Trial to Evaluate PRO 2000/5 Gels for the Prevention of Vaginally Acquired HIV Infection

• Acquisition of HIV infection before or at the 12 month time point, confirmed in a central laboratory, in participants confirmed to be HIV negative at enrollment [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  
• Grade 3 (severe) or 4 (life-threatening) clinical or laboratory adverse event confirmed on examination or repeat testing, respectively [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  

• Acquisition of HIV infection before or at the 6, 9, or beyond 12 month time points, confirmed in a central laboratory, in participants confirmed to be HIV negative at enrollment [ Time Frame: 6, 9 and 12 months ] [ Designated as safety issue: Yes ]
  
• HSV-2 incidence rates by the 9 month time point in participants uninfected at enrollment. Although prevalence rates are high, 75% - 85% in some sites, data from feasibility studies indicate that incidence rates are also likely to be high [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
  
• HSV-2 incidence rates by the 12 month time point in participants uninfected at enrolment. Although prevalence rates are high, 75% - 85% in some sites, data from feasibility studies indicate that incidence rates are also likely to be high [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  
• Cross-sectional prevalence of Neisseria gonorrhoeae at 24 weeks, determined by a positive nucleic acid amplification assay [ Time Frame: 24 weeks/6 months ] [ Designated as safety issue: Yes ]
  
• Cross-sectional prevalence of Chlamydia trachomatis at 24 weeks, determined by a positive nucleic acid amplification assay [ Time Frame: 24 wks/6 months ] [ Designated as safety issue: Yes ]
  

The HIV pandemic continues with an estimated 13,000 new infections each day, the vast majority of which are acquired through heterosexual intercourse. Although consistent and correct use of condoms by men remains the most effective form of protection from heterosexually acquired HIV, women are not always able to negotiate condom use. An effective prophylactic vaccine remains a key objective, but development is slow because of virus variability and difficulty in determining the immunological correlates of protection. Vaginal microbicides are being developed in response to the urgent need for an HIV prevention method that women can control. Licensed spermicides containing nonoxynol-9 (N-9), which has potent anti-HIV activity in vitro, were the first products to be investigated as potential microbicides. However, the association of N-9 and other products belonging to this class (surfactants) with genital epithelial disruption, histologically determined genital inflammation, and reduction in populations of vaginal lactobacilli led to concerns that their use could enhance the risk of HIV transmission. Early Phase 3 studies of N-9 products yielded conflicting results, but more recently, a multicenter randomized placebo-controlled trial of a low dose N-9 formulation demonstrated an increased incidence of HIV infection in the N-9 group compared to placebo. These findings have intensified efforts to develop agents with a more favorable toxicity profile. At least four of these have entered trials to assess effectiveness in preventing vaginally acquired HIV infection: Buffer Gel, Carraguard, cellulose sulfate and PRO 2000/5 Gel. Protocol MDP 301 describes a randomized placebo-controlled trial design to explore the safety and efficacy of two concentrations of PRO 2000/5 Gel.

Participant recruitment and follow-up is complete. Between October 2005 and August 2008, 9404 eligible, sexually active, HIV-uninfected women were enrolled at six or more sites in Africa. Up until February 2008, participants were randomly assigned to 0.5% or 2% PRO 2000/5 Gel treatment arms or a placebo gel arm. Following a recommendation by the Independent Data Monitoring Committee that the 2% PRO2000/5 Gel treatment arm should not continue as there was no more than a small chance of demonstrating benefit, participants enrolled after February 13, 2008 were randomly assigned to the 0.5% PRO 2000/5 gel treatment arm or placebo arm. Participants were instructed to apply a single dose of study gel 1 hour or less before every act of vaginal intercourse using a single-use pre-filled applicator. Participants also receive risk-reduction counseling and condoms, and STD testing. Most study participants were followed for 12 months. A cohort of sero-discordant couples enrolled in Uganda was followed for up to 24 months.

The primary efficacy outcome measure is acquisition of HIV infection at the 12 month time point. Secondary outcomes include measures of HIV infection at the 6, 9 and more than 12 month time points, infection by HSV-2, Neisseria gonorrhoeae, Chlamydia trachomatis, and adverse events.