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Showing papers by "Myron S. Cohen published in 2012"


Journal ArticleDOI
TL;DR: A randomized, clinical trial demonstrated that antiretroviral therapy reduces the sexual transmission of HIV in HIV-serodiscordant couples by more than 96% and proved central to the development of new global HIV-prevention efforts.
Abstract: Purpose of reviewThis review summarizes the development and implementation of a large clinical trial, HIV Prevention Trials Network (HPTN) 052, whose initial results were recently presented and published.Recent findingsA randomized, clinical trial demonstrated that antiretroviral therapy reduces the

261 citations


Journal ArticleDOI
TL;DR: In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, it is found that early ART reduced the generation of latently infected cells, reinforcing and extending the concept that new approaches will be needed to eradicate HIV infection.
Abstract: HIV type 1 (HIV-1) persists within resting CD4+ T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10−4) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4+ T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4+ T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4+ T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.

210 citations


Journal ArticleDOI
TL;DR: It is explained how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV- 1 escape should be considered in the context of immunodominance.
Abstract: HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.

194 citations


Journal ArticleDOI
TL;DR: Improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
Abstract: Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.

138 citations


Journal ArticleDOI
TL;DR: Combo RT displayed excellent performance for detecting established HIV infection and poor performance forDetecting acute HIV infection in this setting, suggesting that it is no more useful than current algorithms.
Abstract: Point-of-care rapid tests for human immunodeficiency virus (HIV) antibody (Ab) detection have facilitated the scale-up of HIV counseling and testing throughout sub-Saharan Africa [1, 2]. The sensitivity of these tests approaches 100% for antibody detection [3, 4]. However, the tests cannot identify persons with acute HIV infection who have not yet developed HIV-specific antibodies [5–7]. Persons with acute HIV infection are often hyperinfectious because of high viral loads [8–12]. Integrating acute HIV infection detection into HIV testing algorithms would enable acutely infected persons to learn their true HIV status, rather than being informed that they were HIV seronegative. Identifying these persons with acute HIV infection could enable intervention to prevent transmission and early treatment, potentially preserving immune function [13, 14]. Identification of acute HIV infection requires detection of HIV nucleic acids or p24 antigens. Available assays are laboratory based, resource intensive, and require follow-up. HIV RNA polymerase chain reaction (PCR), used for either individual or pooled samples, is the reference standard for detecting antibody-negative acute HIV infection, but it is expensive and difficult to implement in resource-poor settings. HIV p24 antigen (Ag) enzyme-linked immunosorbent assays (ELISAs) have good performance characteristics compared with HIV RNA PCR analysis, but they have been challenging to implement on a wide scale. Fourth-generation HIV ELISAs detect both antibodies and antigens [6, 15, 16] but do not distinguish between the two and require venipuncture, a laboratory, and patient follow-up, limiting routine use in most settings. A rapid point-of-care test capable of distinguishing established from acute HIV infection could improve the sensitivity of existing algorithms and enable provision of acute HIV infection results in real time [17]. The Determine® HIV-1/2 Ag/Ab Combo (Combo RT) is a point-of-care rapid test with separate indicators for HIV antibodies and p24 antigen. The Combo RT was designed to identify HIV earlier than other conventional rapid tests. The antibody portion is reported to be analogous to the Determine® HIV-1/2 antibody test, a widely used rapid test for HIV identification. The antigen component of the test is intended to expand the diagnostic spectrum to identify persons with circulating free p24 antigen, unbound to antibodies. During development, Combo RT antigen was assessed using stored serum from commercial seroconversion panels [18]. For primary HIV samples in the pre- or periseroconversion period, the reported sensitivity of the antigen portion of the Combo RT was 92.2%, compared with a fourth-generation HIV ELISA as the reference standard. Specificity of the antigen portion of the test was reported at 96.6%. The Combo RT is currently commercially available outside the United States. We conducted a field evaluation in Lilongwe, Malawi, to assess the accuracy of the antigen portion of Combo RT to detect persons with acute HIV infection. The Roche Monitor HIV RNA PCR assay was used to identify persons with acute HIV infection after routine HIV rapid test evaluation for established HIV infection. We also performed an “ultrasensitive” heat-dissociated p24 antigen ELISA. Finally, in a subset of the study population, we assessed the antibody portion of Combo RT against a standard rapid test antibody algorithm.

130 citations


Journal ArticleDOI
TL;DR: Findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing with positive results are reported.
Abstract: Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. Trial Registration www.ClinicalTrials.gov NCT00084136 Please see later in the article for the Editors' Summary.

122 citations


Journal ArticleDOI
TL;DR: Two opposing viewpoints are presented on universal HIV testing and immediate antiretroviral therapy for infected individuals by Powers, Miller, and Cohen, and Williams and Dye.
Abstract: Universal HIV testing and immediate antiretroviral therapy for infected individuals has been proposed as a way of reducing the transmission of HIV and thereby bringing the HIV epidemic under control. It is unclear whether transmission during early HIV infection—before individuals are likely to have been diagnosed with HIV and started on antiretroviral therapy—will compromise the effectiveness of treatment as prevention. This article presents two opposing viewpoints by Powers, Miller, and Cohen, and Williams and Dye, followed by a commentary by Fraser.

108 citations


Journal ArticleDOI
24 Aug 2012-AIDS
TL;DR: The best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.
Abstract: Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.

101 citations


Journal ArticleDOI
TL;DR: The protection from HIV observed with the TDF and FTC combination in TDF25 and PIP6 suggests an important role for higher FTC concentrations, perhaps in combination with the lower concentrations of tenofovir, in the female genital tract.

79 citations


Journal ArticleDOI
28 Nov 2012-AIDS
TL;DR: The benefits of treatment as prevention for MSM are highly plausible, but not certain, and treatment guidelines for earlier ART initiation should be considered within a combination prevention strategy that includes earlier diagnosis, expanded STI treatment, and structural and behavioral interventions.
Abstract: Objective To review the evidence for antiretroviral 'treatment as prevention' for HIV transmission among MSM. Methods We reviewed studies that assess the biological plausibility that virally suppressive antiretroviral therapy (ART) reduces HIV infectiousness via anal intercourse and the epidemiologic evidence of whether ART has played a role in attenuating HIV incidence among MSM. Results Although ART treatment among MSM is likely to provide some preventive benefit, it is unknown whether it will reduce HIV infectiousness via anal intercourse to the same extent as via penile-vaginal intercourse. Additional research is needed on the pharmacokinetic properties of specific antiretroviral agents in the gastrointestinal tract. Estimates of risk behaviors and the incidence of HIV among MSM before and after the introduction and expansion of ART suggest that the population-level protective benefits of ART may be attenuated by a number of factors, most notably, continuing or increasing frequency of condomless anal intercourse and incidence of other sexually transmitted infections (STIs). Additional studies are needed on the impact of ART on HIV sexual risk behaviors and transmission among MSM outside of developed countries in North America, western Europe, and Australia. Conclusion The benefits of treatment as prevention for MSM are highly plausible, but not certain. In the face of these unknowns, treatment guidelines for earlier ART initiation should be considered within a combination prevention strategy that includes earlier diagnosis, expanded STI treatment, and structural and behavioral interventions.

67 citations


Journal ArticleDOI
TL;DR: The rate of HIV acquisition in young, healthy adults (mostly women) was 3 to 5 per 100 person-years in two trials studying heterosexual transmission of HIV in sub-Saharan Africa, now reported in the Journal.
Abstract: Transmission of the human immunodeficiency virus (HIV) continues at a staggering rate in many areas of the world. The rate of HIV acquisition in young, healthy adults (mostly women) was 3 to 5 per 100 person-years in two trials studying heterosexual transmission of HIV in sub-Saharan Africa, now reported in the Journal (the Preexposure Prophylaxis Trial for HIV Prevention among African Women [FEM-PrEP]1 and the TDF2 study2). This rate of HIV transmission demands the urgent development of new prevention strategies as well as the deployment of all existing strategies, including the use of condoms, male circumcision, and the treatment . . .

Journal ArticleDOI
TL;DR: The construct of the exposure and outcome measures and analysis methods used in ecological studies, and the strengths and weaknesses of ecological analyses, are reviewed to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.
Abstract: Results from several observational studies of HIV-discordant couples and a randomized controlled trial (HIV Prevention Trials Network 052) show that antiretroviral therapy (ART) can greatly reduce heterosexual HIV transmission in stable HIV-discordant couples. However, such data do not prove that ART will reduce HIV incidence at the population level. Observational investigations using ecological measures have been used to support the implementation of HIV treatment for the specific purpose of preventing transmission at the population level. Many of these studies note ecological associations between measures of increased ART uptake and decreased HIV transmission. Given the urgency of implementing HIV prevention measures, ecological studies must de facto be used to inform current strategies. However, the hypothesis that widespread ART can eliminate HIV infection may have raised expectations beyond what we may be able to achieve. Here we review and discuss the construct of the exposure and outcome measures and analysis methods used in ecological studies. By examining the strengths and weaknesses of ecological analyses, we aim to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.

Journal ArticleDOI
TL;DR: Insight is provided into the mechanisms of CD8-mediated virus inhibition and functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.
Abstract: CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8(+) T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8(+) responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8(+) T cells during AHI. Autologous and heterologous CD8(+) T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8(+) T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8(+) antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8(+)-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8(+) T cell-mediated inhibition of virus replication. CD8(+) T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.

Journal ArticleDOI
TL;DR: HIV prevalence in this sexual network of young Black MSM rivals that of sub-Saharan Africa, reflecting dramatically increased risk of acquiring HIV from the moment one entered the network.
Abstract: BACKGROUND HIV infections increased 48% among young Black men who have sex with men (MSM) in the United States between 2006 and 2009. Incomplete understanding of this trend undermines prevention strategy development. We investigated a sexual network to characterize the risk environment in which young Black MSM acquire HIV. METHODS Persons reported to the state after diagnosis of HIV or syphilis were included, along with sexual partners. We used network mapping alongside descriptive and bivariate statistics to characterize network connections. Generalized linear models assessed predictors of having untraceable sex partners. RESULTS The network included 398 individuals and 419 sexual relationships. Three-quarters were Black (n = 299); 92% were MSM. Median age at first network appearance was 26 years and decreased over time (P < 0.001). HIV prevalence was at least 29% (n = 117); serostatus was unknown for 47% of the network, either because they were untraceable (n = 150) or refused HIV testing (n = 39). One in 5 network members diagnosed with HIV had a subsequent incident sexually transmitted infection. In multivariable models, one-time encounters increased the risk of having an untraceable partner (risk ratio = 4.51, 95% CI: 2.27 to 8.97), whereas being acutely HIV infected at diagnosis reduced it (risk ratio = 0.27, 95% CI: 0.08 to 0.89). CONCLUSIONS HIV prevalence in this sexual network of young Black MSM rivals that of sub-Saharan Africa, reflecting dramatically increased risk of acquiring HIV from the moment one entered the network. Prevention efforts for this population must consider the effect of sexual networks on HIV risk and find ways of leveraging network structure to reduce transmission.

Journal ArticleDOI
TL;DR: The results offered a stark reality for HIV-1 prevention and demonstrate yet again that STDs represent a “hidden epidemic,” the title of a compelling Institute of Medicine report published more than a decade ago.
Abstract: The transmission of human immunodeficiency virus type 1 (HIV-1) depends on the infectiousness of the index case (ie, vector) and the susceptibility of the host [1]. The probability of the transmission event has been extensively studied [1–3], and the risk is often described as about 1 in 1000 coital events [4]. However, large numbers of exposures like these are often derived from studies of stable, heterosexual, discordant couples [4, 5]. By definition, the HIV-1–negative partners in these couples can be defined as “exposed and uninfected” at the time of enrollment. The transmission of HIV-1 is almost certainly often more efficient than reflected in studies of couples and is likely enhanced by amplifying factors [6]. Perhaps no other HIV transmission cofactor has attracted as much attention as sexually transmitted diseases (STDs). More than 20 years ago, Wasserheit and colleagues described the transparent and omnipresent relationship between classical STDs and HIV-1, coining this unfortunate marriage of pathogens “epidemiologic synergy” [7].We subsequently showed that infection with Neisseria gonorrhoeae greatly increased shedding of HIV-1from the male genital tract in seminal plasma, offering a biological view of such synergy [8]. In recent years, however, interest in the relationship between STDs and HIV-1 has waned, primarily because it has proven nearly impossible to reduce the spread of HIV-1 through directed or empirical treatment of STDs [9]. In this issue of The Journal of Infectious Diseases, Mlisana et al [10] contribute to this consideration. Because of the limited laboratory infrastructure in lowand middle-income countries, treatment of STDs in women often depends on the recognition of signs and symptoms of vaginal discharge, leading to empirical treatment with antibiotics [11, 12]. Syndromic management is important but often suboptimal since a substantial number of people using this method are overor undertreated [11, 12]. Mlisana and colleagues [10] have further expanded our concerns about syndromic management. Two-hundred forty-two women at risk for HIV-1 infection were enrolled in a prospective cohort. Four things were measured: the presence or absence of a vaginal discharge, detection of ≥1 STD pathogens, vaginal cytokine concentrations, and HIV-1 acquisition. The results offered a stark reality for HIV-1 prevention and demonstrate yet again that STDs represent a “hidden epidemic,” the title of a compelling Institute of Medicine report published more than a decade ago [13]. Only 12.3% of women infected with a pathogen that might cause a vaginal discharge had signs or symptoms of infection. Women with STDs were >3-fold more likely to acquire HIV-1 than those who harbored no pathogens. Women with gonococcal infections, among the most inflammatory of the classical STD agents [14], had had an eye-opening 7fold increased risk of HIV-1 acquisition, bringing us full circle to earlier reports [8]. Surprisingly, inflammatory cytokines were not significantly different in women with symptomatic STDs, compared with asymptomatic infections, although they were greater than in women with no STDs or with bacterial vaginosis. Passmore et al [15] have reported that some unique inflammatory cytokine profiles predict risk for HIV acquisition. How can we fit these observations into sensible HIV-1 prevention strategies? Padian et al [9] have provided an exhaustive summary of interventions designed to prevent HIV-1 transmission, emphasizing the general lack of prevention benefit with treatment of classical STDs. The failure of this approach, in my opinion, is not because STDs are not critically important. Rather, we are simply unable to treat the right infections with the right drugs at the right times, and so the results of the interventions prove disappointing. Sadly, except for hepatitis B virus vaccine and HPV vaccine, STD vaccines are not available. Received 10 February 2012; accepted 13 February 2012; electronically published 19 April 2012. Correspondence: Myron S. Cohen, MD, 130 Mason Farm Rd, CB 7030, University of North Carolina, Chapel Hill, NC 27599-7030 (mscohen@med.unc.edu). The Journal of Infectious Diseases 2012;206:1–2 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/infdis/jis303

Journal ArticleDOI
TL;DR: Two independent advisory committees of the President's Emergency Plan for AIDS Relief and the World Health Organization have since issued analyses that set the stage for broader use of antiretroviral agents in treatment and prevention.
Abstract: In 2011 interim results of HIV Prevention Trials Network study 052, a National Institutes of Health study designed to test the effectiveness of antiretroviral treatment against the spread of HIV, were reported. These results showed that in a stable relationship in which one member of the couple was infected with HIV, treatment of the infected partner with antiretroviral drugs, combined with couples counseling and condom use, resulted in a 96 percent reduction in sexual transmission of HIV-1. This finding led to the use of antiretroviral treatment as a cornerstone of HIV prevention. Independent advisory committees of the President’s Emergency Plan for AIDS Relief (PEPFAR) and the World Health Organization (WHO) have since issued analyses that set the stage for broader use of antiretroviral agents in treatment and prevention. This article describes the separate PEPFAR and WHO recommendations and outlines the design of prospective new trials to test how best to maximize the benefits of early treatment for pr...

Journal ArticleDOI
TL;DR: Understanding the ethical challenges faced in HPTN 052 promises to inform the design and conduct of future complex, long-term clinical trials aimed at addressing critical scientific and public health questions, where data and practice patterns emerge over the course of the trial.
Abstract: Background Obtaining the definitive data necessary to determine the safety and efficacy of using antiretroviral treatment (ART) to reduce the sexual transmission of HIV in heterosexual couples encountered an array of ethical challenges that threatened to compromise HIV Prevention Trials Network (HPTN) 052, the multinational clinical trial addressing this issue that has profound public health implications.Purpose To describe and analyze the major ethical challenges faced in HPTN 052.Methods The ethical issues and modifications of HPTN 052 in response to these issues were cataloged by the principal investigator, the lead coordinator, and the ethicist working on the trial. The major ethical issues that were unique to the trial were then described and analyzed in light of the published literature as well as guidances and policies. The ethical challenges that must be addressed in many clinical trials, such as those related to obtaining informed consent and making provisions for ancillary care, are not describe...

Journal ArticleDOI
27 Jun 2012-PLOS ONE
TL;DR: The proportion of patients remaining in HIV care increased in more recent calendar years and among patients who initiated modern cART regimens and those with higher CD4 cell counts at therapy initiation.
Abstract: Background: Mortality and morbidity from HIV have dramatically decreased in both high- and low-income countries. However some patients may not benefit from combination antiretroviral therapy (cART) because of inadequate access to HIV care including attrition after care initiation. Methodology/Principal Findings: The study population included all HIV-infected patients receiving cART through the Chinese National Free Antiretroviral Treatment Program from 1 January 2003 to 31 December 2010 (n = 106542). We evaluated retention in HIV care and used multivariable Cox proportional hazard models to identify independent factors predictive of attrition. The cumulative probability of attrition from cART initiation was 9% at 12 months 13% at 18 months 16% at 24 months and 24% at 60 months. A number of factors were associated with attrition including younger age male gender and being single or divorced. Patients with higher CD4 cell counts at cART initiation were more likely to drop out of HIV care. The proportion of patients remaining in HIV care increased in more recent calendar years and among patients who initiated modern cART regimens. Conclusions/Significance: Retention in HIV care is essential for optimizing individual and public health outcomes. Attrition even the degree observed in our study can lead to premature morbidity and mortality and possibly affect further transmission of HIV and HIV resistant drug variants. Effective strategies to promote retention in HIV care programs are needed. In China these strategies may include focusing particularly on younger male patients and those with higher CD4 cell counts at therapy initiation.

Journal ArticleDOI
TL;DR: PN programmes are feasible in China, particularly among men who have sex with men and other high-risk groups, and further research on STI PN, is an important public health priority.
Abstract: Objective China9s sexually transmitted infection (STI) epidemic requires comprehensive control programmes. Partner services are traditional pillars of STI control but have not been widely implemented in China. This study was a systematic literature review to examine STI partner notification (PN) uptake in China. Methods Four English and four Chinese language databases were searched up to March 2011 to identify articles on PN of STIs including HIV in China. PN uptake was defined as the number of partners named, notified, evaluated or diagnosed per index patient. Results A total of 11 studies met inclusion criteria. For STI (excluding HIV) PN, a median 31.6% (IQR 27.4%–65.8%) of named partners were notified, 88.8% (IQR 88.4%–90.8%) of notified partners were evaluated and 37.9% (IQR 33.1%–43.6%) of evaluated partners were diagnosed. For HIV PN, a median 15.7% (IQR 13.2%–36.5%) of named partners were notified, 86.7% (IQR 72.9%–90.4%) of notified partners were evaluated and 27.6% (IQR 24.1%–27.7%) of evaluated partners were diagnosed. A mean of 80.6% (SD=12.6%) of patients attempted PN, and 72.4% (IQR 63.8%–81.1%) chose self-referral when offered more than one method of PN. Perceived patient barriers included social stigma, fear of relationship breakdown, uncertainty of how to notify and lack of partner contact information. Perceived infrastructure barriers included limited time and trained staff, mistrust of health workers and lack of PN guidelines. Conclusion PN programmes are feasible in China. Further research on STI PN, particularly among men who have sex with men and other high-risk groups, is an important public health priority. PN policies and guidelines are urgently needed in China.

Journal ArticleDOI
TL;DR: A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.
Abstract: Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6-24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.

Journal ArticleDOI
TL;DR: This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF and will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre-exposure prophylaxis in women.
Abstract: Background and Objectives A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures.

Journal ArticleDOI
TL;DR: The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention and high RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa.
Abstract: BACKGROUND Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions. METHODS A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One rectal tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.

Journal ArticleDOI
TL;DR: Several key statistical considerations are described for the design of this landmark study and an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions.

Journal ArticleDOI
TL;DR: Investigation of the frequency of offering HIV testing among STI care providers in South China and reported physician barriers to HIV testing found substantial variability across providers, which may help scale up HIV provider-initiated testing and counseling programs.
Abstract: Despite expanding sexually transmitted epidemics in South China, the majority of patients presenting to sexually transmitted infection (STI) clinics are not routinely screened for HIV infection. Identifying barriers to offering HIV testing among STI care providers is an important public health priority. The aim of this study was to investigate the frequency of offering HIV testing among STI care providers in South China and reported physician barriers to offering HIV testing. More detailed operational data regarding HIV test offer frequency and barriers to testing may enhance routine HIV testing at STI clinics. A sample of 62 STI care providers within the Pearl River Delta Region of South China completed a survey including socio-demographic and training background information (including sex, age, medical education, year of terminal medical degree, and HIV-specific training), reasons for not offering HIV testing routinely, and physical examination and sexual history taking practices. Frequency of offering HIV testing was calculated based on reports from research assistants and operational data. STI care providers offered HIV testing to 3011/10,592 (28.4%) of their patients. There was substantial variability across providers in the frequency of offering testing, ranging from 3 to 100%. None of the identified physician factors were associated with offering HIV testing 100% of the time in the multivariate model. The most commonly physician reported barriers to HIV testing included: (1) low perceived prevalence of disease and (2) not recommended by current guidelines. Forty-seven providers (76%) reported asking about same sex behaviors rarely or never. Further research on HIV screening practices of STI care providers may help scale up HIV provider-initiated testing and counseling programs.

Journal ArticleDOI
TL;DR: Incomplete prior HIV screening among STD patients in China suggests the need for broadening HIV testing opportunities at STD clinics and similar clinical settings attended by those with increased sexual risk.
Abstract: BACKGROUND: Expanding HIV testing is important among individuals at increased risk for sexual HIV transmission in China but little is known about prior HIV testing experiences among sexually transmitted disease (STD) patients METHODS: This cross-sectional study of 1792 outpatients from 6 public STD clinics in Guangdong Province recorded detailed information about ever having been tested for HIV infection in addition to sociodemographic variables health seeking clinical STD history and HIV stigma using a validated survey instrument RESULTS: A total of 456 (254%) of the STD patients in this sample had ever been tested for HIV infection STD patients who were male had higher income more education were at City A and City C received STD services at public facilities had used intravenous drugs and had a history of an STD were more likely to ever receive an HIV test in multivariate analysis Low perceived HIV risk was the most common reason for not receiving an HIV test Only 77% of the sample reported fear of discrimination or loss of face as influencing their lack of HIV testing CONCLUSION: Incomplete prior HIV screening among STD patients in China suggests the need for broadening HIV testing opportunities at STD clinics and similar clinical settings attended by those with increased sexual risk

Journal ArticleDOI
TL;DR: A test designed to concomitantly detect HIV antibodies and p24 antigen in separate reading frames at the point of care was evaluated among persons attending a sexually transmitted infection clinic and an HIV testing and counseling center in Lilongwe, Malawi, and found that the antibody portion of the test had excellent sensitivity and specificity for detecting established HIV infection.
Abstract: To the Editor—We appreciate the correspondence in this issue of the Journal by Jones et al and Laperche et al evaluating the performance of the Alere Determine HIV-1/2 Ag/Ab Combo test (Combo point-of-care test [POCT]) for the detection of antibodies for established human immunodeficiency virus (HIV) infection and p24 antigen for acute HIV infection (AHI) [1, 2]. We believe that the earliest stages of HIV infection, including AHI, are critical for both individual health and HIV prevention. During AHI, establishment of latency currently renders HIV infection incurable. Persons with AHI also have high viral loads, making them highly contagious for a brief period. AHI therefore represents an important time for intervention [3]. Identification of subjects with AHI is critical, yet challenging. Since persons are antibody-negative during AHI, HIV rapid tests, which detect HIV antibodies, cannot detect AHI. AHI can be detected only with diagnostics capable of identifying HIV RNA, DNA or p24 antigen. To date, most of these diagnostics have been laboratory-based. In a recent issue of the Journal, we evaluated the Combo POCT, a test designed to concomitantly detect HIV antibodies and p24 antigen in separate reading frames at the point of care [4]. Our study was conducted among persons attending a sexually transmitted infection clinic and an HIV testing and counseling center in Lilongwe, Malawi. We found that the antibody portion of the test had excellent sensitivity and specificity for detecting established HIV infection. However, the antigen portion of the test had zero sensitivity and inadequate specificity for detecting AHI. The antigen portion of the test was unable to identify any of the 8 persons with true AHI, and it falsely classified 6 HIV-uninfected persons as having AHI. Such incorrect results could cause considerable mental anguish, confusion, and cost. Jones et al report similar findings among high-risk persons in the United Kingdom [1]. The antibody portion of the Combo POCT had excellent sensitivity and specificity, but the antigen portion of the test had poor sensitivity and specificity. It did not identify the 2 persons with AHI, and it incorrectly classified 2 HIV-uninfected and 1 antibody-positive person as having AHI. They also noted several invalid tests and implementation challenges owing to a narrow reading interval. Laperche et al assess the sensitivity of the Combo POCT at different p24 concentrations and among different clades in archived plasma and stored supernatants [2]. Even in these laboratory settings, the Combo POCT was unable to detect p24 consistently, especially with non-B subtypes. Although laboratory testing can be an important early step for gauging when a test may or may not perform adequately, it simply cannot replace field testing, which is required to determine ultimate utility. This is especially important for a test like the Combo POCT, which is designed to be used at the point of care on finger-stick whole blood. Laperche et al note the difficulty of field testing for AHI. However, we and others have demonstrated the feasibility of this approach. We have reported elsewhere that AHI can be detected routinely in the sexually transmitted infection setting where we conducted our analysis [5], allowing us to conduct ongoing studies related to this stage of HIV disease [6–7]. Although the performance of the antigen portion of the Combo POCT has been disappointing, the goal of identifying persons during AHI is important [8]. Investigators and industry should work together toward designing sensitive and specific diagnostics that can detect AHI at the point of care. These diagnostics must then be field tested before clinical use, regardless of the degree of difficulty involved.

01 Jan 2012
TL;DR: The average of the 95% CI and 95% confidence levels for both the ES and ES (95% CI) scores is 1.0.
Abstract: 0.23 (0.19, 0.28) 0.23 (0.19, 0.28) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) ES (95% CI) ES (95% CI) ES (95% CI) 0.23 (0.19, 0.28) 0.23 (0.19, 0.28) 0.23 (0.19, 0.28) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) ES (95% CI) ES (95% CI) ES (95% CI) 1 0.23 (0.19, 0.28) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) ES (95% CI) ES (95% CI) ES (95% CI) 0.23 (0.19, 0.28) 0.23 (0.19, 0.28) 0.23 (0.19, 0.28) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.64 (0.56, 0.73) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.52, 1.09) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.75 (0.62, 0.91) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) 0.47 (0.36, 0.61) ES (95% CI) ES (95% CI) ES (95% CI) 1

Journal ArticleDOI
TL;DR: The earliest nAb response was highly specific for the early autologous virus but within 1–2 years of infection, low titers of broadly neutraceuticals are found.
Abstract: We have been studying the magnitude, breadth, kinetics and epitope specificity of the neutralizing antibody (nAb) response in early and chronic HIV-1 infection. The earliest nAb response was highly specific for the early autologous virus but within 1–2 years of infection, low titers of broadly neutr