A major study, FACTS 001, shows that a vaginal gel containing the antiretroviral drug, tenofovir, was not effective in preventing HIV among a large, diverse population of young South African women.

The news

STRIVE partner the Wits Reproductive Health and HIV Institute (Wits RHI) released the findings at the Conference on Retroviruses and Opportunistic Infections (CROI) on 24 February 2015 in Seattle.

The study was conducted by Follow-on African Consortium for Tenofovir Studies (FACTS). It compared HIV infection rates between two groups of sexually active HIV-negative women aged 18–30 in nine sites in South Africa:

• those assigned a vaginal gel containing tenofovir for use before and after sex
• those who received a placebo gel

New HIV infections occurred at the same rate in both groups: The HIV incidence was 4% in both groups (i.e. 4 out of 100 women acquired HIV per year). 

Two earlier trials tested tenofovir gel:

1. The CAPRISA 004 study in 2010 reported that tenofovir gel, used before and after sex, reduced the HIV infection rate by 39% among women using the product
2. The VOICE study in 2013 found no statistically significant difference between women who had been asked to use tenofovir gel on a daily basis (irrespective of whether they had sex) and those given a placebo gel.

FACTS 001 showed that the results of CAPRISA 004 could not be replicated in a large study population comprising diverse women across South Africa. In this trial, overall use of the gel by participants was low.

For STRIVE, FACTS 001 spotlights three major points:

• The urgency of addressing young women’s vulnerability to HIV infection
• The need to tackle structural and other barriers that may hinder women’s ability to consistently use effective prevention technologies
• The value of African-led excellence in a major trial like this

I would like to congratulate STRIVE colleagues at Wits RHI, as well the other trial investigators, for the successful completion of FACTS 001. Young women’s high vulnerability to HIV results from the interplay of social and economic forces, which also undermine their ability to use prevention methods. Effective HIV prevention tools for women are urgently needed. Moving forward, we need to both continue to search for products that women can use consistently within the complex realities of their lives, and also seek to address the structural forces that shape their vulnerability in the first place. 

Charlotte Watts, STRIVE Research Director, London School of Hygiene and Tropical Medicine

The study

The FACTS 001 study:

• ran from October 2011 to August 2014
• enrolled 2,059 sexually-active HIV-negative women, aged 18–30 years, at 9 research sites in urban, peri-urban and rural areas of South Africa
• conducted an informed consent process for participants before assigning them to one of the two groups
• counselled participants to use established methods to reduce HIV infection, supplied with condoms and treated for other STIs

Building on experience of previous ARV-based prevention trials with young women, the FACTS study ran an intensive adherence programme, including:

• a client-centred counselling approach
• motivational text messages
• monthly social clubs for participants to discuss adherence challenges and broader social, economic and relationship issues that might reduce their ability to use the gel

Despite all these interventions, adherence was insufficiently consistent.

Great care was taken to ensure that the design of FACTS 001 was sufficiently robust to deliver an authoritative answer and that the conduct of the trial met the highest quality standards. We now know that in this population FACTS 001 disappointingly did not support the results of the CAPRISA 004 study, but it does help chart the course of future research on HIV prevention technology for women, and that in itself has been a worthy investment of resources.

Professor Glenda Gray, FACTS Protocol Co-Chair and President of the South African Medical Research Council

The findings

There was no difference in the rate of new HIV infections occurring in the vaginal tenofovir gel group compared with the placebo group (i.e. there was no evidence that tenofovir gel was effective in preventing HIV in this population).

Out of 2,059 enrolled participants, a total of 123 HIV infections occurred, with 61 new HIV infections in the group assigned to tenofovir gel and 62 in the group assigned to placebo. The HIV incidence was 4% in both groups (i.e. four out of 100 women acquired HIV per year). 

The study measured gel use before and after sex in two ways:

1. counts of returned used applicators from all women in the trial
2. tenofovir drug levels in vaginal samples at quarterly visits from 214 participants in the tenofovir gel group

Using both these measures, the study found that participants appeared to use the gel as directed at least half of the time, but only a small proportion were able to use the gel consistently with sex. Of the 214 women included in the sub-study, 65% had drug detected in some samples and 22% had tenofovir drug detected in all samples. 

The study found no overall significant association between consistent gel use and HIV protection when analysing returned used applicators from all women in the trial. However, HIV acquisition rates were lower in women in the sub-study who reported recent sex and had detectable tenofovir in vaginal fluids.

Vaginal tenofovir gel was safe when used in this population.

A product that is applied around the time of sex may be suitable for some women, but it did not meet the needs of the majority in our study, most of whom were young, single and lived with their parents. Methods that are easier for women to incorporate into their lives are likely to be more effective. 

Professor Helen Rees, FACTS Protocol Chair and Executive Director of Wits RHI in Johannesburg

The research consortium

The Follow-on African Consortium for Tenofovir Studies (FACTS) is:

• an entirely South African-led research consortium
• the first South African group to have successfully undertaken a large HIV clinical trial of this nature
• headed by Protocol Chair Professor Helen Rees, Executive Director of Wits Reproductive Health and HIV Institute (Wits RHI), and Protocol Co-chair Professor Glenda Gray, President of the SA Medical Research Council
• coordinated from the Wits RHI in Johannesburg with data management coordinated by the Perinatal HIV Research Unit (PHRU) in Soweto, South Africa.

Other South African research institutes participating in the FACTS consortium include the Aurum Institute; the Desmond Tutu HIV Foundation; Maternal, Adolescent and Child Health (MatCH Research); the South African Medical Research Council; Mecru Clinical Research Unit (MeCRU); the Qhakaza Mbokodo Research Clinic; the Setshaba Research Centre and the University of Cape Town.

FACTS 001 not only provided critical new evidence for the HIV prevention field, the study also developed the research skills of many emerging African scientists across the country. 

Professor Glenda Gray

The FACTS 001 trial was funded by the South African Departments of Science and Technology and Health, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through USAID and the Bill & Melinda Gates Foundation. It was sponsored by the US non-profit scientific organisation, CONRAD, which – together with the pharmaceutical company Gilead – provided gel products for the study.

The future

The high HIV incidence measured in FACTS 001 reinforces the need for continued research to develop woman-centred HIV-prevention methods. Two Phase III trials – the Ring Study and Aspire – are testing a long-acting vaginal ring containing the drug, dapivirine. Both are nearing completion in various African countries. Other products, including a long-term injectable ARV and an HIV vaccine, are also now in clinical trials. 

Interviews with participants throughout the study taught us that HIV prevention tools for women must be convenient and take account the complex social and economic realities of their lives.

Professor Helen Rees