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Extended Follow-Up Confirms Early Vaccine- Enhanced Risk of HIV

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Extended Follow-Up Confirms Early Vaccine- Enhanced Risk of HIV MAJOR ARTICLE 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) Ann Duerr,1 Yunda Huang,1 Susan Buchbinder,2 Robert W. Coombs,3 Jorge Sanchez,4 Carlos del Rio,5 Martin Casapia,6 Steven Santiago,7 Peter Gilbert,1 Lawrence Corey,1 Michael N. Robertson,8 and for the Step/HVTN 504 Study Team 1Fred Hutchinson Cancer Research Center, University of Washington, Seattle, 2San Francisco Department of Public Health, California, 3Departments of Laboratory Medicine & Medicine, University of Washington, Seattle; 4Asociacion Civil Impacta Salud y Educacion, Lima, Peru; 5Department of Medicine, Emory University School of Medicine and Emory Center for AIDS Research, Atlanta, Georgia; 6Asociacion Civil Selva Amazonica, Iquitos, Peru; 7Care Resource, Miami, Florida, and 8Merck Research Laboratories, West Point, Pennsylvania Background. The Step Study tested whether an adenovirus serotype 5 (Ad5)–vectored human immunodefi- ciency 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 acquisi- tion 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. Clinical Trials Registration. NCT00095576. fi Received 15 November 2011; accepted 6 January 2012; electronically published Despite the recent success of human immunode cien- 4 May 2012. cy virus (HIV) prevention interventions such as male Presented in part: AIDS Vaccine 2010 Conference on Retroviruses and Opportu- nistic Infections, Atlanta, Georgia, 28 September 28–1 October 2010. circumcision, pre-exposure prophylaxis, and microbi- Correspondence: Ann Duerr, MD, PhD, MPH, Fred Hutchinson Cancer Research cides, an effective prophylactic HIV vaccine remains Center, 1100 Fairview Ave N, MS LE-500, PO Box 19204, Seattle, Washington the best long-term strategy for preventing HIV infec- 98109-1024 ([email protected]). The Journal of Infectious Diseases 2012;206:258–66 tion and AIDS. Several lines of evidence suggested the © The Author 2012. Published by Oxford University Press on behalf of the Infectious importance of HIV type 1 (HIV-1)–specific T cells in Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. reducing progression and even acquisition of infection. DOI: 10.1093/infdis/jis342 The Step Study, a phase 2B trial, tested the ability of 258 • JID 2012:206 (15 July) • Duerr et al an HIV vaccine using a replication-defective adenovirus sero- thereafter in the Step Study, which was anticipated to last 4 type 5 (Ad5) vector with subtype B HIV-1 gag/pol/nef inserts years. After the interim analysis and unblinding, participants to prevent HIV infection and/or to reduce early HIV viral were encouraged to continue follow-up in the Step Study and load among study participants who became infected after vac- to enroll in HVTN 504 when it opened at their site. Those cination [1]. This vaccine had been shown to provide amelio- who consented could join HVTN 504 at any point during ration of disease course in nonhuman primates after challenge their follow-up; after entering HVTN 504, HIV-uninfected with HIV-SIV hybrid virus (SHIV) [2, 3] and elicited high- participants had study visits every 3 months until they had level T-cell responses in humans. Three thousand persons, completed a combined follow-up totaling 4 years or until 31 stratified on their preexisting antibody titers to Ad5, were en- December 2009, whichever came first. Study procedures and rolled between December 2004 and March 2007. The initial data collected in the 2 studies were identical, except that planned interim analysis in September 2007 crossed prespeci- HVTN 504 contained additional behavioral assessments at fied futility boundaries for efficacy, indicating no significant 3-month intervals. Screening for HIV infections among study reduction in HIV acquisition or early viral load in participants participants was conducted in a central laboratory and used with baseline Ad5-neutralizing antibody titers of <200. Vacci- serologic tests (enzyme immunoassay) (Uni-Gold Recombin- nations were halted, and participants were unblinded. In post gen HIV Test; Trinity BioTech; or Multispot HIV-1/HIV-2 hoc analyses of data collected before unblinding, more HIV Rapid Test, Bio-Rad) that detected HIV components that were infections were seen among vaccinees than among placebo re- not in the vaccine. All infections were confirmed by Western cipients in some subgroups, notably men who were uncircum- blot and/or viral-load testing and verified by an independent, cised or who had neutralizing antibodies to Ad5 (Ad5 blinded adjudication committee. Specimens taken prior to the seropositive) at enrollment. visit when HIV was first detected serologically were tested for To assess the longer-term risk of HIV infection among Step HIV RNA (Amplicor Monitor version 1.5; Roche) to establish Study participants, the HIV Vaccine Trials Network (HVTN) the earliest time of detectable HIV infection. All participants collaborated with Merck to extend follow-up of Step Study with HIV infection were followed with viral-load and CD4+ participants. After unblinding, participants were encouraged T-cell count monitoring on a separate schedule, which was to remain in follow-up for up to 4 years from the time of first identical for the Step and HVTN 504 studies [4]; participants vaccination or until 31 December 2009, whichever came first. were referred for antiretroviral treatment according to local We report here on the risk of HIV acquisition among vacci- treatment guidelines. Institutional review board approval for nees vs placebo recipients, overall and in the subgroups of the Step Study and for HVTN 504 was obtained at all study male participants stratified by baseline circumcision and Ad5 sites, and all participants gave written informed consent. serostatus, during the entire follow-up period. We also as- sessed whether vaccine effect and the impact of potential Study Objectives and Statistical Analysis vaccine effect modifiers changed over time. All analyses described below assess the modified intent-to- treat (MITT) male cohort—that is, all men who were HIV METHODS negative at study entry and who received at least 1 vaccination. Follow-up time from enrollment in the Step Study until the Study Design and Population end of follow-up (in the Step Study or HVTN 504) (see The Step Study was conducted in regions of the world where Figure 1) was included for analysis. clade B is the predominant HIV-1 subtype (North America, the Caribbean, South America, and Australia), and the study Vaccine Effect on HIV Infection included high-risk, uninfected men who have sex with men The assumption typically made for randomized, double-blind and high-risk heterosexual men and women [1]. Participants clinical trials that risk exposure in the treatment groups is received a vaccine or placebo at baseline, 4 weeks, and 26 equal may be less warranted here due to early unblinding of weeks. Randomization was prestratified by study site, gender, treatment assignment and longer follow-up. To address this, and baseline Ad5 titer (<18, 18–200, 201–1000, >1000). In we adopted 2 modeling strategies to estimate the effect of 2007, after participants were unblinded, they were encouraged treatment on HIV incidence, namely a multivariate Cox pro- to continue to be followed in the Step study and subsequently portional hazards model that adjusts for baseline confounders in a roll-over protocol, HVTN 504. and a semiparametric method that estimates the unconditional hazard ratio (HR) using the baseline covariates as auxiliary Procedures variables [5]. Because the results are similar, only those from The Step Study procedures have been previously described [1]. the former were reported. We also displayed the treatment Briefly, participants were tested for HIV at screening, enroll- effect over time by curves of the cumulative probability of ment, 12 weeks, and 30 weeks and then every 6 months HIV infection in vaccine or placebo recipients, adjusted for Extended Follow-up Confirms Early Vaccine-Enhanced Risk • JID 2012:206 (15 July) • 259 Figure 1. Enrollment profile for enrollment of Step Study participants in protocol HVTN 504. baseline covariates via the Cox model, as well
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