Adaptive Non-Inferiority Margins under Observable Non-Constancy

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy\u27 assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. However, it is often the case that there exist strong, measurable predictors of constancy, such as dosing and adherence, and such predictors can be used to identify situations where the constancy assumption will likely fail. Here we propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population, and further use these predictors to adapt the non-inferiority margin at the end of the study. Population-specific margins can help avoid violations of the constancy assumption, and adaptive margins can help adjust for violations that will inevitably occur in real clinical trials, while at the same time maintain pre-specified levels of type I error and power

Use of Non-Occupational Post-Exposure Prophylaxis does not Lead to an Increase in High Risk Sex Behaviors in Men Who have Sex with Men Participating in the EXPLORE Trial

Non-occupational post-exposure prophylaxis (nPEP) use is an HIV prevention strategy that has been recommended by the CDC to prevent HIV infection after a high risk sexual exposure since 1997. In a behavioral intervention trial of 4,295 MSM we assessed perceptions and use of nPEP over 4 years in six cities across the United States. Overall, 1.9% of MSM reported use of nPEP prior to enrollment, and 6.3% at least once during the trial. Awareness of nPEP was reported by 47.5%, with higher awareness in two sites with funded nPEP programs. Three seroconversions occurred in the 384 visits where nPEP courses were reported, with no effect of nPEP on risk of HIV acquisition in this cohort (hazard ratio = 0.91, 95% confidence interval [0.29, 2.86]). NPEP users were a riskier group: increased odds of nPEP use were observed in association with multiple partners and unprotected receptive and insertive anal sex with HIV infected partners and partners with unknown HIV status. NPEP use was also associated with use of illicit drugs (injection drugs, crack cocaine, hallucinogens, and amphetamines). Importantly, willingness to use nPEP after high risk sex was associated with lower odds of high risk sex. After an episode of nPEP use, nPEP users remained more likely to report high risk sex than those in this cohort who had not previously used nPEP. However, within the subset of people who had previously reported high risk sex, previous nPEP use was not associated with higher odds of high risk sex, thus allaying fears that availability of nPEP would lead to an increase in high risk sex

Use of HIV Case Surveillance System to Design and Evaluate Site-Randomized Interventions in an HIV Prevention Study: HPTN 065

Introduction: Modeling studies suggest intensified HIV testing, linkage-to-care and antiretroviral treatment to achieve viral suppression may reduce HIV transmission and lead to control of the epidemic. To study implementation of strategy, population-level data are needed to monitor outcomes of these interventions. US HIV surveillance systems are a potential source of these data. Methods: HPTN065 (TLC-Plus) Study is evaluating the feasibility of a test, linkage-to-care, and treat strategy for HIV prevention in two intervention communities - the Bronx, NY, and Washington, DC. Routinely collected laboratory data on diagnosed HIV cases in the national HIV surveillance system were used to select and randomize sites, and will be used to assess trial outcomes. Results: To inform study randomization, baseline data on site-aggregated study outcomes was provided from HIV surveillance data by New York City and Washington D.C. Departments of Health. The median site rate of linkage-to-care for newly diagnosed cases was 69% (IQR 50%-86%) in the Bronx and 54% (IQR 33%-71%) in Washington, D.C. In participating HIV care sites, the median site percent of patients with viral suppression (<400 copies/mL) was 57% (IQR 53%-61%) in the Bronx and 64% (IQR 55%-72%) in Washington, D.C. Conclusions: In a novel use of site-aggregated surveillance data, baseline data was used to design and evaluate site randomized studies for both HIV test and HIV care sites. Surveillance data have the potential to inform and monitor sitelevel health outcomes in HIV-infected patients

PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention

Statistical considerations for the HPTN 052 Study to evaluate the effectiveness of early versus delayed antiretroviral strategies to prevent the sexual transmission of HIV-1 in serodiscordant couples

The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1,763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: “immediate” (early) therapy with ART initiated upon enrollment plus HIV primary care, or “delayed” therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200–250 cells/mm3, or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, 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. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015

Serosorting Is Associated with a Decreased Risk of HIV Seroconversion in the EXPLORE Study Cohort

Background: Seroadaptation strategies such as serosorting and seropositioning originated within communities of men who have sex with men (MSM), but there are limited data about their effectiveness in preventing HIV transmission when utilized by HIV-negative men. Methodology/Principal Findings: Data from the EXPLORE cohort of HIV-negative MSM who reported both seroconcordant and serodiscordant partners were used to evaluate serosorting and seropositioning. The association of serosorting and seropositioning with HIV seroconversion was evaluated in this cohort of high risk MSM from six U.S. cities. Serosorting was independently associated with a small decrease in risk of HIV seroconversion (OR = 0.88; 95%CI, 0.81–0.95), even among participants reporting $10 partners. Those who more consistently practiced serosorting were more likely to be white (p = 0.01), have completed college (p =,0.0002) and to have had 10 or more partners in the six months before the baseline visit (p = 0.01) but did not differ in age, reporting HIV-infected partners, or drug use. There was no evidence of a seroconversion effect with seropositioning (OR 1.02, 95%CI, 0.92–1.14). Significance: In high risk HIV uninfected MSM who report unprotected anal intercourse with both seroconcordant and serodiscordant partners, serosorting was associated with a modest decreased risk of HIV infection. To maximize any potential benefit, it will be important to increase accurate knowledge of HIV status, through increased testing frequency

Individual and community-level risk factors for HIV stigma in 21 Zambian and South African communities: analysis of data from the HPTN071 (PopART) study.

OBJECTIVE: To describe the prevalence and determinants of HIV stigma in 21 communities in Zambia and South Africa. DESIGN: Analysis of baseline data from the HPTN 071 (PopART) cluster-randomized trial. HIV stigma data came from a random sample of 3859 people living with HIV. Community-level exposures reflecting HIV fears and judgements and perceptions of HIV stigma came from a random sample of community members not living with HIV (n = 5088), and from health workers (HW) (n = 851). METHODS: We calculated the prevalence of internalized stigma, and stigma experienced in the community or in a healthcare setting in the past year. We conducted risk-factor analyses using logistic regression, adjusting for clustering. RESULTS: Internalized stigma (868/3859, prevalence 22.5%) was not associated with sociodemographic characteristics but was less common among those with a longer period since diagnosis (P = 0.043). Stigma experienced in the community (853/3859, 22.1%) was more common among women (P = 0.016), older (P = 0.011) and unmarried (P = 0.009) individuals, those who had disclosed to others (P < 0.001), and those with more lifetime sexual partners (P < 0.001). Stigma experienced in a healthcare setting (280/3859, 7.3%) was more common among women (P = 0.019) and those reporting more lifetime sexual partners (P = 0.001) and higher wealth (P = 0.003). Experienced stigma was more common in clusters wherever community members perceived higher levels of stigma, but was not associated with the beliefs of community members or HW. CONCLUSION: HIV stigma remains unacceptably high in South Africa and Zambia and may act as barrier to HIV prevention and treatment. Further research is needed to understand its determinants

Pregnancy Does Not Affect HIV Incidence Test Results Obtained Using the BED Capture Enzyme Immunoassay or an Antibody Avidity Assay

Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing.We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent.During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test).These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed

HIV Surveillance in a Large, Community-Based Study: Results from the Pilot Study of Project Accept (HIV Prevention Trials Network 043)

<p>Abstract</p> <p>Background</p> <p>Project Accept is a community randomized, controlled trial to evaluate the efficacy of community mobilization, mobile testing, same-day results, and post-test support for the prevention of HIV infection in Thailand, Tanzania, Zimbabwe, and South Africa. We evaluated the accuracy of in-country HIV rapid testing and determined HIV prevalence in the Project Accept pilot study.</p> <p>Methods</p> <p>Two HIV rapid tests were performed in parallel in local laboratories. If the first two rapid tests were discordant (one reactive, one non-reactive), a third HIV rapid test or enzyme immunoassay was performed. Samples were designated HIV NEG if the first two tests were non-reactive, HIV DISC if the first two tests were discordant, and HIV POS if the first two tests were reactive. Samples were re-analyzed in the United States using a panel of laboratory tests.</p> <p>Results</p> <p>HIV infection status was correctly determined based on-in country testing for 2,236 (99.5%) of 2,247 participants [7 (0.37%) of 1,907 HIV NEG samples were HIV-positive; 2 (0.63%) of 317 HIV POS samples were HIV-negative; 2 (8.3%) of 24 HIV DISC samples were incorrectly identified as HIV-positive based on the in-country tie-breaker test]. HIV prevalence was: Thailand: 0.6%, Tanzania: 5.0%, Zimbabwe 14.7%, Soweto South Africa: 19.4%, Vulindlela, South Africa: 24.4%, (overall prevalence: 14.4%).</p> <p>Conclusions</p> <p>In-country testing based on two HIV rapid tests correctly identified the HIV infection status for 99.5% of study participants; most participants with discordant HIV rapid tests were not infected. HIV prevalence varied considerably across the study sites (range: 0.6% to 24.4%).</p> <p>Trial Registration</p> <p>ClinicalTrials.gov registry number <a href="http://www.clinicaltrials.gov/ct2/show/NCT00203749">NCT00203749</a>.</p

Effect of Universal Testing and Treatment on HIV Incidence - HPTN 071 (PopART).

BACKGROUND: A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent. METHODS: In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South Africa (total population, approximately 1 million) to group A (combination prevention intervention with universal antiretroviral therapy [ART]), group B (the prevention intervention with ART provided according to local guidelines [universal since 2016]), or group C (standard care). The prevention intervention included home-based HIV testing delivered by community workers, who also supported linkage to HIV care and ART adherence. The primary outcome, HIV incidence between months 12 and 36, was measured in a population cohort of approximately 2000 randomly sampled adults (18 to 44 years of age) per community. Viral suppression (<400 copies of HIV RNA per milliliter) was assessed in all HIV-positive participants at 24 months. RESULTS: The population cohort included 48,301 participants. Baseline HIV prevalence was 21% or 22% in each group. Between months 12 and 36, a total of 553 new HIV infections were observed during 39,702 person-years (1.4 per 100 person-years; women, 1.7; men, 0.8). The adjusted rate ratio for group A as compared with group C was 0.93 (95% confidence interval [CI], 0.74 to 1.18; P = 0.51) and for group B as compared with group C was 0.70 (95% CI, 0.55 to 0.88; P = 0.006). The percentage of HIV-positive participants with viral suppression at 24 months was 71.9% in group A, 67.5% in group B, and 60.2% in group C. The estimated percentage of HIV-positive adults in the community who were receiving ART at 36 months was 81% in group A and 80% in group B. CONCLUSIONS: A combination prevention intervention with ART provided according to local guidelines resulted in a 30% lower incidence of HIV infection than standard care. The lack of effect with universal ART was unanticipated and not consistent with the data on viral suppression. In this trial setting, universal testing and treatment reduced the population-level incidence of HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 071 [PopArt] ClinicalTrials.gov number, NCT01900977.)