PRO 2000 microbicide gel failed to protect women against HIV infection in the largest microbicide study to date, partners in the Microbicide Development Programme’s 301 study have announced.
PRO 2000 had appeared to reduce the risk of HIV infection by around 30% in a smaller study, HIV Prevention Trials Network study 035, but this result was just outside the bounds of statistical significance, and could have been due to chance.
Researchers and advocates for microbicide development have been awaiting the results of the much larger MDP 301 study to judge whether the compound truly had any protective effect.
Microbicide gels that can be used by women in the vagina to protect against HIV infection have been tested in a number of studies, and until the HPTN 035 study, none showed any evidence that they could prevent HIV infection in women.
Developing prevention methods that reduce women’s vulnerability to HIV infection is critical for control of the HIV epidemic.
It is estimated that over 60% of those who become infected each year in Africa are women, and there is a strong need for prevention technologies other than condoms that can be controlled by women. Microbicide gels that can be used by women have been a major focus of research.
PRO 2000 is a non-antiretroviral compound which was chosen as a microbicide because it blocks entry to cells that could be infected by HIV, and because it showed promise in animal models.
The MDP 301 study randomised women to receive PRO 2000 gel at one of two strengths (0.5% or 2%) or an inert gel (the placebo arm). The study was double-blinded, which meant that neither women nor clinic staff knew what product they were receiving.
Women were instructed to apply the gel up to one hour before sexual intercourse. They were counselled on safe sexual behaviour and encouraged to use condoms, which were provided free of charge.
In 2008 the trial’s data and safety monitoring committee decided after an interim analysis that the higher strength gel arm had no chance of producing a statistically significant difference, and halted recruitment to it.
The study recruited 9385 women, compared to 3099 women in the HPTN 035 study, and because of the larger number of participants, more infections took place in the study. As a result MDP 301 has much greater power to detect differences in infection rates.
However, after one year of microbicide use, there was no significant difference in the risk of infection between women who received PRO 2000 or the placebo gel. PRO 2000 failed to show a protective effect (hazard ratio 1.05 [95% confidence interval 0.82 – 1.34], p=0.172).
There were 130 HIV infections out of 3,156 women who were given 0.5% PRO 2000 gel (4.5 per 100 person years), and 123 HIV infections out of 3,112 given the placebo gel (4.3 per 100 person years).
Chief Investigator, Dr Sheena McCormack of the Medical Research Council said: “This result is disheartening; particularly in light of the results of a smaller trial sponsored by the US National Institutes of Health (NIH) which suggested that PRO 2000 could reduce the risk of HIV infection by 30 per cent. Nevertheless we know this is an important result and it shows clearly the need to undertake trials which are large enough to provide definitive evidence for whether or not a product works.”
A South African trial participant commented: “Even though the gel proved not to be effective, we played a role in the fight against HIV. We learnt a lot about caring for ourselves, such as using condoms. We also learnt to encourage others to test for HIV and we gained confidence in helping those who were already infected.”
Unlike the recently-reported Thai study of an HIV vaccine, which showed that the product was partially effective in a population at low or medium risk of HIV infection, the MDP 301 study recruited women at high risk for HIV infection. HIV incidence in the study was moderately high (around 4.5% of women became infected in the course of a year’s follow-up), reflecting the real-world conditions in which a new prevention method is most urgently needed.
The full results of MDP 301 are likely to be presented and published early in 2010, and the field is now awaiting the results of a South African study of a microbicide containing the antiretroviral drug tenofovir.
That study, the CAPRISA 004 trial, is testing the use of tenofovir gel in women in KwaZulu-Natal, and the results are expected to be presented in the summer of 2010.
CAPRISA 004 is a pilot study, and will be followed by results from the VOICE study, which is directly comparing a tenofovir gel with oral tenofovir pre-exposure prophylaxis (PrEP) in 4200 women at 10 sites in South Africa, Malawi, Uganda, Zambia and Zimbabwe.
This sequence of studies will provide evidence about the potential for the use of antiretroviral drugs in microbicides, but even if they show that tenofovir gel works, the cost of conducting further large trials could make it difficult to raise funding in the current financial climate.
A negative result in either of these studies could make funders reluctant to support further studies of ARV-based microbicide approaches.
MDP 301 was one of the largest HIV-related trials ever conducted, recruiting women in Zambia, Tanzania, South Africa and Uganda. The study was a partnership between academic institutions in the United Kingdom and national research institutions, and has contributed to a substantial increase in the capacity of African research institutions to carry out clinical trials.
Professor Jonathan Weber, co-Chair of the MDP Programme Management Board from the Division of Medicine at Imperial College London, said: "This is a disappointing result for the product, as the trial shows that it is not effective. However, the trial itself was very well designed and undertaken, so we know that the results are definitive.
"It is unfortunate that this microbicide is ineffective at preventing HIV infection, but it’s still vital for us as scientists to continue to look for new ways of preventing HIV. There are many research groups exploring different avenues to tackle HIV; it is a slow process, but we are making progress. Now that we know this microbicide is not the answer, we can concentrate on other treatments that might be."
MDP 301 was funded by the United Kingdom government’s Department for International Development, and by the UK’s Medical Research Council.