MICROBICIDE GEL SAFE BUT NOT EFFECTIVE IN PREVENTING HIV INFECTION
Durban, 14 December 2009: A clinical trial involving 9385 women in East and Southern Africa has demonstrated that a vaginal microbicide gel PRO 2000 (0.5%) while safe does not prevent HIV infection in women. The HIV Prevention Research Unit of the South African Medical Research Council, Africa Centre for Health and Population Studies of the University of KwaZulu-Natal and the Reproductive Health and HIV Research Unit of the University of the Witwatersrand participated in the trial. Additional sites were in Uganda, Zambia and Tanzania. The first results of the study, known as MDP 301, were released today.
“This was a large and important trial and while it’s disappointing that PRO 2000 did not show an effect against HIV infection, nonetheless the product was safe and the trial was well conducted,” says Professor Helen Rees, Executive Director of the Reproductive Health and HIV Research Unit. “The extraordinary partnerships developed between researchers, participants and communities have taught us important lessons that we will carry into future studies and we are greatly indebted to the women who participated in the MDP 301 study.”
The researchers agree that while the results mean the end of the road for PRO 2000 – and the entire “second generation” of microbicide formulations, they are upbeat about next generation microbicides which are already in trials. The robust research plans in progress are focusing on promising microbicide candidates including products containing highly effective antiretroviral drugs that are used to treat people living with HIV/AIDS.
Microbicides are gels, foams or creams being developed for the purpose of preventing the vaginal sexual transmission of HIV to women and other sexually transmitted infections when applied topically inside the vagina.
Previous microbicide clinical trials have yielded insignificant results or were stopped prematurely. However, earlier this year, there was cautious excitement about the results of the HPTN 035 study which suggested that the microbicide 0.5% PRO 2000 may be 30% efficacious in reducing HIV infections among women although these results were not significant.
Prof Gita Ramjee reflected on the results of the HPTN 035 and MDP 301 when she commented: “While the glimmer of hope that we saw in HPTN 035 has not been supported by the outcome from this very large MDP 301 trial; the study has provided us with a definitive result which confirms that 0.5% PRO 2000 has no further clinical role in HIV prevention. However, research must continue due to the disproportional rate of new HIV infections among women in sub-Saharan Africa. ARV-based microbicides are developed using proven HIV treatment drugs. These are being tested to determine their effectiveness in HIV prevention. Trials with these products are already underway.”
MDP 301 was conducted between September 2005 and September 2009 and enrolled 9385 women at several research centres in 4 countries. In addition to the three centres in South Africa, research centres were located in Mazabuka (Zambia), Masaka (Uganda) and Mwanza (Tanzania). In Masaka, the trial population consisted of mostly HIV discordant couples and some concordant couples. In Tanzania, women were recruited from high risk groups whereas at all other centres, participants were women from the general communities.
The clinical trial tested the microbicide gels at two different doses for safety and their ability to prevent HIV infection against a placebo (gel with no activity against HIV): The active gel tested was PRO 2000 (0.5% and 2% doses), developed by Indevus Pharmaceuticals, Inc., in Lexington, Massachusetts, U.S.A and now owned by ENDO pharmaceuticals. In earlier laboratory and animal testing, PRO 2000 demonstrated a protective effect against HIV and other sexually transmitted infections by preventing HIV cell entry.
A total of 15818 women were screened for participation in the study. In screening for HIV prior to enrolment into the trial, 26% of the women overall were found to be infected. In Durban of the 4694 women who volunteered to test for HIV prior to study participation, 36% (1699) were found to be HIV positive, at Africa Centre of the 1775 volunteers 28% (495) were HIV positive and in Johannesburg of the 3670 volunteers 19% (688) were HIV positive. For other sites 29% (673) of 2335 screened in Mazabuka (Zambia), 10% (111) of 1161 discordant couples screened in Masaka (Uganda), and 20% (437) of 2183 women screened in Mwanza (Tanzania) were HIV positive at the outset.
Women enrolled in the study for an average of 12 months (up to 24 months in Uganda) from September 2005 to September 2009. Participants were originally randomized in approximately equal numbers to one of the three study groups: 0.5% PRO 2000 (n= 3326), 2%PRO2000 (n=2734) and an inactive placebo gel (n=3325). Allocation to 2% PRO 2000 gel was stopped in February 2008 as Independent data safety monitoring committee suggested that continuation of the 2%group would have little chance to show effectiveness.
All participants underwent a comprehension test to assess their understanding of the trial prior to enrolment and throughout the study. They received detailed information about the possible risks and benefits of trial participation prior to enrolment and were monitored closely throughout the study. Participants were told to apply the gel one hour prior to sex. Relatively few left the study before it was completed; over 80% of the women enrolled in the study completed their scheduled period in the study.
The MRC sites in Durban enrolled 2391, (633 on 2% PRO 2000, 878 on 5% PRO 2000, 880 on placebo), Africa Centre enrolled 1177 women (353 2% PRO 2000, 413 on 0.5% PRO 2000 and 411 on placebo), and the RHRU sites enrolled 2499 (764 were on 2% PRO 2000, 867 on 0.5% PRO 2000 and 868 on placebo).
In the course of four years, between 2005 and 2009, the total number of new HIV infections in the whole trial (9385 women) was 418. For each site the rate of new HIV infections were: 6.1% in Durban, 4.3% at Africa Centre (Mtubatuba), 5% in Johannesburg, 4% in Zambia, 1.5% in Tanzania and 4.8% in Uganda.
Rate of new HIV infection rates infections among participants who used 0.5% PRO 2000 was 4.5% compared to 4.3% in the placebo arm. This difference was not significant suggesting that 0.5% had no effect on HIV when compared to the placebo.
Data in the 2% arm up until February 2008 showed HIV infection rate of 4.7% in women who used 2% PRO2000 compared with 3.9% in placebo arm. This difference was not significant, suggesting that 2% PRO 2000 was safe but had no effect on HIV.
All women in the study who became HIV positive were provided counselling and were referred for ongoing psychosocial care. Women were also invited to remain in contact with sites for long term care and monitoring of their HIV infections, and referrals were made to local health service providers for ongoing care.
A participant in the trial, Nozipho Mpanza voiced her thoughts on the outcome of the study: “Even though the gel proved not to be effective, we played a role in the fight against HIV. We learnt about caring for ourselves –like screening for cervical cancer and using condoms. This research taught us a lot, when we joined we learnt about the benefit of condoms, we even learnt to encourage others to test for HIV and we gained confidence of helping those already infected”.
“Despite the results, the MDP 301 trial provided an opportunity to deliver HIV prevention education to thousands of women at risk of HIV,” says Mitzy Gafos, Co–Principal Investigator at Africa Centre. “The completion of this trial is testament to the commitment and dedication of participants and their partners. The commitment demonstrated by the women in the trial communities must spur us on in the continued search for safe, effective and acceptable HIV prevention options for women.”
Trial communities and study participants are currently being informed of the study results and counselled on HIV prevention messages and safe sex practices to curb the high rates of new infections seen among young women.
Currently, women comprise half of all people worldwide living with HIV. In sub-Saharan Africa, women represent nearly 60 percent of adults living with HIV, and in several southern African countries young women are at least three times more likely to be HIV-positive than young men.
In most cases, women become infected with HIV through unprotected sexual intercourse with an infected male partner. Although no microbicides are approved or available for use, an effective product could provide women with an HIV prevention method that they could initiate. This would be particularly helpful in situations where it is difficult or impossible for women to negotiate condom use with their male partners to prevent HIV transmission.
Department for International Development (DfID)
UK Medical Research Council (MRC)
For more information about the MDP 301 clinical study, see http://www.mdp.mrc.ac.uk
For more information contact Thesla Palanee.
Partners in Prevention Study Results
Herpes medication does not reduce the risk of HIV transmission from individuals with HIV and genital herpes but demonstrates modest reduction in HIV disease progression and leads to new important insights about HIV transmission.
“This landmark study was necessary to answer the question of whether treating genital herpes could prevent HIV transmission. While acyclovir did not reduce HIV transmission it has shown that potent combination interventions will be needed to curb the spread of HIV in Southern Africa. Trials such as this one provide evidence for policy makers about what does and doesn’t work for HIV prevention”. Sinead Delany-Moretlwe – Head of Research Cluster at RHRU.
For more information contact:
Dr Sinead Delany-Moretlwe: email: [email protected] tel: +27 11 358 5414
The Reproductive Health and HIV Research Unit (RHRU) worked with the University of Washington in the Partners in Prevention Study. The study found that acyclovir, a
drug widely used as a safe and effective treatment to suppress herpes simplex virus‐2 (HSV‐2), which is the most common cause of genital herpes, does not reduce the risk of HIV transmission when taken by people infected with both HIV and HSV‐2.
RHRU’s Research Cluster has been investigating Herpes and its effect on HIV since 2003. In 2007 the HSV/HIV Shedding study showed that treating HIV positive participants with acyclovir reduced the viral load in both plasma and genital secretions. The HPTN 039 study, which was completed in 2008, showed that treating HIV negative people with acyclovir to suppress genital herpes did not reduce their chances of becoming infected with HIV.
Comments from Dr Francois Venter – Head of the Joburg HIV Cluster at RHRU and President of the South African HIV Clinicians Society
“The Partners in Prevention study did not show protection against HIV transmission. There was a lot of scientific plausibility regarding the theory driving the researchers, and serves to remind us that there are no short cuts in this form of research. We need solid proof before we use interventions. The researchers have done an excellent job in showing that acyclovir does not prevent transmission when given to HIV positive people, using the best research methods.
There was, however, some interesting information from the study, suggesting that acyclovir may slow progression to AIDS. We lack effective non-antiretroviral medication for HIV positive people with preserved immune systems, and acyclovir may be an option, if shown to be meaningful and cost-effective. The researchers are looking at this, and we look forward to the results.
Lastly, for people with HIV and recurrent herpes (a common and unpleasant symptom), the drug worked very well, and doctors need to consider using the drug as prophylaxis”.
RHRU Research Staff met with members of the Community Advisory Group to discuss the trial results.
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