The results from the four-year trial, which took place in South Africa, Tanzania, Uganda and Zambia, revealed that PRO 2000 (0.5 % concentration) was safe as tested but provided no protection against HIV.

South African Medical Research Council statement:

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.

‘€œThis 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. ‘€œThe 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 ‘€œsecond 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: ‘€œWhile 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: ‘€œEven 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’€.

‘€œDespite 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. ‘€œThe 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.

Formal statement  by President  of the Southern African HIV Clinicians Society, Professor Francois Venter:

The results of the PRO 2000 microbicide MDP 301 study are very disappointing.  The researchers have done a fine job, and have fully answered the question. Despite this result, the product was safe when used by women in the trial. This should be reassuring given previous concerns about the safety of microbicides.

We must keep insisting on these studies ‘€“ things work in animal studies or initial human studies, like pro-2000 did ‘€“ but may not pan out in the larger studies. There are no short cuts.

While the rate of new HIV infections appears to be slightly lower than in the community outside of the trial, it is still very high. These women were given intensive behaviour change messages, in a very sophisticated environment. In addition, they had access to condoms, both female and male.  Yet, new infection rates remained high. It raises very worrying questions about traditional prevention approaches that rely on behaviour modifications with condoms.

It is quite clear we need more potent prevention interventions, and that traditional approaches, even when done very well, probably have very limited effects. Existing prevention that works, like circumcision and mother-to-child prevention, must be implemented as a priority.  Then we need more potent prevention ‘€“ maybe antiretrovirals in microbicides or as a tablet to protect HIV negative people after sex, or simply to render HIV positive people non-infectious by treating their HIV properly.  We also need novel behaviour change interventions that are more effective than the current approaches.  It really can’€™t be business as usual.

Dr. Zeda Rosenberg, CEO of the International Partnership for Microbicides, issued the following statement on the results of the Phase III effectiveness study of PRO 2000:

Today the UK-based Microbicide Development Programme (MDP), a partnership of African and European researchers, announced the results of its Phase III clinical trial of PRO 2000, a vaginal gel being tested to prevent HIV transmission to women during sex.

The results revealed that PRO 2000 (0.5 % concentration), an early generation microbicide candidate, was safe as tested but did not provide protection against HIV as compared to a placebo.

One arm of the MDP study testing PRO 2000 in a 2% strength gel was discontinued in 2008 when the study’€™s Independent Data Monitoring Committee concluded that it was not likely to show benefit in preventing HIV. The four-year PRO 2000 study (MDP 301) was the largest microbicide trial to date, and involved some 9,404 participants across six research centres in South Africa, Tanzania, Uganda and Zambia.

While results of a smaller study of 0.5% PRO 2000 released earlier this year signaled potential support for the product, today’€™s announcement provides conclusive evidence that PRO 2000 is not an effective tool for HIV prevention, and closes the chapter on the early generation of microbicides that were based on large polyanions thought to non-specifically block HIV from attaching to its target cells.

IPM acknowledges the hard work of the UK’€™s Microbicide Development Programme, its staff, the communities in which the trials took place, and, especially, the study participants and their families.

While IPM was not involved in the PRO 2000 study, all of us working to develop new HIV-prevention tools will incorporate valuable lessons from the study into our own trial designs to conduct the most efficient and safe trials. The fact that this study was able to engage nearly 10,000 women over four years testifies to the shared commitment to give women the power to protect themselves ‘€” and to stop the spread of HIV.

The need remains urgent. According to a recent report on the health challenges facing women and girls by the World Health Organization, HIV/AIDS is now the number one killer of women of reproductive age in the world, particularly in developing countries where the epidemic has hit hardest.

Fortunately, microbicide development has already entered a new and promising chapter. In the last few years, researchers have begun work on a potentially highly potent generation of long-acting microbicide products containing antiretrovirals (ARVs) and formulated as long-acting vaginal rings, gels and films.

These next generation products are based on the same ARVs already being used to treat HIV/AIDS and to prevent mother-to-child transmission. ARVs work by specifically targeting the virus and either preventing it from entering a healthy cell or from replicating once it is inside the cell.

Antiretroviral treatment (ART) has saved millions of lives across the globe. Adapting these highly potent treatments to create female-initiated prevention technologies has the potential to transform the global response to HIV infection.

ARV-based microbicides are already being studied in clinical trials in Africa, Europe and North America sponsored by IPM and other organizations, including CAPRISA in South Africa and the Microbicide Trials Network, a global research network funded by the US National Institutes of Health. IPM and others are working to find ways to deliver ARVs in formulations that are acceptable to women and their partners, easy for women to use, and can potentially provide long-lasting protection against HIV, such as once-daily gels, films, and tablets as well as longer-lasting monthly vaginal rings.

Challenges lie ahead, but ARV-based microbicides remain one of the best hopes for female-initiated HIV-prevention, and we are confident that safe and effective products are within reach. With the next generation of product development well underway, the microbicide field can focus on products that have already proven effective in treating HIV and show tremendous promise for prevention. We do this alongside donors, advocates, national governments, and private sector partners who continue to provide steadfast and commendable support for these efforts.

Our shared responsibility stems from the knowledge that HIV continues to devastate communities and families around the world. By one day putting the power of protection into women’€™s hands, we give them the power to help stop the spread of HIV/AIDS.

Funding and Support for HIV Prevention Research Must Continue, according to AVAC

Reacting to today’€™s announcement, AVAC executive director Mitchell Warren said, ‘€œOf course, we are disappointed to hear these results, since we always hope that such a trial will actually prove effectiveness. Yet we are confident that MDP 301, because it was so well implemented, provides vital information to help researchers and communities move forward in the search for safe and effective microbicides.’€

Although this product had looked promising in animal studies and in earlier human studies, the MDP 301 trial provided a clear answer that this product does not work. ‘€œBut it is just as clear that this is by no means the end of the line for microbicide research,’€ Warren added. ‘€œAround the world today, thousands of researchers and trial participants are continuing the important work of discovering and testing other, more potent microbicide candidates as well as additional biomedical prevention options. Scientists, funders, advocates and others in the field must now ensure that key lessons learned from this trial are incorporated into developing better products and into planning for new trials.’€

A trial of this complexity and magnitude is a great accomplishment in the effort to stem the tide of the HIV pandemic. Everyone involved, especially the trial staff and volunteers, deserve thanks and credit for their dedicated efforts and important contributions.                

‘€œWe especially want to thank the more than 9,300 heroic women who have participated in this trial. Each one of these volunteers and their communities made a significant contribution to HIV prevention research,’€ Warren said. ‘€œAs we move forward in our search for new HIV prevention options, researchers will need the help of tens of thousands more volunteers around the world. We hope that many more communities and individuals will follow in the footsteps of the MDP 301 trial participants.’€

While this trial did not result in an effective product, it was a successful trial ‘€“ it gave a clear result, even if that result is disappointing. In many ways, this trial should serve as a model for future HIV prevention trials as it will provide critical scientific information as well as important lessons from the extensive social science component and the comprehensive community engagement and preparation undertaken by the trial staff. The principal investigators and trial staff developed several innovative integrated approaches for working with participants and communities to ensure retention in the trial and to track women’€™s use of the product.

‘€œThe HIV prevention field must now take the lessons learned from this trial and apply those systematically to a rational plan for future microbicide development’€, said Polly Harrison, Director of the Alliance for Microbicide Development, an AVAC partner. ‘€œSuch a plan must include broadening the pipeline of candidate microbicides; making strategic decisions about which candidates should go forward in human trials; and ensuring that there is adequate funding for the additional trials that will be needed in the coming years.’€

Warren and Harrison agree that the entire HIV prevention research field must commit to working together to share knowledge, new information and innovative ideas, and to ensuring that there is coordination across prevention research disciplines and among researchers, implementers and communities.

Today, there are many more HIV prevention options in large-scale trials, including vaccines, other microbicides with different mechanisms of action and oral pre-exposure prophylaxis (PrEP) ‘€“ antiretroviral drugs being tested for prevention. Important results from these trials are anticipated in 2010 and beyond. In addition, in the last few years, clinical trials have also shown that medical male circumcision can be effective at preventing HIV infection in heterosexual men. More recently, in October, results from a large clinical trial with over 16,000 participants in Thailand provided evidence for the first time that it is possible to reduce the risk of HIV infection with a vaccine.

‘€œWe need to continue the drive for comprehensive HIV prevention,’€ Warren added. ‘€œThat means perfecting methods and ensuring access for all who need them to existing HIV prevention and treatment options, including male and female condoms, behavior change counseling, male circumcision, clean needles, harm reduction and antiretroviral drugs; ensuring continued research to find effective new options, including microbicides, vaccines and PrEP; and planning to integrate these new interventions into combination programs.’€

More information about the MDP 301 trial results and PRO 2000 is available at: www.avac.org/pro2000.