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BACKGROUND VRC01 is a human IgG1 broadly neutralizing antibody (bnAb) that binds to the HIV-1 envelope glycoprotein. It is being evaluated in two ongoing Phase 2b trials, the first efficacy assessment of a passively-administered bnAb for HIV-1 prevention. HVTN 104 was a phase 1 trial of VRC01. SETTING We measured serum concentrations and serum neutralization of VRC01 in 1079 longitudinal samples collected after passive administration of VRC01 in 84 HVTN 104 participants. As assays for measuring VRC01 serum neutralization titers are resource-intensive, we investigated approaches to predicting such titers. METHODS Serum concentration was measured using an anti-idiotypic ELISA assay. Serum neutralization ID50 titers and in vitro neutralization potency IC50 of the VRC01 clinical lot were measured against Env-pseudoviruses. Three approaches were used to predict serum neutralization ID50 titers based on (1) observed serum concentration divided by IC50, (2) pharmacokinetics model-predicted serum concentration divided by IC50, and (3) joint modeling of the longitudinal serum concentrations and ID50 titers. RESULTS All 3 approaches yielded satisfactory prediction of neutralization titers against viruses of varied sensitivities; the median fold differences (FDs) of observed-over-predicted ID50 titers were between 0.95 and 1.37. Approach 3 generally performed the best with fold differences between 0.95 and 0.99 and

Purpose of review Models of implementation of known-effective interventions for HIV prevention indicate that an efficacious vaccine to prevent HIV infection would be critical for controlling the HIV pandemic. Key issues in the design of future HIV vaccine trials are: first, how to develop reliable immunological correlates of vaccine efficacy, second, how to down-select candidate vaccine regimens into efficacy trials, and third, how to learn about vaccine efficacy in the context of the evolving HIV prevention landscape. Recent findings Whereas in the past phase-I/-II HIV vaccine trials have addressed the first and second points using a small set of immunological assays and readouts, recently they have used a battery of assays with highly multivariate readouts. In addition, systems vaccinology studies of other pathogens measuring PBMC transcriptomics and other immunological features pre- and postfirst vaccination are demonstrating value, for example, providing discoveries that preimmunization and early postimmunization cell population markers can predict the influenza-specific antibody titer that is a correlate of vaccine protection. The HIV prevention landscape continues to evolve, and the design and analysis of vaccine trials is evolving alongside, to accommodate increasingly dynamic and regional standards of HIV prevention. Summary Development of interpretable and robust functional assays, in addition to the associated bioinformatics and statistical analytic tools, is needed to improve the assessment of correlates of protection in efficacy trials and the down-selection of candidate vaccine regimens into efficacy trials. Moreover, high-priority trials should integrate systems vaccinology, including the analysis of prevaccination and early postvaccination markers.

Purpose of review The genetic characterization of HIV-1 breakthrough infections in vaccine and placebo recipients offers new ways to assess vaccine efficacy trials. Statistical and sequence analysis methods provide opportunities to mine the mechanisms behind the effect of an HIV vaccine. Recent findings The release of results from two HIV-1 vaccine efficacy trials, Step/HVTN-502 (HIV Vaccine Trials Network-502) and RV144, led to numerous studies in the last 5 years, including efforts to sequence HIV-1 breakthrough infections and compare viral characteristics between the vaccine and placebo groups. Novel genetic and statistical analysis methods uncovered features that distinguished founder viruses isolated from vaccinees from those isolated from placebo recipients, and identified HIV-1 genetic targets of vaccine-induced immune responses. Summary Studies of HIV-1 breakthrough infections in vaccine efficacy trials can provide an independent confirmation to correlates of risk studies, as they take advantage of vaccine/placebo comparisons, whereas correlates of risk analyses are limited to vaccine recipients. Through the identification of viral determinants impacted by vaccine-mediated host immune responses, sieve analyses can shed light on potential mechanisms of vaccine protection.

We investigated effects of vaccination with AIDSVAX B/E HIV-1 candidate vaccine on blood and seminal plasma HIV-1 RNA viral loads (BVL and SVL, respectively) in vaccine recipients (VRs) and placebo recipients (PRs) who acquired infection.Linear mixed models were fitted for repeated measurements of BVL. Generalized estimating equations were used to assess the difference in SVL detectability between VRs and PRs.A total of 196 participants became HIV-1 infected during the trial. Thirty-two (16%) became infected with HIV-1 subtype B and 164 (84%) with HIV-1 subtype CRF01_AE. Per protocol-specified analysis, there were no differences in BVL levels between VRs and PRs. When stratified by HIV-1-infecting subtype, vaccination with AIDSVAX B/E was initially associated with higher BVL among HIV-1 CRF01_AE-infected VRs compared with HIV-1 CRF01_AE-infected PRs; however, this difference did not persist over time. HIV-1 subtype B-infected VRs had slightly higher BVL levels and were more likely to have detectable SVL during the follow-up period than HIV-1 subtype B-infected PRs.Subtle differences in BVL and SVL were detected between VRs and PRs. These results may help to further understand the dynamics between HIV-1 vaccination, HIV-1-infecting subtypes, and subsequent viral expression in different body compartments.

A successful HIV vaccine would have a substantial impact on acquisition of infection, progression of disease among the infected, or infectiousness of the infected. Current vaccine candidates are anticipated to have their major effect on viremia, however, with the expectation that this would induce or be concordant with a reduced rate of AIDS, death, or infectiousness. Although direct assessment of disease progression or infectiousness may be impractical, available potential surrogates for these endpoints may be misleading. This article summarizes the proceedings of a National Institute of Allergy and Infectious Disease-sponsored workshop to explore the use of surrogate endpoints for licensure of an HIV vaccine. Early, medium, and late endpoints were discussed, along with challenges such as surrogate validity, the confounding effect of antiretroviral therapy initiation, and potential selection bias in the vaccine and placebo recipients who become infected. Results from 5 hypothetic HIV vaccine clinical trials with ambiguously successful results were presented to an expert panel for interpretation and discussion of next steps. Key recommendations included assessing magnitude and durability of surrogate effects, generalization across populations, and directed improvement of vaccines. Use of acquisition and a postinfection surrogate as coprimary endpoints was supported, along with use of composite endpoints and exploration of heterogeneity in vaccine efficacy by characteristics of the host and virus.

Single-dose nevirapine given to women and infants reduces mother-to-child HIV transmission but nevirapine resistance develops in a large percentage of women. The objective was to determine whether the maternal nevirapine dose could be eliminated in the setting of zidovudine prophylaxis. A 2 x 2 factorial randomized clinical trial with a double-blinded peripartum factor designed to assess the equivalence of maternal single-dose nevirapine versus placebo with respect to HIV transmission. A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana resulting in 694 live first-born infants. HAART was available for women with AIDS. All women received a background of zidovudine from 34 weeks gestation through delivery and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor. Main outcome measures: The primary endpoint was infant HIV infection by the 1-month visit. Of the 694 infants in this equivalence study 15 (4.3%) of 345 in the maternal nevirapine arm were HIV infected by 1 month versus 13 (3.7%) of 349 in the maternal placebo arm (95% confidence interval for difference _2.4% to 3.8%) meeting pre-determined equivalence criteria. Nevirapine resistance at 1 month postpartum was detected in 45% of a random sample of women who received nevirapine. In the setting of maternal zidovudine and infant zidovudine plus singledose nevirapine infant HIV infection rates were similar whether women received single-dose nevirapine or placebo. This strategy avoids the potential for maternal nevirapine resistance. (authors)

Objective: To determine whether different HIV-1 genotypes present in a single cohort, in Dar es Salaam, Tanzania, showed differences in timing for transmission from mothers to their infants. Methods: We determined the maternal viral load, transmission time and the HIV-1 envelope (env) subtype of 253 HIV-1-infected infants enrolled in a randomized double-blind placebo-controlled trial to examine the efficacy of vitamins in decreasing mother-to-child transmission in Tanzania. Classification of HIV-1 positivity in utero was based on PCR results at birth. Infants were classified as intrapartum infected if they scored negative for the sample collected at birth and positive for the sample collected at 6 weeks of age. Results: We found significant differences in the distribution of transmission time according to subtype. A higher proportion of HIV-1 with subtype C env (C-env) was transmitted in utero than HIV-1 with subtype A env (A-env), subtype D env (D-env), or both combined. Conclusions: The identification of patterns of mother-to-child transmission times among HIV-1 genotypes may be useful in the selection of drug regimens for chemoprophylaxis. Based on our results, the efficacy of regimens administered only at labor may not protect as large a fraction of infants born in geographical regions with subtype C-env epidemics as compared to epidemics in regions where subtypes A-env and D-env predominate in the population.

Background: Botswana has the highest rate of HIV infection in the world estimated at 36% among the population aged 15–49 years. To improve antiretroviral (ARV) treatment delivery we conducted a cross-sectional study of the social cultural and structural determinants of treatment adherence. Methods: We used both qualitative and quantitative research methodologies including questionnaires and interviews with patients receiving ARV treatment and their health care providers to elicit principal barriers to adherence. Patient report and provider estimate of adherence (>/95% doses) were the primary outcomes. Results: One hundred nine patients and 60 health care providers were interviewed between January and July 2000; 54% of patients were adherent by self-report while 56% were adherent by provider assessment. Observed agreement between patients and providers was 68%. Principal barriers to adherence included financial constraints (44%) stigma (15%) travel/migration (10%) and side effects (9%). On the basis of logistic regression if cost were removed as a barrier adherence is predicted to increase from 54% to 74%. Conclusions: ARV adherence rates in this study were comparable with those seen in developed countries. As elsewhere health care providers in Botswana were often unable to identify which patients adhere ad-here to their ARV regimens. The cost of ARV therapy was the most significant barrier to adherence. (authors)

Objectives At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Design Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Methods Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. Results In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. Conclusion A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.