HIV proviral copies were on the order of 104 per lavage (103 copies/ml lavage fluid). Our laboratory quantified HIV RNA and DNA in cervicovaginal secretions from women in the WITS cohort during the third trimester of pregnancy; levels of HIV DNA, but not RNA, and proviral heterogeneity were positively associated with perinatal HIV transmission [7,140].Table 5: Studies on HIV DNA in cervicovaginal secretions.Infectiousness of cervicovaginal leukocytes Early studies on HIV isolation from cervical swabs did not separate cells from cell-free fractions; the culture rate averaged 43% [140,147–150]. Due to heavy contamination of vaginal lavages with endogenous bacteria and fungus, HIV culture is now usually conducted with filtered cell-free fractions, yielding culture rates ranging from 11 to 22% [147,151,152]. Only one study to date has compared the HIV culture rate from cell-free vs. cell-associated fractions of cervicovaginal lavage samples: HIV was cultured from 12 of 55 (22%) cell-free supernatants and five of 22 (23%) cell lysates [147]. Although correlates of HIV culture from cervicovaginal cell pellets have not been studied, it is possible that HIV-infected leukocytes from reproductive aged women with normal vaginal flora are inactivated by lactic acid produced by lactobacilli and are, therefore, less infectious [118]. We predict that HIV-infected genital leukocytes from women with neutral vaginal pH due to conditions such as bacterial vaginosis and low estrogen states [153] are more infectious than those from reproductive aged women with vaginal pH in the 3.5–5.0 range and are more capable of cell-associated HIV transmission. Recently a sensitive short-term MAGI culture assay was used to improve the detection rate of infectious HIV in filtered female genital secretions. Although the overall culture rate was 51%, there was only a weak correlation between MAGI plaque (infectious virus) numbers and HIV RNA viral load. In addition, 10 out of 32 women with more than 10 000 HIV RNA copies/lavage had undetectable levels of infectious HIV in the MAGI plaque assay. The investigators speculated that the discrepancy may indicate inactivation of cell-free virus in genital secretions, possibly by neutralizing antibodies, low pH or innate immune mediators [152]. These data support the potential importance of cell-associated HIV transmission. HIV target cells in genital mucosae Following vaginal intercourse, HIV from an infectious partner enters an environment that contains a multitude of factors contributed from both male and female genital secretions. (The rectal environment is not as well studied but would be expected to contain many of the same components.) As discussed above, several factors in semen and cervicovaginal secretions (antimicrobial peptides, X4/R5 chemokines, anti-HIV antibodies) can inactivate cell-free HIV, but may not affect HIV-infected cells. Factors in this environment that have been determined to potentially affect cell-associated HIV transmission are mucins, large hydrophilic molecules that lubricate and protect genital mucosal epithelia, and endogenous vaginal lactobacilli that produce lactic acid to maintain a low pH [56]. In an in-vitro model system, lymphocytes and activated seminal leukocytes were able to traverse midcycle cervical mucus, although they failed to penetrate thicker substrates representing the viscosity of mucus present during the luteal phase of the menstrual cycle and pregnancy [154]. Macrophages and T cells were immobilized and eventually killed by low pH conditions commonly found in the human vagina [118]. However, after intercourse, the pH of cervicovaginal secretions is neutralized for several hours by the mild alkalinity of seminal plasma [155,156], providing seminal and cervicovaginal leukocytes a window of opportunity to reach the target genital epithelium. Furthermore, bacterial vaginosis and low-estrogen conditions underlying premenarchal, postpartum and postmenopausal states are also associated with elevated vaginal pH levels [153]. Thus, it appears probable that infected leukocytes in genital secretions can remain viable at least for several hours after intercourse in healthy reproductive aged women and longer in women with bacterial vaginosis and other conditions associated with elevated vaginal pH, and are capable of shuttling HIV through genital secretions to the epithelium. Stratified squamous epithelial surfaces, such as those covering vaginal, ectocervical, rectal, and foreskin tissues, are comprised of a thick multicellular epithelial layer, whereas columnar epithelia such as those covering endocervical, penile urethra, and anal mucosae consist of a polarized monolayer of epithelial cells. In either case, unless the epithelial layer is compromised, infectious organisms such as HIV must traverse or find target cells within the epithelial layer. Transmission electron microscopy studies have demonstrated that HIV-infected T cells and monocytes readily bind to mucosal epithelial cells, and that their attachment induces directional budding of HIV toward the epithelial surface where virions can accumulate within intersynaptic clefts and enter endosomal-like structures within epithelial cells (Fig. 2) [157,158]. Infectious virions may be sequestered by epithelial cells to await an opportunity to infect an appropriate target cell [159–161], which could be recruited to the site through release of chemokines or other proinflammatory signals by the infecting cell and/or affected epithelial cell [162], or virions may be transcytosed across columnar epithelial cells to infect cells in the lamina propria [163,164]. We and others have also shown that macrophages and T cells can infiltrate columnar and stratified epithelial layers (described in more detail below) and, therefore may, if infected with HIV, directly infect cells within or below the epithelium.Fig. 2: HIV-infected leukocyte interaction with epithelial cells: attachment and directional viral shedding. (a) Scanning electron micrograph showing HIV-infected lymphocytes adhering to the surface of an epithelial cell (magnification ×10 000). (b) Transmission electron micrograph of HIV-infected macrophage from semen releasing virus after contact with a genital tract epithelial cell (magnification ×15 000). Original photographs provided by David M. Phillips with permission from the Population Council, New York. Part (a) reproduced from [4].There is considerable regional, as well as interindividual and intraindividual variation in the density of the leukocyte cell populations that may serve as HIV target cells in genital mucosae [165,166]. There are usually few CD4+ T cells within the squamous epithelial layer, although they can be abundant under inflammatory conditions. However, macrophages and Langerhans cells are normally abundant within stratified squamous epithelia and can potentially be infected by HIV and/or transport virus to target cells in regional lymph nodes. The lamina propria that lies under the epithelial layer and dermal papillae that protrude into the stratified squamous epithelium, contain numerous HIV-susceptible host cells (CD4+ lymphocytes, macrophages, and dendritic cells). Transformation zones delineating the transition from stratified squamous to columnar epithelium (e.g., cervical os, rectal/anal junction, fossa navicularis at the opening of the penile urethra) contain an especially enriched population of HIV target cells [166]. HIV may also infect target cells in the uterine endometrium and fallopian tubes [167]. Concentrations of intraepithelial HIV target/host cells in the genital mucosa are substantially increased during infection/inflammation [166]. In addition, use of irritating compounds such as the spermicide Nonoxynol-9 (N-9) can damage the genital and rectal epithelium, resulting in inflammation and recruitment of lymphocytes, macrophages, PMNs, and other cells into the epithelial layer and secretions [168–171]. After intercourse, numbers of HIV-susceptible host cells are increased in cervicovaginal tissue and secretions, and potentially in rectal tissues and secretions, due to chemokines and other chemoattractants in semen and pro-inflammatory effects of semen on mucosal epithelial cells [172,173]. These conditions would be expected to enhance cell-associated HIV transmission. Evidence for cell-associated HIV transmission Clinical studies The sexual transmission of HIV is a rare event: estimates for the probability of HIV transmission per unprotected coital act range from 1 in 200–2000 for male-to-female transmission, 1 in 200–10 000 for female-to-male transmission, and 1 in 10–1600 for male-to-male transmission [174]. Studies on the genetic composition of HIV recovered from blood of individuals newly infected with HIV-1 indicate that in the majority of cases, regardless of the transmission route, a single R5 tropic, CD4-dependent virus from an infected partner is responsible for productive clinical infections [175–183]. This suggests that HIV is usually transmitted via a single HIV virion or infected cell. A different transmission pattern has been observed in studies of sex workers and STI patients, where multiple genetic variants can establish an infection in the recipient, probably due to compromise of the mucosal barrier and/or increased numbers of HIV target cells at the infection site [183–186]. HIV quasispecies in semen often differ genetically from those in peripheral blood [187–191], and at least two studies provide evidence that genetic sequences of cell-free HIV differ from those of cell-associated HIV in semen [189,192]. It, therefore, should be possible to determine whether the initial transmission event is mediated by a cell-free virion or an HIV-infected cell. Investigators set out to distinguish between these possibilities in acute seroconverters and found that the genotype of the infecting virus matched that of HIV in semen cells of the transmitter in three out of five cases (one heterosexual and two male homosexual couples) [189]. More studies of this kind are needed to determine the prevalence and risk factors of cell-associated HIV transmission. Other evidence that seminal leukocytes can cross the vaginal epithelium in humans is provided by a study that showed that unprotected heterosexual intercourse induces an allogeneic response in women that is specific for their sexual partner's human leukocyte antigen (HLA) [193]. This reaction was not observed in couples that always used condoms and is likely induced by exposure to seminal leukocytes because sperm do not express classical HLA antigens [194]. As the human vagina is a poor antigen induction site for systemic immune responses [195] and the allogeneic response was detected in peripheral blood, it is probable that the partners' leukocytes crossed the mucosal epithelium to stimulate an immune response in draining lymph nodes. A weak but significant alloimmune response was also observed in the male partners and could be attributed to exposure to partner's vaginal leukocytes. In this study, PBMCs from women with allogeneic immunity inhibited HIV-1 infection of activated T cells from their partners, providing evidence that allogeneic immunity could protect against cell-associated HIV transmission. Animal studies Feline immunodeficiency virus model The first animal model of cell-associated retroviral transmission across vaginal and rectal mucosal epithelia was the feline immunodeficiency virus (FIV) infection model. FIV, a lentivirus with characteristics similar to HIV, primarily infects T cells and causes an AIDS-like immunodeficiency disease in cats. FIV was one of the first animal models used to deduce mechanisms of HIV transmission and pathogenesis [196–198]. FIV can be transmitted via atraumatic instillation of infected T cells or cell-free virus onto vaginal or rectal mucosa [199,200], and this model was used to evaluate the efficacy of early topical microbicide candidates against vaginal and rectal transmission of cell-associated FIV [199,201]. The FIV model has also been used extensively for vaccine development; despite facing the numerous challenges of developing a vaccine to protect against a T-cell tropic retrovirus (genetic diversity, CD4+ T-cell depletion, immune-mediated enhancement of viral in

The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons.For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART.In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries.In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft-Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: -2.4 vs. -1.1 ml/min; P=0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P=0.02), and resolved after stopping pre-exposure prophylaxis (mean change: -0.1 vs. 0.0 ml/min; P=0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.

Objective: Although HAART can suppress genital shedding and sexual transmission of HIV, men who have sex with men (MSM) have experienced a resurgent HIV epidemic in the HAART era. Many HIV-infected MSM continue to engage in unsafe sex, and sexually transmitted infections (STIs) or other factors may promote genital HIV shedding and transmission in this population despite HAART. In this study, we determined the prevalence of seminal HIV shedding in HIV-infected MSM on stable HAART, and its relationship with a number of clinical, behavioral and biological variables. Design: Sexually active HIV-infected men using HAART were recruited from an MSM health clinic to provide semen and blood samples. Methods: HIV levels were assessed in paired semen and blood samples by PCR. Clinical and behavioral data were obtained from medical records and questionnaires. Herpes simplex virus 2 (HSV-2) serostatus, seminal HSV-2 DNA, and markers of genital inflammation were measured using standard laboratory methods. Results: Overall, HIV-1 was detected in 18 of 101 (18%) blood and 30 of 101 (30%) semen samples. Of 83 men with undetectable HIV in blood plasma, 25% had HIV in semen with copy numbers ranging from 80 to 2560. Multivariate analysis identified STI/urethritis (P = 0.003), tumor necrosis factor α (P = 0.0003), and unprotected insertive anal sex with an HIV-infected partner (P = 0.007) as independent predictors of seminal HIV detection. Conclusion: STIs and genital inflammation can partially override the suppressive effect of HAART on seminal HIV shedding in sexually active HIV-infected MSM. Low seminal HIV titers could potentially pose a transmission risk in MSM, who are highly susceptible to HIV infection.

Testing for HIV and other sexually transmitted diseases (STD) remains a cornerstone of public health prevention interventions. This analysis was designed to explore the frequency of testing, as well as health system and personal barriers to testing, among a community-recruited sample of Black men who have sex with men (MSM) at risk for HIV and STDs. Black MSM (n = 197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered assessment, with optional voluntary HIV counseling and testing. Logistic regression procedures examined factors associated with not having tested in the 2 years prior to study enrollment for: (1) HIV (among HIV-uninfected participants, n = 145) and (2) STDs (among the entire mixed serostatus sample, n = 197). The odds ratios and their 95% confidence intervals obtained from this analysis were converted to relative risks. (1) HIV: Overall, 33% of HIV-uninfected Black MSM had not been tested for HIV in the 2 years prior to study enrollment. Factors uniquely associated with not having a recent HIV test included: being less educated; engaging in serodiscordant unprotected sex; and never having been HIV tested at a community health clinic, STD clinic, or jail. (2) STDs: Sixty percent had not been tested for STDs in the 2 years prior to study enrollment, and 24% of the sample had never been tested for STDs. Factors uniquely associated with not having a recent STD test included: older age; having had a prior STD; and never having been tested at an emergency department or urgent care clinic. Overlapping factors associated with both not having had a recent HIV or STD test included: substance use during sex; feeling that using a condom during sex is "very difficult"; less frequent contact with other MSM; not visiting a health care provider (HCP) in the past 12 months; having a HCP not recommend HIV or STD testing at their last visit; not having a primary care provider (PCP); current PCP never recommending they get tested for HIV or STDs. In multivariable models adjusting for relevant demographic and behavioral factors, Black MSM who reported that a HCP recommended getting an HIV test (adjusted relative risk [ARR] = 0.26; p = 0.01) or STD test (ARR = 0.11; p = 0.0004) at their last visit in the past 12 months were significantly less likely to have not been tested for HIV or STDs in the past 2 years. Many sexually active Black MSM do not regularly test for HIV or STDs. HCPs play a pivotal role in encouraging testing for Black MSM. Additional provider training is warranted to educate HCPs about the specific health care needs of Black MSM, in order to facilitate access to timely, culturally competent HIV and STD testing and treatment services for this population.

Despite several decades of clinical trials assessing the impact of etiological treatment of sexually transmitted diseases (STDs) to decrease HIV acquisition and transmission, almost all of these trials have not proven to be efficacious. Increasing evidence suggests that specific STD treatment alone may not be sufficient to alter the genital tract inflammatory milieu that is created by STDs. This paper examines the associations between STDs and HIV susceptibility and infectiousness, and considers the role of chronic and refractory inflammation to create an environment that potentiates HIV and STD transmission and acquisition by reviewing biological, observational, and clinical trial data.

Background Depression is highly prevalent in people with HIV and has consistently been associated with poor antiretroviral therapy (ART) adherence. Integrating cognitive behavioural therapy (CBT) for depression with adherence counselling using the Life-Steps approach (CBT-AD) has an emerging evidence base. The aim of this study was to test the efficacy of CBT-AD. Methods In this three-arm randomised controlled trial in HIV-positive adults with depression, we compared CBT-AD with information and supportive psychotherapy plus adherence counselling using the Life-Steps approach (ISP-AD), and with enhanced treatment as usual (ETAU) including Life-Steps adherence counselling only. Participants were recruited from three sites in New England, USA (two hospital settings and one community health centre). Patients were randomly assigned (2:2:1) to receive CBT-AD (one Life-Steps session plus 11 weekly integrated sessions lasting up to 1 h each), ISP-AD (one Life-Steps session plus 11 weekly integrated sessions lasting up to 1 h each), or ETAU (one Life-Steps session and five assessment visits roughly every 2 weeks), randomisation was done with allocation software, in pairs, and stratified by three variables: study site, whether or not participants had been prescribed antidepressant medication, and whether or not participants had a history of injection drug use. The primary outcome was ART adherence at the end of treatment (4 month assessment) assessed via electronic pill caps (Medication Event Monitoring System [MEMS]) with correction for pocketed doses, analysed by intention to treat. Findings Patients were recruited from Feb 26, 2009, to June 21, 2012. Patients who were assigned to CBT-AD (94 randomly assigned, 83 completed assessment) had greater improvements in adherence (estimated difference 1·00 percentage point per visit, 95% CI 0·34 to 1·66, p=0·003) and depression (Center for Epidemiological Studies depression [CESD] score estimated difference −0·41, −0·66 to −0·16, p=0·001; Montgomery-Asberg depression rating scale [MADRS] score −4·69, −8·09 to −1·28, p=0·007; clinical global impression [CGI] score −0·66, −1·11 to −0·21, p=0·005) than did patients who had ETAU (49 assigned, 46 completed assessment) after treatment (4 months). No significant differences in adherence were noted between CBT-AD and ISP-AD (97 assigned, 87 completed assessment). No study-related adverse events were reported. Interpretation Integrating evidenced-based treatment for depression with evidenced-based adherence counselling is helpful for individuals living with HIV/AIDS and depression. Future efforts should examine how to best disseminate effective psychosocial depression treatments such as CBT-AD to people living with HIV/AIDS and examine the cost-effectiveness of such approaches. Funding National Institute of Mental Health, National Institute of Allergy and Infectious Diseases.

<h3>Importance</h3> Transgender youth, including adolescent and young adult transgender women assigned a male sex at birth who identify as girls, women, transgender women, transfemale, male-to-female, or another diverse transfeminine gender identity, represent a vulnerable population at risk for negative mental health and substance use outcomes. Diagnostic clinical interviews to assess prevalence of mental health, substance dependence, and comorbid psychiatric disorders in young transgender women remain scarce. <h3>Objective</h3> To report the prevalence of mental health, substance dependence, and comorbid psychiatric disorders assessed via clinical diagnostic interview in a high-risk community-recruited sample of young transgender women. <h3>Design, Setting, and Participants</h3> Observational study reporting baseline finding from a diverse sample of 298 sexually active, young transgender women aged 16 through 29 years (mean age, 23.4 years; 49.0% black, 12.4% Latina, 25.5% white, and 13.1% other minority race/ethnicity) and enrolled in Project LifeSkills, an ongoing randomized controlled HIV prevention intervention efficacy trial in Chicago and Boston, between 2012 and 2015. <h3>Exposure</h3> Transfeminine gender identity. <h3>Main Outcomes and Measures</h3> Age- and site-adjusted prevalence and comorbidities of mental health and substance dependence disorders assessed via the Mini-International Neuropsychiatric Interview, including 1 or more diagnoses, 2 or more comorbid diagnoses, major depressive episode (current and lifetime), past 30-day suicidal risk (no/low risk vs moderate/high risk), past 6-month generalized anxiety disorder and posttraumatic stress disorder, and past 12-month alcohol dependence and nonalcohol psychoactive substance use dependence. <h3>Results</h3> Of the 298 transgender women, 41.5% of participants had 1 or more mental health or substance dependence diagnoses; 1 in 5 (20.1%) had 2 or more comorbid psychiatric diagnoses. Prevalence of specific disorders was as follows: lifetime and current major depressive episode, 35.4% and 14.7%, respectively; suicidality, 20.2%; generalized anxiety disorder, 7.9%; posttraumatic stress disorder, 9.8%; alcohol dependence, 11.2%; and nonalcohol psychoactive substance use dependence, 15.2%. <h3>Conclusions and Relevance</h3> Prevalence of psychiatric diagnoses was high in this community-recruited sample of young transgender women. Improving access to routine primary care, diagnostic screening, psychotherapy, and pharmacologic treatments, and retention in care in clinical community-based, pediatric, and adolescent medicine settings are urgently needed to address mental health and substance dependence disorders in this population. Further research will be critical, particularly longitudinal studies across development, to understand risk factors and identify optimal timing and targets for psychosocial interventions.

Purpose of review To review the most recent studies assessing the preparedness of healthcare practitioners to provide anti-HIV preexposure prophylaxis (PrEP) and suggest areas for future implementation research. Recent findings As PrEP is a biobehavioral intervention, healthcare providers are likely to play a critical role in implementing PrEP in care settings. Studies suggest that many specialized providers are aware of PrEP and support its provision as a public health intervention, though knowledge and acceptance are less among generalists. Therefore, utilization of PrEP by clinicians has been limited to a few early adopters. Concerns about the efficacy and long-term safety of PrEP, and perceived barriers to prescribing PrEP, could limit prescribing behaviors and intentions. Resistance to performing routine HIV risk assessments by clinicians is an additional barrier to implementing PrEP, although innovative tools to help clinicians routinely perform risk assessments, are being developed. Summary Interventions are needed to engage a broader array of healthcare providers in PrEP provision. Utilizing a framework based on diffusion of innovation theory, this review proposes strategies that can be implemented and evaluated to increase PrEP prescribing by healthcare providers. If resources are invested in training clinicians to provide PrEP, then these stakeholders could enhance the use of PrEP as part of a prevention package by primary providers.

<h3>Importance</h3> Emerging data warrant the integration of biomedical and behavioral recommendations for human immunodeficiency virus (HIV) prevention in clinical care settings. <h3>Objective</h3> To provide current recommendations for the prevention of HIV infection in adults and adolescents for integration in clinical care settings. <h3>Data Sources, Study Selection, and Data Synthesis</h3> Data published or presented as abstracts at scientific conferences (past 17 years) were systematically searched and reviewed by the International Antiviral (formerly AIDS) Society—USA HIV Prevention Recommendations Panel. Panel members supplied additional relevant publications, reviewed available data, and formed recommendations by full-panel consensus. <h3>Results</h3> Testing for HIV is recommended at least once for all adults and adolescents, with repeated testing for those at increased risk of acquiring HIV. Clinicians should be alert to the possibility of acute HIV infection and promptly pursue diagnostic testing if suspected. At diagnosis of HIV, all individuals should be linked to care for timely initiation of antiretroviral therapy (ART). Support for adherence and retention in care, individualized risk assessment and counseling, assistance with partner notification, and periodic screening for common sexually transmitted infections (STIs) is recommended for HIV-infected individuals as part of care. In HIV-uninfected patients, those persons at high risk of HIV infection should be prioritized for delivery of interventions such as preexposure prophylaxis and individualized counseling on risk reduction. Daily emtricitabine/tenofovir disoproxil fumarate is recommended as preexposure prophylaxis for persons at high risk for HIV based on background incidence or recent diagnosis of incident STIs, use of injection drugs or shared needles, or recent use of nonoccupational postexposure prophylaxis; ongoing use of preexposure prophylaxis should be guided by regular risk assessment. For persons who inject drugs, harm reduction services should be provided (needle and syringe exchange programs, supervised injection, and available medically assisted therapies, including opioid agonists and antagonists); low-threshold detoxification and drug cessation programs should be made available. Postexposure prophylaxis is recommended for all persons who have sustained a mucosal or parenteral exposure to HIV from a known infected source and should be initiated as soon as possible. <h3>Conclusions and Relevance</h3> Data support the integration of biomedical and behavioral approaches for prevention of HIV infection in clinical care settings. A concerted effort to implement combination strategies for HIV prevention is needed to realize the goal of an AIDS-free generation.

Background We investigated the impact of antimicrobials in cervicovaginal lavage (CVL) from HIV(+) and HIV(−) women on target cell infection with HIV. Since female reproductive tract (FRT) secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+) and (−) women inhibit HIV infection. Methodology/Principal Findings CVL from 32 HIV(+) healthy women with high CD4 counts and 15 healthy HIV(−) women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti-HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and anti-gp160 HIV IgG antibodies were measured by ELISA. When CXCR4 and CCR5 tropic HIV-1 were incubated with CVL from HIV(+) women prior to addition to TZM-bl cells, anti-HIV activity in CVL ranged from none to 100% inhibition depending on the viral strains used. CVL from HIV(−) controls showed comparable anti-HIV activity. Analysis of CH077.c (clone of an R5-tropic, mucosally-transmitted founder virus) viral inhibition by CVL was comparable to laboratory strains. Measurement of CVL for antimicrobials HBD2, trappin-2/elafin, SLPI and MIP3α indicated that each was present in CVL from HIV(+) and HIV(−) women. HBD2 and MIP3α correlated with anti-HIV activity as did anti-gp160 HIV IgG antibodies in CVL from HIV(+) women. Conclusions/Significance These findings indicate that CVL from healthy HIV(+) and HIV(−) women contain innate and adaptive defense mechanisms that inhibit HIV infection. Our data suggest that innate endogenous antimicrobials and HIV-specific IgG in the FRT can act in concert to contribute toward the anti-HIV activity of the CVL and may play a role in inhibition of HIV transmission to women.

Purpose of review People who inject drugs (PWID), sex workers, and MSM simultaneously bear a high burden of HIV and stigma and discrimination. The purpose of this review was to summarize recent information about the understanding of the HIV care cascade among PWID, sex workers, and MSM populations around the globe. Recent findings A review of the published literature relating to the care cascade in these three key populations was conducted. Data on the care cascade among key populations are sparse, particularly for PWID and sex workers. In the 12 countries in which a study or report of the care cascade was available stratified by these populations, all three populations have care cascade outcomes that are far below the 90–90–90 target set by the Joint United Nations Programme on HIV/AIDS (UNAIDS) for 2020. Culturally tailored interventions, including colocation of services and peer navigators, can improve care cascade outcomes among key populations. Summary Key populations’ care cascade outcomes must be included in international reporting metrics to expand cascade data for these groups. Improving care cascade outcomes in these key populations through culturally tailored interventions should be a priority in the coming years.