The announcement that the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study did not demonstrate protection against HIV in women prescribed daily tenofovir gel is a grave disappointment to CAPRISA.
Professor Salim Abdool Karim, Director of CAPRISA, and Pro Vice-Chancellor (Research) at the University of KwaZulu-Natal, who is a site investigator in the VOICE trial, said that “These results were totally unexpected as there is good evidence from laboratory research, animal studies and human trials showing that tenofovir gel prevents HIV. However, science does not always produce the answer we hope for. This is particularly pertinent when a drug’s effectiveness is dependent on a complex combination of the biological activity of the drug and the human behaviour influencing use of the drug as prescribed during the study. I look forward to seeing the complete results and, in particular, an analysis of whether the drug levels in the female genital tract provides any clues to the study’s outcome.”
The VOICE study is designed to test whether antiretrovirals, either as tablets or as gels, are safe and effective in preventing sexual transmission of HIV in women from South Africa, Zimbabwe and Uganda. CAPRISA enrolled 623 of the 5029 women in the VOICE study; 360 at the CAPRISA eThekwini clinic in Durban, which was also one of the sites where the CAPRISA 004 study was conducted, and 263 at the Aurum clinic in Klerksdorp.
On 16 September 2011, the tenofovir tablet component of the VOICE study was discontinued after interim results showed that it was no better than placebo in preventing HIV in the study women, in contrast to results of a study (PartnersPrEP) which reported 62% reduction in HIV incidence in HIV discordant couples using tenofovir tablets daily as prophylaxis. Two months later, on 17 November 2011, a scheduled review of the VOICE study’s data by the independent Data Safety and Monitoring Board (DSMB) revealed that the incidence rate of HIV infection in the women assigned to daily tenofovir gel was 6.0% compared to 6.1% in women assigned to placebo gel. Based on this latest review, the tenofovir gel component of the VOICE study is being discontinued while the tenofovir/emtricitabine tablet component is continuing to study completion.
Following the announcement in July 2010 that the CAPRISA 004 study demonstrated that tenofovir gel used before and after sex reduced HIV infection by 39% and genital herpes by 51%, there was high hope that the VOICE study of daily tenofovir gel would show similar promising results. As highlighted in previous microbicide studies, to be able to demonstrate effectiveness of a microbicide gel, women have to consistently use the right amount of the right drug to get the right drug levels in the right cells at the right time. At present, it is unclear whether the VOICE study’s unexpected outcome could be due to inadequate or non-use of the gel by women in the study, to insufficient drug levels in women at the time of HIV exposure during sex, or to some other reason. A detailed analysis of the study data, anticipated in late 2012, will be critical to understanding the reasons for these perplexing tenofovir gel results as well as the VOICE trial’s recently announced surprising results that tenofovir tablets also did not prevent HIV infection.
There is a substantial body of evidence on the effect of tenofovir on HIV infection – some of which contributed to the compelling rationale for undertaking the VOICE study - which is the only trial to study both tenofovir tablets and tenofovir gel. Research on tenofovir gel to date has shown that:
Tenofovir gel prescribed for use before and after sex reduced the chance of acquiring HIV by 39%. Different types of analyses in the CAPRISA 004 study showed consistent results ranging from 39% to 45% protection.
Tenofovir gel prescribed for use before and after sex reduced genital herpes acquisition by 51%. A recent laboratory study confirmed the mechanism of action of high doses of tenofovir, which is seen with gel but not tablets, against HSV-2 and provided further evidence from tissue culture and animal models for this effect.
Tenofovir gel demonstrated a clear dose-response relationship - the higher the adherence, the higher the level of HIV protection, reaching 54% protection against HIV in the most consistent gel users.
Tenofovir gel showed a strong correlation between tissue concentrations of the drug and the level of protection against HIV infection. The higher the level of drug detected in the genital compartment of women in the CAPRISA 004 trial, the greater the level of protection against HIV infection.
- Tenofovir gel has been shown repeatedly to be highly effective in the cervical explant tissue challenge model and in monkeys - in the recent monkey challenge study conducted by the CDC, not a single monkey exposed to SIV after application of tenofovir gel became infected.
Taken together, this set of promising findings makes continued research on tenofovir gel imperative and provides a strong rationale for the ongoing FACTS 001 study, which is being conducted by a consortium of South African researchers to assess the effectiveness of coital use of tenofovir gel in 2200 women in South Africa. It is anticipated that the FACTS 001 study, together with the VOICE study, is well placed to provide new insights into tenofovir gel and HIV infection in women. In light of these new results from the VOICE study, CAPRISA has initiated a review of its portfolio of tenofovir gel studies including CAPRISA 008, which provides post-trial access to tenofovir gel for women from the CAPRISA 004 trial and assesses implementation of tenofovir gel through family planning clinics. As additional data from the VOICE trial become available, CAPRISA will continually assess its tenofovir gel research plans – with the overall goal of empowering women with a safe and effective microbicide.
Young women in Africa bear the brunt of the HIV epidemic, with HIV rates up to 8 higher than the rates in their male counterparts. For women unable to assure mutual monogamy or consistent condom use, microbicides are a critically important technology. The need for a woman-controlled HIV prevention technology remains urgent.
Released on: 25 November 2011
CAPRISA (www.caprisa.org) is an AIDS research institute of the University of KwaZulu-Natal and Columbia University. Its headquarters are at the Nelson R Mandela School of Medicine, University of KwaZulu-Natal in Durban, South Africa. CAPRISA is a designated UNAIDS Collaborating Centre for HIV Prevention Research. The main goal of CAPRISA is to undertake globally relevant and locally responsive research that contributes to understanding HIV pathogenesis, prevention and epidemiology, as well as the links between tuberculosis and AIDS care. CAPRISA comprises four research programmes: HIV pathogenesis & vaccines, HIV and TB treatment, Microbicides, and HIV prevention and epidemiology.
Contact: Salim S. Abdool Karim, work: +27 31 260 4550, cell: +27 82 7769705, firstname.lastname@example.org
NIAID Statement: NIH Discontinues Tenofovir Vaginal Gel in ‘VOICE’ HIV Prevention Study… click here