Effectiveness of Cellulose Sulfate Vaginal Gel for the Prevention of HIV Infection: Results of a Phase III Trial in Nigeria

Tulane University, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(11):e3784. DOI: 10.1371/journal.pone.0003784
Source: PubMed


This trial evaluated the safety and effectiveness of 6% cellulose sulfate vaginal gel in preventing male-to-female vaginal transmission of HIV, gonorrhea and chlamydial infection.
This Phase III, double-blind, randomized, placebo-controlled trial was conducted between November 2004 and March 2007 in Lagos and Port Harcourt, Nigeria. We enrolled 1644 HIV-antibody negative women at high risk of HIV acquisition. Study participants were randomized 1:1 to cellulose sulfate or placebo and asked to use gel plus a condom for each act of vaginal intercourse over one year of follow-up. The participants were evaluated monthly for HIV, gonorrhea and chlamydial infection, and for adverse events.
The trial was stopped prematurely after the data safety monitoring board of a parallel trial concluded that cellulose sulfate might be increasing the risk of HIV. In contrast, we observed fewer infections in the active arm (10) than on placebo (13), a difference that was nonetheless not statistically significant (HR = 0.8, 95% CI 0.3-1.8; p = 0.56). Rates of gonorrhea and chlamydial infection were lower in the CS group but the difference was likewise not statistically significant (HR = 0.8, 95% CI 0.5-1.1; p = 0.19 for the combined STI outcome). Rates of adverse events were similar across study arms. No serious adverse events related to cellulose sulfate use were reported.
Cellulose sulfate gel appeared to be safe in the evaluated study population but we found insufficient evidence that it prevented male-to-female vaginal transmission of HIV, gonorrhea or chlamydial infection. The early closure of the trial compromised the ability to draw definitive conclusions about the effectiveness of cellulose sulfate against HIV. NCT00120770.

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Available from: Saïd Abdellati, Jul 14, 2014
    • "A: μ 30 y Invisible Condom ® formulations and applicator were well-tolerated when applied intravaginally bid for 2 w 70–86% compliance; however, only 20% of gel applications coincided with sex[23]Cellulose[Cotonou, Benin]gel use: 63% AWMP, 94% AWOP (last 7 d);[Kampala, Uganda]gel use: 60% AWMP, 85% AWOP (last 7 d);[Durban, South Africa]gel use: 91% AWMP, 95% AWOP (last 7 d);[Chennai, India]gel use: 38% AWMP, 91% AWOP (last 7 d);[24][25](Continued)[Isipingo, Durban, KwaZulu-Natal]Gel: μ 92% at LS (SELF); CLS: μ 58% (SELF); μ 55% covered acts[26][Masaka, Uganda]A: μ 32 y; E: 2% ≥ secondary; NP: 0% >1 partner (last 1 w); CF: median 1 APW; AI: <0.5% (last 4 w); CLS: 70%; FP: 27%;[Mwanza, Tanzania]A: μ 30 y; E: 5% ≥ secondary; NP: 3% >1 partner (last 1 w); CF: median 1 APW; AI: <0.5% (last 4 w); CLS: 33%; FP: 50%;[CF: median 2 APW; AI: 46% (ever); CLS: 61%; FP: 89%;[Kamwala, Zambia]A: μ 23 y; E: 9% ≥ secondary; NP: 3% >1; CF: median 3 APW; AI: 3% (ever); CLS: 77%; FP: 98%;[Chitungwiza, Zimbabwe]A: μ 26 y; E: 29% ≥ secondary; NP: 3% >1; CF: median 5 APW; AI: 1% (ever); CLS: 87%; F: 99%[Harare, Zimbabwe][31](Continued) "

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    • "Another polyanion, Ushercell (cellulose sulfate; Polydex Pharmaceuticals, Toronto, ON, Canada), a contraceptive product possessing anti-HIV activity by binding to the V3 loop of gp120 of the HIV-1 envelope can inhibit the entry of both CXCR4 and CCR5-tropic virus.45 However, different clinical trials indicated that it has no beneficial effect in curtailing the risk of HIV transmission and its use may increase the risk of HIV infection, possibly owing to toxicity of the active ingredient or the hyperosmolar gel vehicle (iso-osmolar placebo).46,47 "
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    ABSTRACT: Microbicides, primarily used as topical pre-exposure prophylaxis, have been proposed to prevent sexual transmission of HIV. This review covers the trends and challenges in the development of safe and effective microbicides to prevent sexual transmission of HIV Initial phases of microbicide development used such surfactants as nonoxynol-9 (N-9), C13G, and sodium lauryl sulfate, aiming to inactivate the virus. Clinical trials of microbicides based on N-9 and C31G failed to inhibit sexual transmission of HIV. On the contrary, N-9 enhanced susceptibility to sexual transmission of HIV-1. Subsequently, microbicides based on polyanions and a variety of other compounds that inhibit the binding, fusion, or entry of virus to the host cells were evaluated for their efficacy in different clinical setups. Most of these trials failed to show either safety or efficacy for prevention of HIV transmission. The next phase of microbicide development involved antiretroviral drugs. Microbicide in the form of 1% tenofovir vaginal gel when tested in a Phase IIb trial (CAPRISA 004) in a coitally dependent manner revealed that tenofovir gel users were 39% less likely to become HIV-infected compared to placebo control. However, in another trial (VOICE MTN 003), tenofovir gel used once daily in a coitally independent mode failed to show any efficacy to prevent HIV infection. Tenofovir gel is currently in a Phase III safety and efficacy trial in South Africa (FACTS 001) employing a coitally dependent dosing regimen. Further, long-acting microbicide-delivery systems (vaginal ring) for slow release of such antiretroviral drugs as dapivirine are also undergoing clinical trials. Discovering new markers as correlates of protective efficacy, novel long-acting delivery systems with improved adherence in the use of microbicides, discovering new compounds effective against a broad spectrum of HIV strains, developing multipurpose technologies incorporating additional features of efficacy against other sexually transmitted infections, and contraception will help in moving the field of microbicide development forward.
    Full-text · Article · Oct 2013 · HIV/AIDS - Research and Palliative Care
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    • "Unfortunately, the clinical results were disappointing. One of the cellulose sulfate trials even showed higher HIV seroincidence in the cellulose sulfate arm [9], while another efficacy trial indicated no inhibitory effect of cellulose sulfate on the risk of HIV-1 transmission [10]. Efficacy trial of carrageenan demonstrated that carrageenan gel was safe, but lacked efficacy against HIV-1 transmission [11]. "
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    ABSTRACT: Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides.
    Full-text · Article · Mar 2013 · PLoS ONE
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