Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition

Abstract

Background: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear.

Methods: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC₈₀) of acquired isolates was measured with the TZM-bl assay.

Results: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC₈₀ <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates.

Conclusions: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).

Figure 1.. Overall Cumulative Incidence of HIV-1 Acquisition and Prevention Efficacy.

Panels A and B show the cumulative incidence of human immunodeficiency virus type 1 (HIV-1) acquisition in the HIV Vaccine Trials Network (HVTN) 704/HIV Prevention Trials Network (HPTN) 085 trial (conducted in the Americas and Europe and involving persons who were assigned male sex at birth or are transgender and who have sex with cisgender men or transgender persons) and HVTN 703/HPTN 081 (involving at-risk heterosexual women in sub-Saharan Africa), respectively. Participants in the low-dose group received 10 mg of VRC01 per kilogram of body weight, those in the high-dose group received 30 mg per kilogram, and those in the placebo group received saline placebo. The insets show the same data on an enlarged y axis. Panel C shows the annualized incidence of HIV-1 acquisition and a forest plot of prevention efficacy at the week 80 visit in each trial and pooled over both trials. CI denotes confidence interval.

Figure 2.. Prevention Efficacy of VRC01 against HIV-1 of Different in Vitro Sensitivities (IC₈₀) to VRC01.

Each acquired virus (162 infected participants) was evaluated as an Env-pseudotyped virus in the TZM-bl target cell assay. Panel A shows prevention efficacy (pooled VRC01 groups vs. placebo) over the 80-week trial period against each virus for the three prespecified 80% inhibitory concentration (IC₈₀) categories: less than 1 μg per milliliter, 1 to 3 μg per milliliter, and greater than 3 μg per milliliter. Panel B shows a forest plot of prevention efficacy (pooled VRC01 groups vs. placebo) at the week 80 visit for the three prespecified IC₈₀ categories.

Figure 3.. Cumulative Incidence of HIV-1 Infection and Prevention Efficacy According to IC₈₀ Category.

Panel A shows the estimated prevention efficacy (pooled VRC01 groups vs. placebo) at the week 80 visit with 95% confidence intervals plotted against quantitative IC₈₀. Box-and-whisker plots above the graph show the distribution of acquired virus IC₈₀ values for each primary end-point infection, stratified according to treatment group. A red triangle indicates an acquired virus in the designated VRC01 group, and a blue circle an acquired virus in the placebo group. In the box-and-whisker plots, the right and left sides of the box indicate the interquartile range, the vertical line the median, and the whiskers the range. Data on virus neutralization were missing for eight infections in HVTN 704/HPTN 085 and four infections in HVTN 703/HPTN 081; these cases were excluded. Panel B shows the distribution of viral loads at detection, stratified according to treatment group and IC₈₀ category. A red dot indicates an acquired virus in the designated VRC01 group, and a blue dot an acquired virus in the placebo group. In the box-and-whisker plots, the top and bottom of the box indicate the interquartile range, the horizontal line the median, and the whiskers the range. The shapes drawn around the box plots in Panel B are violin plots showing the kernel probability density of the viral load data at different viral load values.