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)

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00095576.

Figure 1.

Enrollment profile for enrollment of Step Study participants in protocol HVTN 504.

Figure 2.

Overall and subgroup cumulative incidence of human immunodeficienvy virus (HIV) infections over 48 months of follow-up. Covariate-adjusted probability of HIV infection curves and their differences (placebo group − vaccine group [P – V]) are shown for vaccine and placebo recipients overall and by baseline circumcision status and adenovirus serotype 5 (Ad5) antibody serostatus: uncircumcised, Ad5-seropositive men (Uncirc/Ad5⁺) (A); uncircumcised, Ad5-seronegative men (Uncirc/Ad5⁻) (B); circumcised, Ad5-seropositive men (Circ/Ad5⁺) (C); and circumcised, Ad5-seronegative men (Circ/Ad5⁻) (D).

Figure 3.

Estimated probability of increased risk of human immunodeficiency virus (HIV) infection associated with vaccination as a function of baseline adenovirus serotype 5 (Ad5) titer (natural log). The Ad5 titers below the cut-off of 18 were treated as equal to 18 for analysis. The solid curve is the point estimate, and the dashed lines are the 95% point-wise confidence intervals.

Figure 4.

Unadjusted instantaneous hazard ratio (vaccinees vs placebo recipients [V:P]) for the population of uncircumcised and/or adenovirus serotype 5 (Ad5)–seropositive modified intent-to-treat men during the entire follow-up period. All data were used in constructing the curves, but several of the first and last months of follow-up were not included in the figure to avoid unstable confidence interval estimates.