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.
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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.
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Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of ...adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
ClinicalTrials.gov NCT00903084.
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Although efficacy is unknown, many men who have sex with men (MSM) attempt to reduce HIV risk by adapting condom use, partner selection, or sexual position to the partner's HIV serostatus. We ...assessed the association of seroadaptive practices with HIV acquisition.
We pooled data on North American MSM from four longitudinal HIV-prevention studies. Sexual behaviors reported during each six-month interval were assigned sequentially to one of six mutually exclusive risk categories: (1) no unprotected anal intercourse (UAI), (2) having a single negative partner, (3) being an exclusive top (only insertive anal sex), (4) serosorting (multiple partners, all HIV negative), (5) seropositioning (only insertive anal sex with potentially discordant partners), and (6) UAI with no seroadaptive practices. HIV antibody testing was conducted at the end of each interval. We used Cox models to evaluate the independent association of each category with HIV acquisition, controlling for number of partners, age, race, drug use, and intervention assignment. 12,277 participants contributed to 60,162 six-month intervals with 663 HIV seroconversions. No UAI was reported in 47.4% of intervals, UAI with some seroadaptive practices in 31.8%, and UAI with no seroadaptive practices in 20.4%. All seroadaptive practices were associated with a lower risk, compared to UAI with no seroadaptive practices. However, compared to no UAI, serosorting carried twice the risk (HR = 2.03, 95%CI:1.51-2.73), whereas seropositioning was similar in risk (HR = 0.85, 95%CI:0.50-1.44), and UAI with a single negative partner and as an exclusive top were both associated with a lower risk (HR = 0.56, 95%CI:0.32-0.96 and HR = 0.55, 95%CI:0.36-0.84, respectively).
Seroadaptive practices appear protective when compared with UAI with no seroadaptive practices, but serosorting appears to be twice as risky as no UAI. Condom use and limiting number of partners should be advocated as first-line prevention strategies, but seroadaptive practices may be considered harm-reduction for men at greatest risk.
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BACKGROUND:Building on several decades of innovative HIV prevention and treatment programming in San Francisco, in 2014, a small group of academic, civic, and community leaders launched Getting to ...Zero San Francisco, a city-wide consortium focused on getting to zero HIV infections, zero HIV-related deaths, and zero HIV stigma and discrimination.
SETTING:San Francisco city and county.
METHODS:The consortium operates under the principles of collective impact composed of 5 componentsa common agenda, shared measurement, mutually reinforcing activities, continuous communication, and organization backbone. Two flagship initiatives are describedcitywide scale-up of pre-exposure prophylaxis and rapid antiretroviral therapy upon diagnosis.
RESULTS:The number of new HIV diagnoses declined by over 50% from 399 to 197 from 2013 to 2018; the time from diagnosis to viral suppression decreased from 134 to 62 days during that period. However, continued racial/ethnic disparities in new HIV diagnoses and viral suppression rates point to the need for the Getting to Zero San Francisco committees to focus on racial/ethnic equity as a primary focus. Cisgender and transgender women, people who inject drugs, and people who are homeless also have lower viral suppression rates; ongoing initiatives are attempting to address these disparities.
CONCLUSION:A collective impact implementation strategy that operates by unifying municipal organizations toward a common goal was associated with citywide gains in reducing new HIV diagnosis and time to viral suppression in San Francisco. Formal evaluation of this strategy will help elucidate under which conditions this approach is most likely to succeed.
Summary Background In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated ...men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. Methods To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-γ ELISPOT and intracellular cytokine staining assays, using a case–cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2lo ) CD4+ T cells expressing CCR5. Findings We detected interferon-γ-secreting HIV-specific T cells (range 163/106 to 686/106 peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon γ or tumor necrosis factor α (TNFα), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0·4–1·0%) in 117 of 160 (73%) participants, expressing predominantly either interferon γ alone or with TNFα. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2lo /CCR5+CD4+ T cells did not differ between cases and non-cases. Interpretation Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial. Funding National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and Merck Research Laboratories.
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Summary Background Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed ...the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. Methods We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov , number NCT00095576. Findings In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio HR 1·2 95% CI 0·6–2·2). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4·61 vs 4·41 log10 copies per mL, one tailed p value for potential benefit 0·66). The vaccine elicited interferon-γ ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2·3 95% CI 1·2–4·3) and uncircumcised men (3·8 1·5–9·3), but was not increased in Ad5 seronegative (1·0 0·5–1·9) or circumcised (1·0 0·6–1·7) men. Interpretation This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored. Funding Merck Research Laboratories; the Division of AIDS, National Institute of Allergy and Infectious Diseases, in the US National Institutes of Health (NIH); and the NIH-sponsored HIV Vaccine Trials Network (HVTN).
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IMPORTANCE: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. OBJECTIVE: To ...evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. EVIDENCE REVIEW: New evidence was collected since the previous International Antiviral (formerly AIDS) Society–USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. FINDINGS: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. CONCLUSION AND RELEVANCE: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.
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