title: PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial.
abstract: BACKGROUND
  Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa.
  
  
  METHODS
  Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212.
  
  
  RESULTS
  We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86-91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8-5·4] for 0·5% PRO2000 vs 4·3 [3·6-5·2] for placebo, hazard ratio 1·05 [0·82-1·34], p=0·71), and at discontinuation (4·7 [3·8-5·8] for 2% PRO2000 gel, 3·9 [3·0-4·9] for 0·5% PRO2000 gel, and 3·9 [3·1-5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9-5·4) in the 0·5% PRO2000 group and 3·9 (3·2-4·6) in the placebo group; and was 4·5 (3·7-5·5) in the 2% PRO2000 group at discontinuation.
  
  
  CONCLUSIONS
  Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use.
  
  
  BACKGROUND
  UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.
authors.affiliation: MRC Clinical Trials Unit, London, UK. smc@ctu.mrc.ac.uk
authors.forename: Sheena
authors.initials: S
authors.lastname: McCormack
authors.forename: Gita
authors.initials: G
authors.lastname: Ramjee
authors.forename: Anatoli
authors.initials: A
authors.lastname: Kamali
authors.forename: Helen
authors.initials: H
authors.lastname: Rees
authors.forename: Angela M
authors.initials: AM
authors.lastname: Crook
authors.forename: Mitzy
authors.initials: M
authors.lastname: Gafos
authors.forename: Ute
authors.initials: U
authors.lastname: Jentsch
authors.forename: Robert
authors.initials: R
authors.lastname: Pool
authors.forename: Maureen
authors.initials: M
authors.lastname: Chisembele
authors.forename: Saidi
authors.initials: S
authors.lastname: Kapiga
authors.forename: Richard
authors.initials: R
authors.lastname: Mutemwa
authors.forename: Andrew
authors.initials: A
authors.lastname: Vallely
authors.forename: Thesla
authors.initials: T
authors.lastname: Palanee
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sookrajh
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lacey
authors.forename: Janet
authors.initials: J
authors.lastname: Darbyshire
authors.forename: Heiner
authors.initials: H
authors.lastname: Grosskurth
authors.forename: Albert
authors.initials: A
authors.lastname: Profy
authors.forename: Andrew
authors.initials: A
authors.lastname: Nunn
authors.forename: Richard
authors.initials: R
authors.lastname: Hayes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weber
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000998:Antiviral Agents / Q000008:administration & dosage*; D017280:Condoms / Q000706:statistics & numerical data; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000453:epidemiology / Q000517:prevention & control*; D015497:HIV-1; D006801:Humans; D008875:Middle Aged; D009282:Naphthalenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects; D011108:Polymers / Q000008:administration & dosage* / Q000009:adverse effects; D012725:Sexual Behavior; D012749:Sexually Transmitted Diseases / Q000517:prevention & control; D014622:Vaginal Creams, Foams, and Jellies / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D009282:Naphthalenesulfonates; C120231:PRO 2000; D011108:Polymers; D014622:Vaginal Creams, Foams, and Jellies