Globally, 17.5 million women are living with HIV. Women now represent more than 60% of people living with HIV in Africa, and in several southern African countries, young women are at least three times more likely to be HIV-positive than young men. Most women acquire HIV from sexual intercourse with their male partners. Traditional ABC approaches to reducing the risk of HIV from sex are often difficult, sometimes impossible, for women to implement. Women urgently need new HIV prevention technologies, and an effective microbicide could turn the tide of the HIV pandemic.

CAPRISA is conducting effectiveness trials of new generation microbicides as well as studies on genital tract immunology and factors in the vagina which may influence the risk of HIV transmission.

Why is CAPRISA conducting a trial of tenofovir gel for HIV prevention?

When did the trial begin and how was it designed?

What is a microbicide?

Why is CAPRISA's tenofovir gel study important?

Where are the clinical trial sites located?

What candidate microbicide is being studied?

If women participating in this study use condoms, how will you find out if the gels are effective?

When will the trial be completed and results known?

How does this trial differ from other microbicide trials?

What approvals were required for this trial to get underway?

Do women participating in the study provide informed consent?

What are the medical benefits for women participating in the study?

What is being done to ensure the safety of the study participants?

What happens if a participant acquires HIV during the study?

If tenofovir gel does prove to be effective at preventing HIV infection in this trial, how will it be made available?

About the organizations conducting this trial

Why is CAPRISA conducting a trial of tenofovir gel for HIV prevention?

The CAPRISA 004 study is being conducted to establish whether the vaginal use of tenofovir gel is safe and whether it can prevent male-to-female sexual transmission of HIV. Specifically, researchers conducting CAPRISA 004 are evaluating the safety and effectiveness of tenofovir in comparison to a placebo gel (a matched gel with no active ingredient) in sexually active women at risk for human immunodeficiency virus (HIV) infection in South Africa. read more: Download PDF

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When did the trial begin and how was it designed?

CAPRISA 004 is a phase IIb, two-arm, double-blind, randomized, controlled trial assessing the safety and effectiveness of 1% tenofovir gel, a candidate vaginal microbicide, in 980 sexually active HIV uninfected women at risk for HIV infection in South Africa. After each participant provides informed consent and undergoes extensive risk-reduction counseling, each participant will be randomly assigned to one of the two study groups: tenofovir gel or placebo gel. Women will be provided with a supply of single-use, pre-filled applicators according to their randomisation and will be given instructions to apply a first dose of the assigned study product within 12 hours prior to coitus and insert a second dose as soon as possible within 12 hours after coitus. They will be advised to use only two doses of gel in a 24-hour period. Because both gels and applicators look the same, neither researchers nor participants know who has been assigned to use which gel during the 16 - to 30-month period they are in the study. Participants in both groups also receive condoms, intensive counseling, and other routine interventions for reducing HIV risk, such as treatment of symptomatic sexually transmitted infections. The trial, which started on 23 May 2007, is being conducted at CAPRISA's Vulindlela and eThekwini Clinical Research Sites, and will run for a total of 30 months. Results, which are expected in 2010, should indicate if tenofovir gel is safe and effective as a vaginal microbicide to prevent HIV infection.

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What is a microbicide?

Microbicides are substances that are designed to reduce or prevent the sexual transmission of HIV or other sexually transmitted infections when applied either in the vagina or rectum. In South Africa, they are being tested for the prevention of male-to-female transmission when applied vaginally. Such products would let women at risk of HIV have greater control over preventing infection. Microbicides are formulated as foams, gels, creams, suppositories, films, and even as a sponge or vaginal ring. No such products are currently on the market or available to the public. However, scientists around the world - including South African researchers Durban, Johannesburg, Pretoria, and Cape Town -- are conducting research on several potential microbicides. Of these, 10 have proven safe and effective in animals and are now being tested in people in the United States, Africa and India. Several microbicide products are being tested in clinical trials in South Africa to establish whether they can prevent HIV infection in women. read more: Download PDF

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According to statistics from UNAIDS, nearly half of the 39.5 million people living with HIV/AIDS worldwide are women. In sub-Saharan Africa, women account for 59% of all infected adults. Young women are especially vulnerable. Worldwide, 60% of the 15- to 24-year-olds with HIV are women. In sub-Saharan Africa, women aged 15 to 24 with HIV represent 76% of the total cases in that age group, outnumbering their male peers by three to one.

Between 70 and 90% of all HIV infections in women are due to heterosexual intercourse. Moreover, women are twice as likely as their male partners to acquire HIV during sex, due in part to biological factors that make women more vulnerable. Notwithstanding the greater vulnerability of women, current options to reduce transmission and acquisition of HIV infection remain limited for women. New technologies to prevent the sexual transmission of HIV in women are urgently needed. Although correct and consistent use of male condoms has been shown to prevent HIV transmission, women are often unable to convince their male partners to use condoms.

If proven effective, microbicides could be an important prevention approach for many women who cannot rely on abstinence or on their male partners using condoms. Even a partially effective microbicide could have a profound impact on the dynamics of HIV transmission. According to mathematical modeling conducted by the London School of Hygiene and Tropical Medicine, 2.5 million HIV infections could be averted over 3 years if a microbicide with 60% effectiveness were used in 73 low-income countries.

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The CAPRISA 004 tenofovir gel trial is being conducted at two sites in South Africa; the CAPRISA eThekwini Clinical Research Site, located in central Durban, and the Vulindlela Clinical Research Site, located in a rural setting approximately 90 minutes outside of Durban.

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The candidate microbicide, tenofovir gel, is an antiviral gel manufactured by Gilead Sciences, Inc., and licensed to CONRAD, a non-profit research organization based in the United States. Tenofovir gel is designed to protect against HIV infection by inhibiting viral replication in susceptible cells. The active ingredient, Tenofovir, is a highly specific reverse transcriptase inhibitor that prevents the normal reverse transcription of viral RNA into DNA in host (infected) cells. An oral formulation of tenofovir was approved by the US Food and Drug Administration (FDA) in October 2001. It has since been actively marketed by Gilead Sciences for the treatment of HIV and is used by thousands of individuals infected with HIV in many countries.

Tenofovir gel has undergone extensive laboratory study and, before CAPRISA 004, was tested in other early-phase human safety clinical trials. The pre-clinical laboratory research and studies in animals suggested the tenofovir gel may prevent sexual transmission of HIV, while the early-phase clinical studies indicated the gels were well tolerated and safe to proceed to further testing in larger trials.

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Researchers provide participants free condoms and extensive, risk-reduction counseling in order to reduce the risk of HIV for all women in the trial. If every single participant used a condom for every act of sexual intercourse during the study, it would be nearly impossible for researchers to evaluate the effectiveness of the microbicides, as condoms provide protection against infection. But in reality, women are not always able to convince their partners to use condoms or to use them all the time. The effectiveness of the gel is therefore assessed through the protection it may provide when condoms are not used in coitus. The study also takes into account any additional benefit of the gel when used by participants in those coital acts which involve condoms.

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The study is expected to be completed in December 2009. Results of the entire trial are expected in early 2010.

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This is the first effectiveness study of an antiretroviral drug formulated as a microbicide gel for prevention of HIV. It is also the first microbicide trial where the consortium of partners is being led by a developing country institution - the Centre for the AIDS Programme of Research in South Africa (CAPRISA) based at the University of KwaZulu-Natal in Durban, South Africa. This is the first microbicide trial being co-funded by a developing country government agency, namely LifeLab, and is the first microbicide trial where public sector pricing has been secured for Southern African Development Community (SADC) countries and a voluntary license for local South African manufacture, if cheaper, has been secured up front.

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The trial underwent extensive and rigorous review, including by South African regulatory authorities, the Medicines Control Council, and the ethics committees of the University of KwaZulu-Natal and Family Health International. The University of KwaZulu-Natal Ethics Committee reviewed this study protocol to ensure that study is scientifically valid and ethically conducted as well as to provide oversight throughout the duration of the trial. In addition, both sites conducting the trial have a local community advisory board to facilitate community involvement in the trial.

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Each woman is provided with detailed information on the study. The informed consent process ensures that women understand the study procedures as well as the risks and benefits of the study; the need to practice safer sex behaviors regardless of which study group they are assigned to; the importance of adherence to study treatment; and the potential medical risks associated with participation. Participants are under no obligation to participate and may leave the study, without consequence, at any time. Once the woman has understood the study, she is then approached to provide written informed consent prior to both screening and enrollment using forms translated into Zulu.

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Participants receive free risk-reduction counseling and testing for HIV as well as routine physical and pelvic exams and contraceptive counseling and services. In addition, testing for and treatment of other non-HIV sexually transmitted infections are provided free of charge to both participants and their partners.

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CAPRISA 004 was designed according to the most rigorous international ethical standards and every possible measure is taken to protect the wellbeing of participants. CAPRISA 004 follows strict national and international procedures for monitoring and reporting, including regular reviews by a Protocol Safety Review Team (PSRT) as well an independent Data and Safety Monitoring Board (DSMB). The PSRT meets on a quarterly basis to review overall blinded study safety information while the DSMB regularly reviews trial data (including unblinded data when needed) to ensure that participants are not being adversely affected by the microbicide. If a DSMB has any safety concerns, it may, at any time, recommend that a study modify its procedures or be discontinued. Likewise, a DSMB may choose to halt a trial if there is compelling evidence for a therapy's effectiveness.

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CAPRISA 004 is being conducted in settings where there is high background HIV prevalence and many women are at high risk of infection. Potential study participants who volunteer to undergo HIV testing as part of the study screening process may discover that they are HIV-positive. The CAPRISA 004 researchers will provide all HIV test results with post-test counseling and these volunteers will be referred to local AIDS treatment services. Such services include the PEPfAR and Global Fund-funded CAPRISA AIDS Treatment (CAT) Programme as well as other local facilities that provide medical and psychosocial AIDS care and support.

The wellbeing of the women in the trial is our highest concern. CAPRISA 004 researchers do their best to reduce participants' risk. The study provides condoms and frequent HIV prevention counseling to participants. Still, some women may become infected during participation in the study if they have unprotected sex with an infected partner. Uninfected study participants who seroconvert during the follow-up period of the study will have a number of options available to them for care. They may choose to participate in one of the long-term CAPRISA acute infection cohort studies, which have excellent provisions for care, antiretroviral therapy and support for those infected with HIV. Women who do not wish to continue in any of these studies after becoming infected will be referred to their preferred AIDS care provider: this could include the CAT Programme, or government or non-governmental AIDS care services of their choice for ongoing clinical management and care.

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Depending on the results of CAPRISA 004, which is a Phase IIb trial, researchers may consider conducting a larger Phase III trial to obtain more conclusive data regarding tenofovir's potential effectiveness for preventing sexual transmission of HIV. If the current study finds strong enough evidence that tenofovir is safe and effective, the CAPRISA 004 consortium of investigators will work with manufacturers and sponsors to gain regulatory approval of the product by relevant drug regulatory authorities, such as the South African Medicines Control Council. We will also work together to ensure there is affordable access in South Africa and resource-poor settings where the needs are greatest.

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CAPRISA (the Centre for the AIDS Program of Research in South Africa) is a multi-institutional AIDS research organisation, with diverse expertise in basic and molecular epidemiology, virology, immunology, infectious disease medicine, bioinformatics, statistics, ethics and health policy. CAPRISA is also 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 five research programmes viz. HIV pathogenesis, HIV vaccines, HIV and TB treatment, microbicides, and prevention and epidemiology

CONRAD is dedicated to improving reproductive health, particularly in developing countries where the need is greatest, by supporting the development of better, safer, and more acceptable methods to prevent pregnancy and sexually transmitted infections (STIs), including HIV/AIDS. The program offers both financial support as well as technical assistance for the various stages of product development. Research is conducted at CONRAD's preclinical facility and Clinical Research Center at Eastern Virginia Medical School (EVMS) and in collaboration with investigators at universities, research institutions, and private companies worldwide.

Family Health International is dedicated to improving lives, knowledge, and understanding worldwide through a highly diversified program of research, education, and services in family health and HIV/AIDS prevention, care, and treatment. Since its inception in 1971, FHI has formed partnerships with national governments and local communities in countries throughout the developing world to support lasting improvements in the health of individuals and the effectiveness of entire health systems. FHI has a staff of more than 1,700 people and offices in 40 countries.

LIFElab is the trade name of the East Coast Biotechnology (ECoBio) Regional Innovation Centre. It is one of three Biotechnology Regional Innovation Centres (BRICs) that were set up by the Department of Science and Technology (DST) under the auspices of its National Biotechnology Strategy. This centre is funding a training programme for microbicide clinical trials.

For more information, please contact: Professor Salim Abdool Karim, Director, or Prof Quarraisha Abdool Karim, Associate Scientific Director, CAPRISA, email: karims1 [at] ukzn.ac.za / abdoolq2 [at] ukzn.ac.za

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