The need for HIV prevention that women can use and control
HIV/AIDS is particularly severe in Africa, where women bear a disproportionate burden of the epidemic. One of the most crucial challenges in HIV prevention in Africa is to reduce the high infection rates among young women. Worldwide, just over half of all people living with HIV are women, and 70-90 per cent of all HIV infections among women are through heterosexual intercourse.1 In sub-Saharan Africa, women aged fifteen- to twenty-four years with HIV represent 76 per cent of the total cases in that age group, outnumbering their male peers by as much as eight to one.1 Although the majority of new HIV cases in the United States are through male-to-male sexual contact, heterosexual contact accounts for 84 per cent of new infections among women.
Women have few options to reduce their risk of acquiring HIV infection. They are often unable to convince their male partners, especially husbands and regular partners, to be monogamous and/or to use condoms. New technologies to enable women to protect themselves from sexual transmission of HIV are urgently needed. One of those is topical microbicides-products designed to prevent HIV and other sexually transmitted infections.2-4 They can potentially be applied vaginally or rectally and, importantly, they are unique as being a female-controlled option.
The CAPRISA 004 trial
After several years of disappointing microbicide trials that were unable to show protection against HIV infection,5-10 or were even potentially harmful,11-13 the results of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial, released in July 2010, finally provided the evidence that the antiretroviral drug, tenofovir gel, used before and after sex can prevent HIV infection in women.14 This landmark study has been heralded as one of the most significant scientific breakthroughs in the fight against HIV/AIDS with global health leaders calling the results "a game changer," "a true breakthrough for AIDS prevention," and "a significant milestone for women in the thirty year history of the HIV/AIDS epidemic."
The CAPRISA 004 trial was a double-blind, randomized, placebo-controlled trial including 889 rural and urban South African women, aged eighteen to forty years, who were sexually active and HIV-negative. A total of 445 randomly assigned women received vaginal applicators containing a 1 per cent concentration of tenofovir in a gel formulation, and 444 women received applicators filled with a placebo gel that looked identical to the study gel but did not contain tenofovir. Study participants, who received HIV risk-reduction counseling, condoms, and monthly examinations, were told to apply no more than two gel doses in twenty-four hours: the first dose anytime within twelve hours before sex, and a second dose as soon as possible within twelve hours after sex.
The HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years, compared to 9.1 per 100 women-years in the placebo gel arm. Tenofovir gel reduced HIV acquisition by 39 per cent overall, and the protective effect of tenofovir gel against HIV infection reached 54 per cent in women who used the gel consistently.
Tenofovir gel was also shown to be 51 per cent effective in preventing herpes simplex type 2 virus.15 Genital herpes infection is an incurable lifelong condition, which potentiates the spread of HIV infection. Tenofovir gel is the first medical technology shown to prevent genital herpes, which is one of the most common sexually transmitted diseases globally.
Unique features of the CAPRISA 004 trial CAPRISA 004 provided the proof-of-concept evidence that an antiretroviral drug can prevent sexual transmission of HIV in women. In addition to being the first study to demonstrate the effectiveness of a vaginal microbicide for the prevention of HIV, the CAPRISA 004 trial was the first microbicide trial where the consortium of partners was 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. The trial was uniquely co-funded by both the United States Government, through the United States Agency for International Development, and the Technology Innovation Agency, a biotechnology agency of the South African Government Department of Science and Technology. Significantly, CAPRISA 004 was the first microbicide trial where a royalty-free voluntary license for local manufacture and distribution had been secured up front.
Next steps The promising findings of the CAPRISA 004 trial have provided new hope for HIV prevention. Soon after the CAPRISA 004 trial results were presented at the 2010 International AIDS Conference in Vienna, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) hosted a large international consultation to define priority steps to speed up the global implementation of tenofovir gel.16 Additional studies are required by regulatory agencies to confirm and extend the results of the study for the licensure of tenofovir gel for HIV prevention. The ongoing placebo-controlled studies, including the VOICE study conducted by the Microbicide Trials Network which is testing daily use of tenofovir gel and tenofovir tablets as pre-exposure prophylaxis, and the Follow-on African Consortium for Tenofovir Studies 001 trial, which is assessing tenofovir gel using the same coitally-related dosing regimen as the CAPRISA 004 trial, were two of the studies identified as high priorities since they will provide the additional data needed for licensure.
In addition, there are often significant gaps between the level of protection achieved in clinical trials and those achieved in real-world implementation in the health service. Therefore, research to devise effective strategies for the scaling of the use of tenofovir gel was also identified as a high priority at the WHO/UNAIDS consultation.
CAPRISA is, embarking on two important studies to inform future health service implementation of tenofovir gel: the CAPRISA 008 trial assesses the effectiveness of an implementation model which integrates tenofovir gel provision into existing family planning services; and the CAPRISA 009 trial assesses the optimal choice of combination antiretroviral therapy to treat women who became infected while using tenofovir gel, thereby addressing questions on treatment choices and drug resistance.
Unlike depending on condom use and partner faithfulness, tenofovir gel enables women to take control of their HIV and herpes risks. In South Africa alone, this new prevention technology could avert an estimated 1.3 million new HIV infections and 800,000 AIDS deaths over the next twenty years.17 Implemented on a broader scale, tenofovir gel could save millions of lives. unc Notes 1 UNAIDS Report on the global AIDS Epidemic 2010, 2 A. B. Stone, P.J. Hitchcock ,"Vaginal microbicides for preventing the sexual transmission of HIV," AIDS (1994) 8:S285-S93. 3 C. J. Elias, C. Coggins, "Female controlled methods to prevent sexual transmission of HIV," AIDS (1996)10:S43-S51. 4 IWGVM "Recommendations for the development of vaginal microbicides," AIDS (1996)10:1-6. 5 P. J. Feldblum, A. Adeiga, R. Bakare, S. Wevill, A. Lendvay, F. Obadaki, et al. "SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria," PLoS ONE (2008) 3(1):e1474. 6 V. Halpern, F. Ogunsola, O. Obunge, C-H Wang, N. Onyejepu, O. Oduyebo, et al. "Effectiveness of Cellulose Sulfate Vaginal Gel for the Prevention of HIV Infection: Results of a Phase III Trial in Nigeria," PLoS ONE (2008) 3(11):e3784. doi:10.1371/journal.pone.0003784. 7 S. McCormack, G. Ramjee, A. Kamali, H. Rees, AM Crook, M. Gafos, et al. "PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial," Lancet (2010) DOI:10.1016/S0140-6736(10)61086-0. 8 L. Peterson, K. Nanda, B.K. Opoku, W.K. Ampofo, M. Owusu-Amoako, A.Y. Boakye, et al. "SAVVY (C31G) Gel for Prevention of HIV infection in Women: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Ghana," PLoS ONE(2007) 2(12):e1312. doi:10.71/journal.pone.0001312. 9 R. E.Roddy, L. Zekeng, K.A. Ryan, U. Tamoufe, S.S.Weir, E.L. Wong, "A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases," New England Journal of Medicine (1998)339(8):504-10. 10 S. Skoler-Karpoff, G. Ramjee, K. Ahmed, L. Altini, M. G. Plagianos, B. Friedland, et al. "Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial," The Lancet (2008) 372(9654):1977-87. 11 J. Kreiss, E. Ngugi, K. Holmes, J. Ndinya-Achola, P. Waiyaki, P. L. Roberts, et al. "Efficacy of nonoxynol 9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes," Jama (1992) 268(4):477-82. 12 L. van Damme, G. Ramjee, M. Alary, B. Vuylsteke, V. Chandeying, H. Rees, P. Sirivongrangson, S.S. Abdool Karim, et al. "Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial," Lancet (2002) 360:971-77. 13 L. Van Damme, R. Govinden, F.M. Mirembe, F. Guedou, S. Solomon, M. L. Becker, et al. "Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission," New England Journal of Medicine (2008) 359(5):463-72. 14 Q. Abdool Karim, S. S. Abdool Karim, J.A. Frohlich, A. C. Grobler, C. Baxter, L. E. Mansoor, et al. "Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women," Science (2010) 329:1168-74. 15 Q. Abdool Karim, S. S. Abdool Karim, on behalf of the CAPRISA 004 Trial Group. CAPRISA 004: Effectiveness & safety of vaginal microbicide 1% tenofovir gel for prevention of HIV infection in women. XVIII International AIDS Conference. Vienna, Austria, 2010. 16 WHO, UNAIDS. Next steps 1% tenofovir gel. 2010 Meeting report. 17 B. G. Williams, S. S. Abdool Karim, E. Gouws, Q. Abdool Karim. Potential impact of tenofovir gel on the HIV epidemic in South Africa. XVIII International AIDS Conference. Vienna, Austria, 2010.