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1.  Sexual Role and Transmission of HIV Type 1 among Men Who Have Sex with Men, in Peru 
The Journal of infectious diseases  2005;191(0 1):S147-S158.
In Latin America, men who have sex with men (MSM) have traditionally practiced role segregation—that is, the adoption of a fixed role (insertive or receptive) rather than a versatile role (both practices) during anal sex. Previous modeling has shown that role segregation may yield a lower incidence of human immunodeficiency virus (HIV) type 1 infection, compared with role versatility; however, the modeling assumed no risk of acquiring HIV-1 during insertive sex, which is now recognized as unlikely. We reexamine the issue by use of a deterministic model incorporating bidirectional transmission and data from a cohort study of MSM in Lima, Peru, to demonstrate the potential effects of role segregation on the trajectory of the HIV-1 epidemic. In Lima, 67% of MSM reported segregated roles in their recent male partnerships. A population of MSM with identical contact rates but complete role versatility would have twice the prevalence of HIV-1 infection throughout the epidemic’s first 3 decades. Preferential mixing among versatile MSM does not change overall prevalence but affects which individuals become infected.
doi:10.1086/425268
PMCID: PMC4063354  PMID: 15627225
2.  A systematic review of alcohol use and sexual risk-taking in Latin America 
Objective
To provide an account of published literature on the association between alcohol use and sexual risk-taking, focusing on Latin America.
Methods
A search of MEDLINE, Embase, Web of Science, LILACS, and Cochrane databases identified 561 unique articles. After excluding those that were not directly relevant, 30 studies were retained for review.
Results
Twenty-seven studies showed direct or indirect associations between alcohol abuse and unprotected/risky sex. Three studies, however, showed no association between these variables, suggesting that the public health message of safer sex may have been effective.
Conclusions
Further research is needed to identify factors and behaviors that could be modified to reduce the association between alcohol use disorders and risky sexual behavior.
PMCID: PMC3895327  PMID: 24301738
Alcoholic intoxication; alcohol-related disorders; alcoholism; sexual behavior; unsafe sex; HIV; sexually transmitted diseases; Latin America; South America
3.  A call to action for comprehensive HIV services for men who have sex with men 
Lancet  2012;380(9839):424-438.
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.
doi:10.1016/S0140-6736(12)61022-8
PMCID: PMC3805059  PMID: 22819663
4.  Screening for Drug and Alcohol Use Disorders and Their Association with HIV-Related Sexual Risk Behaviors among Men Who Have Sex with Men in Peru 
PLoS ONE  2013;8(8):e69966.
Background
Peru's HIV epidemic is concentrated among men who have sex with men (MSM). The contribution of alcohol use disorders (AUDs) to known high-risk behaviors associated with HIV transmission in this context has not been well characterized.
Methods
Between June and October 2011, 5,148 sexually active MSM were recruited using convenience sampling in five cities to participate in a cross-sectional bio-behavioral survey. Five high-risk sexual criteria previously associated with incident HIV infection in this setting were selected a priori as the dependent outcomes. Screening for AUDs used the validated Alcohol Use Disorders Identification Test (AUDIT) and AUDS were stratified by severity. Unadjusted and adjusted odds ratios (AOR) were computed to establish the independent correlates of the five dependent outcomes.
Results
The majority (62.8%) of participants met screening criteria for having an AUD, which were independently correlated with each of the following high-risk sexual risk behaviors in the previous 6 months: 1) >5 sexual partners [AOR = 1.76; (1.54–2.02)]; 2) sex with an HIV-infected partner [AOR = 1.29; (1.03–1.62)]; 3) having a sexually transmitted infection [AOR = 1.38; (1.13–1.68)]; 4) being a sex worker [AOR = 1.61; (1.40–1.87)]; and 5) unprotected sex during last encounter [AOR = 1.22; (1.09–1.38)]. Recent drug use was also correlated with having >5 sexual partners [AOR = 1.42 (1.19–1.71)], sex work [AOR = 1.97 (1.63–2.39)] and unprotected sex during last encounter [AOR = 1.31 (1.11–1.54)]. For each dependent variable, the association with AUDs significantly increased with increasing AUD severity.
Conclusions
AUDs are highly prevalent among MSM in Peru and are associated with increased HIV risk-taking behaviors that are associated with HIV transmission. Strategies that target problematic drinking such as medication-assisted therapy, behavioral counseling and structural interventions could potentially reduce risky behaviors and ultimately reduce HIV transmission among MSM in Peru.
doi:10.1371/journal.pone.0069966
PMCID: PMC3735581  PMID: 23936364
5.  Sexual risk behaviors, circumcision status and pre-existing immunity to adenovirus type 5 among men who have sex with men participating in a randomized HIV-1 vaccine efficacy trial: Step Study 
Background
The Step Study found that men who had sex with men (MSM) who received an adenovirus type 5 (Ad5) vector-based vaccine and were uncircumcised or had prior Ad5 immunity had a higher HIV incidence than MSM who received placebo. We investigated whether differences in HIV exposure, measured by reported sexual risk behaviors, may explain the increased risk.
Methods
Among 1,764 MSM in the trial, 724 were uncircumcised, 994 had prior Ad5 immunity and 560 were both uncircumcised and had prior Ad5 immunity. Analyses compared sexual risk behaviors and perceived treatment assignment among vaccine and placebo recipients, determined risk factors for HIV acquisition and examined the role of insertive anal intercourse in HIV risk among uncircumcised men.
Findings
Few sexual risk behaviors were significantly higher in vaccine vs. placebo recipients at baseline or during follow-up. Among uncircumcised men, vaccine recipients at baseline were more likely to report unprotected insertive anal intercourse with HIV negative partners (25.0% vs. 18.1%; p=0.03). Among uncircumcised men who had prior Ad5 immunity, vaccine recipients were more likely to report unprotected insertive anal intercourse with partners of unknown HIV status (46.0% vs. 37.5%; p=0.05). Vaccine recipients remained at higher risk of HIV infection compared to placebo recipients (HR =2.8; 95% CI:1.7, 6.8) controlling for potential confounders.
Interpretation
These analyses do not support a behavioral explanation for the increased HIV infection rates observed among uncircumcised men in the Step Study. Identifying biologic mechanisms to explain the increased risk is a priority.
This study is registered with ClinicalTrials.gov, number NCT00095576.
doi:10.1097/QAI.0b013e31825325aa
PMCID: PMC3392543  PMID: 22421748
HIV vaccines; gay men; sexual behaviors
6.  Correction: What Drives the US and Peruvian HIV Epidemics in Men Who Have Sex with Men (MSM)? 
PLoS ONE  2013;8(7):10.1371/annotation/9a6a0c8e-2d01-4f36-9ab8-f9fdfce6497b.
doi:10.1371/annotation/9a6a0c8e-2d01-4f36-9ab8-f9fdfce6497b
PMCID: PMC3714381
7.  Extended Follow-up Confirms Early Vaccine-Enhanced Risk of HIV Acquisition and Demonstrates Waning Effect Over Time Among Participants in a Randomized Trial of Recombinant Adenovirus HIV Vaccine (Step Study) 
The Journal of Infectious Diseases  2012;206(2):258-266.
Background. The Step Study tested whether an adenovirus serotype 5 (Ad5)–vectored human immunodeficiency virus (HIV) vaccine could prevent HIV acquisition and/or reduce viral load set-point after infection. At the first interim analysis, nonefficacy criteria were met. Vaccinations were halted; participants were unblinded. In post hoc analyses, more HIV infections occurred in vaccinees vs placebo recipients in men who had Ad5-neutralizing antibodies and/or were uncircumcised. Follow-up was extended to assess relative risk of HIV acquisition in vaccinees vs placebo recipients over time.
Methods. We used Cox proportional hazard models for analyses of vaccine effect on HIV acquisition and vaccine effect modifiers, and nonparametric and semiparametric methods for analysis of constancy of relative risk over time.
Results. One hundred seventy-two of 1836 men were infected. The adjusted vaccinees vs placebo recipients hazard ratio (HR) for all follow-up time was 1.40 (95% confidence interval [CI], 1.03–1.92; P = .03). Vaccine effect differed by baseline Ad5 or circumcision status during first 18 months, but neither was significant for all follow-up time. The HR among uncircumcised and/or Ad5-seropositive men waned with time since vaccination. No significant vaccine-associated risk was seen among circumcised, Ad5-negative men (HR, 0.97; P = 1.0) over all follow-up time.
Conclusions. The vaccine-associated risk seen in interim analysis was confirmed but waned with time from vaccination.
Clinical Trials Registration. NCT00095576.
doi:10.1093/infdis/jis342
PMCID: PMC3490694  PMID: 22561365
8.  Successes and challenges of HIV prevention in men who have sex with men 
Lancet  2012;380(9839):388-399.
Men who have sex with men (MSM) have been substantially affected by HIV epidemics worldwide. Epidemics in MSM are re-emerging in many high-income countries and gaining greater recognition in many low-income and middle-income countries. Better HIV prevention strategies are urgently needed. Our review of HIV prevention strategies for MSM identified several important themes. At the beginning of the epidemic, stand-alone behavioural interventions mostly aimed to reduce unprotected anal intercourse, which, although somewhat efficacious, did not reduce HIV transmission. Biomedical prevention strategies reduce the incidence of HIV infection. Delivery of barrier and biomedical interventions with coordinated behavioural and structural strategies could optimise the effectiveness of prevention. Modelling suggests that, with sufficient coverage, available interventions are sufficient to avert at least a quarter of new HIV infections in MSM in diverse countries. Scale-up of HIV prevention programmes for MSM is difficult because of homophobia and bias, suboptimum access to HIV testing and care, and financial constraints.
doi:10.1016/S0140-6736(12)60955-6
PMCID: PMC3670988  PMID: 22819659
9.  A cross-sectional study of knowledge of sex partner serostatus among high-risk Peruvian men who have sex with men and transgender women: implications for HIV prevention 
BMC Public Health  2013;13:181.
Background
Knowledge of a sex partner’s HIV serostatus can influence sexual behavior and inform harm-reduction strategies. We sought to determine how often Peruvian men who have sex with men (MSM) and transgender women (TW) knew the HIV serostatus of their sex partners, if this knowledge was associated with any predictive factors or unprotected anal intercourse (UAI), and if UAI was associated with partner serostatus.
Methods
We analyzed data from the 2008 Peruvian MSM Sentinel Surveillance Survey. Data were collected by CASI about each participant’s three most recent male sex partners. Primary outcome was knowledge of a partner's HIV test result. Multivariate analysis assessed the effect of age, education, sexual identity, number of male partners, alcohol use during intercourse, type of partnership and length of partnership using logistic regression.
Results
735 participants provided data on 1,643 of their most recent sex partners from the last 3 months. 179/735 (24.4%) of all participants knew HIV test results for at least one of their 3 most recent partners, corresponding to 230/1643 (14.0%) of all sexual partnerships in the last 3 months. In multivariate analysis, casual (OR: 0.27, 95% CI: 0.17-0.42) and exchange sex (OR: 0.31, 95% CI: 0.11-0.88) partners, compared to stable partners, were negatively associated with knowledge of partner serostatus, whereas relationships lasting longer than one night (<3 months OR: 2.20, 95% CI: 1.39-3.51; 3 months to 1 year OR: 3.00, 95% CI: 1.80-5.01; ≥ 1 year OR: 4.13, 95% CI: 2.40-7.10) were positively associated with knowledge of partner serostatus. Knowledge of partner serostatus was not associated with unprotected anal intercourse with that partner.
Conclusions
Few MSM and TW in Peru know their partners’ HIV serostatus. Our findings suggest that the type and length of partnership influence the likelihood of knowing a partner’s serostatus. Further research should explore the contexts and practices of partner communication, their effect on sexual behavior, and interventions to promote discussion of HIV testing and serostatus as an HIV prevention strategy in this population.
doi:10.1186/1471-2458-13-181
PMCID: PMC3599550  PMID: 23448153
10.  (1RS,2RS)-4,4′-(1-Aza­niumyl-2-hy­droxy­ethane-1,2-di­yl)dipyridinium tetra­chlorido­platinate(II) chloride 
The title compound, (C12H16N3O)[PtCl4]Cl, consists of a 4,4′-(1-aza­niumyl-2-hy­droxy­ethane-1,2-di­yl)dipyridinium trication, a square-planar tetra­chloridoplatinate(II) dianion and a chloride ion. In the cation, the pyridinium rings attached to the central 1-aza­niumyl-2-hy­droxy­ethane fragment have an anti conformation, as indicated by the central C—C—C—C torsion angle of −166.5 (6)°, and they are inclined to one another by 63.5 (4)°. In the crystal, the cations and anions are linked through N—H⋯Cl and O—H⋯Cl hydrogen bonds. There are also π–π contacts [centroid–centroid distances = 3.671 (4) and 3.851 (4) Å] and a number of C—H⋯Cl inter­actions present, consolidating the formation of a three-dimensional supra­molecular structure.
doi:10.1107/S160053681300425X
PMCID: PMC3588516  PMID: 23476502
11.  Uncommon Pathways of Immune Escape Attenuate HIV-1 Integrase Replication Capacity 
Journal of Virology  2012;86(12):6913-6923.
An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = −0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF114–121) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ∼35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.
doi:10.1128/JVI.07133-11
PMCID: PMC3393549  PMID: 22496233
12.  What Drives the US and Peruvian HIV Epidemics in Men Who Have Sex with Men (MSM)? 
PLoS ONE  2012;7(11):e50522.
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.
doi:10.1371/journal.pone.0050522
PMCID: PMC3510067  PMID: 23209768
13.  Short Report: Lack of Evidence of Hepatitis C and HIV Co-Infection among Men Who Have Sex with Men in Peru 
Hepatitis C virus (HCV) infection occurs among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) because of shared routes of transmission. To assess the association between HCV and HIV infection among MSM in Peru, we conducted a matched case-control study (162 HIV-positive cases and 324 HIV-negative controls) among participants of an HIV sentinel surveillance survey in six urban cities. The HCV infection was initially screened using anti-HCV ELISA and immunoblot assay, and thereafter confirmed by the HCV RNA qualitative assay. Among cases, no confirmed HCV infection was found while among controls, only two confirmed HCV infections were reported (0.62%). This matched case-control reports a very low probability of association between HCV and HIV co-infection and suggests a very low prevalence of HCV infection among MSM in Peru.
PMCID: PMC3500390  PMID: 19556587
14.  Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings 
PLoS Medicine  2012;9(8):e1001290.
Thomas Campbell and colleagues report findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing.
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.
Editors' Summary
Background
Despite the enormous gains in reducing HIV-related illness and death over the past decade, there are still considerable challenges to meeting the global goal of universal access to highly active antiretroviral treatment—a combination of effective drugs that attack the HIV virus in various ways—to everyone living with HIV/AIDS who could benefit from treatment. In recognition of the related financial, technical, and system obstacles to providing universal access to HIV treatment, in 2010 the UN agency responsible for HIV/AIDS—UNAIDS—launched an ambitious plan called Treatment 2.0, which aims to simplify the way HIV treatment is currently provided. One of the main focuses of Treatment 2.0 is to simplify drug regimes for the treatment of HIV and to make treatment regimes less toxic. In line with Treatment 2.0, the World Health Organization currently recommends that antiretroviral regimens for the initial treatment of HIV should include two nucleoside reverse transcriptase inhibitors (zidovudine or tenofovir disoproxil fumarate [DF] with lamivudine or emtricitabine) and a non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine.)
Why Was This Study Done?
Most of the evidence about the safety and effectiveness of clinical trials come from clinical trials in high-income countries and thus is not generally representative of the majority of people with HIV. So in this study, the researchers conducted a randomized controlled trial in diverse populations in many different settings to investigate whether antiretroviral regimens administered once daily were as effective as twice-daily regimens and also whether a regimen containing the drug atazanavir administered once daily was as safe and effective as a regimen containing efavirenz—data from previous studies have suggested that atazanavir has characteristics, such as its side effect profile, which may make it more suitable for low income settings.
What Did the Researchers Do and Find?
The researchers recruited eligible patients from centers in Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand, the United States, and Zimbabwe—almost half (47%) were women. Then the researchers randomly assigned participants to one of three regimens: efavirenz 600 mg daily plus co-formulated lamivudine-zidovudine 150 mg/300 mg twice daily (EFV+3TC-ZDV); or atazanavir 400 mg once daily, plus didanosine-EC 400 mg once daily, plus emtricitabine 200 mg once daily (ATV+DDI+FTC); or efavirenz 600 mg once daily plus coformulated emtricitabine-tenofovir-DF 200 mg/300 mg once daily (EFV+FTC-TDF). During the study period ATV+DDI+FTC was found to be inferior to EFV+3TC-ZDV, so the Multinational Data Safety Monitoring Board ordered this arm of the trial to stop. Then a year later, due to the low number of treatment failures (deaths, severe HIV disease, or serious opportunistic infections) in the remaining two arms, the board advised the trial to stop early. So the researchers analyzed the data obtained up to this point and pooled the results from all of the centers.
The researchers found that during an average of 184 weeks of follow-up, there were 95 treatment failures (18%) among 526 participants taking EFV+FTC-TDF compared to 98 failures among 519 participants taking EFV+3TC-ZDV. During an average 81 weeks follow-up, there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV. As for safety, 243 (46%) participants assigned to EFV+FTC-TDF reached a safety endpoint (grade 3 disease, abnormal lab measurement, or the need to change drug) compared to 313 (60%) in the EFV+3TC-ZDV group. Importantly, the researchers found that there was greater risk of safety events for women assigned to EFV+3TC-ZDV and also that the atazanavir-based regimen had a higher relative efficacy in women compared to men.
What Do These Findings Mean?
These findings suggest that in diverse populations, EFV+FTC-TDF is as effective as EFV+3TC-ZDV but importantly, the once-daily dosing of EFV+FTC-TDF makes this regimen useful for the initial treatment of HIV, especially in low-income countries. Therefore, as per the guidance in Treatment 2.0, EFV+FTC-TDF in a single combination tablet that can be taken once a day is an attractive option. These findings also indicate that as ATV+DDI+FTC was found to be inferior to the other regimens, this combination should not be used in the initial treatment of HIV. These findings also add to the evidence that antiretroviral efficacy and safety can differ between women and men and support further development of sex-specific recommendations for antiretroviral regimen options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001290.
The UNAIDS website has more information about Treatment 2.0; and the WHO website provides technical information
For an introduction to the treatment of HIV/AIDS see http://www.avert.org/treatment.htm; the AVERT site also has personal stories from women living with HIV/AIDS
AIDSmap provides information for individuals and communities affected by HIV/AIDS
The ACTG website provides information about research to improve treatment of HIV and related complications
doi:10.1371/journal.pmed.1001290
PMCID: PMC3419182  PMID: 22936892
15.  Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults 
Abstract
The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 × 109 or 1 × 1010 viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-γ ELISPOT gag 15-mer assay with positive responses defined as ≥55 SFC/106 PBMCs and ≥4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/106 PBMCs in the placebo, 1 × 109 vp/dose, and 1 × 1010 vp/dose groups, respectively. Overall, responses to 1 × 1010 vp were 85% and 68% in subjects with low (≤200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 × 1010 vp/dose groups than in the 1 × 109 vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity.
doi:10.1089/aid.2010.0151
PMCID: PMC3422055  PMID: 20854108
16.  Serological Immunity to Adenovirus serotype 5 is not Associated with Risk of HIV Infection: a Case-control Study 
AIDS (London, England)  2011;25(2):153-158.
Background
Adenoviruses are among the most promising vectors for the development of an HIV vaccine. The results of the phase IIB study of the adenovirus serotype 5-based Merck Trivalent HIV vaccine have raised the concern that serological immunity to Ad5 could be linked to HIV acquisition risk in high-risk individuals. We examined the association between adenovirus serostatus and the rate of incident HIV infection in populations at elevated risk of HIV acquisition.
Methods
We performed a nested case-control study of Ad5 serostatus among 299 HIV-infected and 590 matched HIV-uninfected persons participating in MACS and in HPTN 039, a study of HSV-2 suppression among adults in the U.S., South America and Africa. Appropriate HIV cases and controls were identified in each cohort, and Ad5 neutralizing antibody titers were compared in these two groups.
Results
In MACS and HPTN 039, the relative risks of incident HIV infection among Ad5 seropositive vs. Ad5 seronegative individuals were 1.1 (95% CI 0.8–1.5, p = 0.57) and 1.0 (95% CI 0.4 – 2.3, p = 0.99) respectively. HIV-1 acquisition rates did not vary significantly by Ad5 neutralizing antibody titer.
Conclusions
The presence of Ad5 neutralizing antibodies is not linked to the risk of HIV acquisition among populations at elevated risk of HIV infection.
doi:10.1097/QAD.0b013e328342115c
PMCID: PMC3057418  PMID: 21150554
Adenovirus; serology; MSM; HIV; acquisition risk; vaccine
17.  Herpes simplex virus type 2 suppressive therapy with acyclovir or valacyclovir does not select for specific HIV-1 resistance in HIV-1/HSV-2 dually-infected persons 
The Journal of infectious diseases  2011;203(1):117-121.
Recent in vitro studies suggest that acyclovir may directly inhibit HIV-1 replication and can select for a specific HIV-1 reverse transcriptase mutation (V75I) with concomitant loss of an anti-HIV-1 effect. We tested for HIV-1 genotypic resistance at reverse transcriptase codon 75 in plasma from 168 HIV-1 infected persons from Botswana, Kenya, Peru, and the US taking daily acyclovir or valacyclovir for between 8 weeks and 24 months. No V75I cases were detected (95% confidence interval: 0-2.2%). These prospective in vivo studies suggest that standard-dose acyclovir or valacyclovir does not select for HIV-1 resistance.
doi:10.1093/infdis/jiq013
PMCID: PMC3024584  PMID: 21148504
HSV-2; HIV-1 resistance; V75I
18.  Herpes Simplex Virus Type 2 Suppressive Therapy with Acyclovir or Valacyclovir Does Not Select for Specific HIV-1 Resistance in HIV-1/HSV-2 Dually Infected Persons 
The Journal of Infectious Diseases  2011;203(1):117-121.
Recent in vitro studies suggest that acyclovir may directly inhibit HIV-1 replication and can select for a specific HIV-1 reverse transcriptase mutation (V75I) with concomitant loss of an anti-HIV-1 effect. We tested for HIV-1 genotypic resistance at reverse transcriptase codon 75 in plasma from 168 HIV-1–infected persons from Botswana, Kenya, Peru, and the United States taking daily acyclovir or valacyclovir for between 8 weeks and 24 months. No V75I cases were detected (95% confidence interval, 0%–2.2%). These prospective in vivo studies suggest that standard-dose acyclovir or valacyclovir does not select for HIV-1 resistance.
doi:10.1093/infdis/jiq013
PMCID: PMC3024584  PMID: 21148504
19.  Definition of the viral targets of protective HIV-1-specific T cell responses 
Background
The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.
Methods
Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.
Results
For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.
Conclusions
The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.
doi:10.1186/1479-5876-9-208
PMCID: PMC3292987  PMID: 22152067
HIV specific CTL; clade B; clade C; HLA; vaccine immunogen design; functional avidity; epitope; entropy; immune correlate
20.  Effect of Acyclovir on HIV-1 Set Point among HSV-2 Seropositive Persons during Early HIV-1 Infection 
The Journal of infectious diseases  2010;202(5):734-738.
We evaluated whether acyclovir suppression during human immunodeficiency virus type 1 (HIV-1) acquisition reduces HIV-1 set point, increases CD4 cell counts, and selects reverse-transcriptase mutations among 76 HIV-1 seroconverters identified in a placebo-controlled trial of twice-daily acyclovir (400 mg) for the prevention of HIV acquisition in herpes simplex virus type 2 (HSV-2)–seropositive persons (HIV Prevention Trials Network study 039). We found no significant difference in plasma HIV-1 RNA levels (P<.30)or CD4 cell counts (P<.85) between the acyclovir and placebo recipients. V75I and other mutations in HIV-1 reverse transcriptase reported from in vitro acyclovir studies were not observed. In conclusion, acyclovir suppression during HIV-1 seroconversion and the subsequent 6 months does not affect HIV-1 set point.
doi:10.1086/655662
PMCID: PMC2964878  PMID: 20649426
Acyclovir; HIV-1 seroconversion; HIV-1 viral set point; HSV-2
21.  Prevalence and Correlates of Human Herpesvirus 8 Infection among Peruvian Men who have Sex with Men 
Background
Infection with human herpesvirus 8 (HHV-8) is common among men who have sex with men (MSM) in North America and Europe, and is also found to be endemic in some regions of South America. Little is known about HHV-8 prevalence and its correlates among MSM in the Andean region.
Methods
We assessed HHV-8 seroprevalence among 497 MSM recruited for the 2002 Peruvian HIV sentinel surveillance program using a combined HHV-8 enzyme immunoassay and immunofluorescence assay algoritm. Logistic regression was used to estimate Odds Ratios (OR) and their 95% confidence intervals (CI) to determine the association between selected covariates and HHV-8 seropositivity.
Results
483 (97%) of 497 men had stored sera and demographic data available for analysis. 131 (66.5%, 95% CI 63.1%-69.9%) of 197 HIV-infected and 80 (26.7%, 95% CI 24.4%-29.0%) of 300 HIV-uninfected MSM had serologic evidence of HHV-8 infection. Factors independently associated with HHV-8 infection were education <12 years (OR 1.7, 95% CI 1.1-2.7), anal receptive sex with the last partner (OR 2.0, 95% CI 1.2-3.3), self-reported STI symptoms during the last year (OR: 1.9, 95% CI 1.2-3.0), and co-infection with HIV (OR 4.2, 95% CI 2.8-6.4) and Chronic Hepatitis B (OR 4.9, 95% CI 1.5-15.8). MSM with long-standing HIV infection were more likely to have serologic evidence of HHV-8 infection when compared to men with recently-acquired HIV (OR: 3.8, 95% CI 1.7-9.1).
Conclusions
HHV-8 infection is common among both HIV-infected and negative MSM in Lima, Peru. HHV-8 seropositivity is correlated with anal receptive sex, self-reported STI symptoms, and HIV infection among these MSM, and thus appears to be sexually transmitted. HHV-8 infection appears to be acquired after HIV infection, suggesting that future studies should evaluate the mode of HHV-8 transmission and prevention strategies among HIV-infected MSM.
doi:10.1097/QAI.0b013e31818d5bf8
PMCID: PMC3138205  PMID: 18989224
Human Herpesvirus 8; Homosexual Men; Human Immunodeficiency Virus; Peru; Sexually Transmitted Infections
22.  Hepatitis B Infection and Association with Other Sexually Transmitted Infections Among Men Who Have Sex with Men in Peru 
To assess the epidemiology of hepatitis B virus (HBV) infection among men who have sex with men (MSM) in Peru, we evaluated the prevalence and associated risk factors for HBV serologic markers among participants of a HIV sentinel surveillance conducted in 2002–2003. The standardized prevalences for total antibodies to hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (HBsAg) were 20.2% and 2.8%, respectively. Individuals with human immunodeficiency virus (HIV-1) infection had significantly higher anti-HBc (44.3% versus 19.3%) and HBsAg (9.5% versus 2.3%) prevalences than uninfected men. Increasing age (adjusted odds ratio [AOR] = 1.06), versatile sexual role (AOR = 1.59), sex in exchange for money/gifts (AOR = 1.58), syphilis (AOR = 1.74), HIV-1 infection (AOR = 1.64), and herpes simplex virus type 2 (HSV-2, AOR = 2.77) infection were independently associated with anti-HBc positivity, whereas only HIV-1 infection (AOR = 3.51) and generalized lymph node enlargement (AOR = 3.72) were associated with HBsAg positivity. Pre-existing HBV infection is very common among Peruvian MSM and was correlated with sexual risk factors. MSM in Peru constitute a target population for further HBV preventive and treatment interventions.
doi:10.4269/ajtmh.2010.10-0003
PMCID: PMC2912599  PMID: 20595501
23.  A post-trial assessment of factors influencing study drug adherence in a randomized biomedical HIV-1 prevention trial 
AIDS and behavior  2011;15(5):897-904.
High adherence and maintenance of blinding are critical for placebo-controlled efficacy trials of HIV-1 biomedical prevention strategies. We assessed adherence to study drug and factors affecting adherence, including perceived randomization group, in a post-trial questionnaire of participants who completed HPTN 039, a randomized, placebo-controlled trial of HSV-2 suppression with twice-daily acyclovir to reduce HIV-1 acquisition. Of the 3172 trial participants, 2003 (63%) completed the post-trial questionnaire. Of these 2003, 72% reported missing a dose of study drug less than twice a week. Study drug adherence was not compromised by perceived randomization or genital ulcer symptoms during the study. Alcohol use was cited as an adherence barrier in some populations. Assessment of study drug adherence during and at the end of trials can evaluate perceptions of randomization and adherence by randomization arm, help to better understand barriers to and motivations for adherence, and develop interventions to increase adherence for future trials.
doi:10.1007/s10461-010-9853-2
PMCID: PMC3076532  PMID: 21104007
Adherence; Biomedical prevention; HIV-1; Clinical trials
24.  Clinical and virologic efficacy of herpes simplex virus type 2 suppression by acyclovir in a multi-continent clinical trial 
The Journal of infectious diseases  2010;201(8):1164-1168.
Acyclovir suppressive therapy (400 mg twice daily) reduces herpes simplex virus type 2 (HSV-2) associated genital ulcer disease (GUD) and lesional HSV shedding. In an international trial of acyclovir for HSV-2 suppression to prevent HIV acquisition (HPTN 039), acyclovir had a smaller effect on the frequency of GUD as well as the frequency and quantity of lesional HSV DNA in African women and Peruvian men compared with men in the United States. The observed regional variation in the clinical and virologic efficacy of acyclovir for HSV suppression warrants further evaluation of determinants of responses to acyclovir.
doi:10.1086/651381
PMCID: PMC2856478  PMID: 20214474
herpes simplex virus type 2; acyclovir; suppression; genital ulcer disease; viral shedding; genital herpes
25.  The potential role of biomarkers in HIV preventive vaccine trials: a critical review 
Background
Successful conduct of HIV vaccine efficacy trials entails identification and enrollment of at-risk populations, assessment of appropriate endpoints as measures of vaccine efficacy for prevention of HIV acquisition and amelioration of disease course among infected vaccinees, as well as identification of potential confounders or effect modifiers. While not invariably useful and bringing their own cost in terms of measurement and validation, a variety of biomarkers may aid at each stage of trial conduct.
Methods
A review of selected articles, chosen based on quality, relevance of the biomarker to HIV vaccine trials, and availability of the publication, was conducted. The authors also drew experience from current trials and other planned or ongoing trials.
Conclusions
Biomarkers are available to assess HIV incidence in potential study populations but care is needed in interpreting results of these assays. During trial conduct, STIs such as HSV-2 may act as effect modifiers on primary and secondary endpoints, including HIV incidence and set point viral load. The utility of STI biomarkers will likely depend heavily on local epidemiology at clinical trial sites. Analyses from recent large HIV vaccine efficacy trials point to the complexities in interpreting trial results and underscore the potential utility of biomarkers in evaluating confounding and effect modification.
doi:10.1097/QAI.0b013e3181adcbbe
PMCID: PMC2920071  PMID: 19512938
HIV vaccine trials; HIV incidence; biomarkers; randomized controlled trials; STIs; hepatitis

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