Microbicides 2006: Challenges for the clinical development of microbicides — overview

Even though the clinical development of microbicides, products used in the vagina or rectum to prevent HIV acquisition, has advanced dramatically in the last few years, study investigators are concerned about a number of challenges that could potentially undermine their ability to show whether these products truly work or not, according to progress reports at the Microbicides 2006 Conference last month in Cape Town.

As a result of some of these challenges, big pharmaceutical companies have been hesitant to enter the field in the first place — the studies are in resource-limited settings with limited infrastructure, must enrol large numbers of high risk and often disadvantaged women. The participants speak many different languages and have different levels of literacy; they have to understand and provide consent to the study and continue coming to their scheduled clinic visits, adhere to the study protocol and not get pregnant.

But with a mix of public and private financing, after years of safety and acceptability studies, eight large clinical efficacy studies of microbicides have begun. Although one has been discontinued, mounting so many trials in such a brief period is a logistical triumph and testimony to the dedication of the researchers involved. The trials include:

• The Carraguard study is one of the furthest along in implementation. Carraguard contains a seaweed extract that acts as an HIV fusion or entry inhibitor. Formulated as a gel, the microbicide is being compared to placebo in a randomised controlled trial by the Population Council at three sites in South Africa (Cape Town, Durban and Limpopo). The study will be unblinded for final efficacy analysis in the second quarter of 2007.
• Cellulose Sulfate (CS) is another entry inhibitor formulated as a gel that is being compared to HEC gel (a non-active gel placebo) in two randomised controlled trials. Trial #1 is in Uganda, South Africa, India, Benin and Burkina Faso. The last follow-up in this study is expected be in July 2008, data analysis should occur in December 2008, with results in March 2009.Trial # 2 is in Lagos, and Port Harcourt, Nigeria. The last follow-up in this study is expected to be in January 2008, with results due sometime later that year.
• HIV Prevention Trials Network (HPTN) study 035 is comparison of 0.5% PRO 2000 (another gel entry inhibitor) and BufferGel (an acidic buffering gel) versus two controls -- a placebo gel and open label no gel arm. The trial is looking at safety and efficacy against HIV and also bacterial vaginosis, a number of sexually transmitted infections (STIs) and pregnancy at six sites in Malawi, South Africa, Zimbabwe, Zambia, and one site in the United States. The trial is currently in still in a safety analysis phase, but will roll over uninterrupted into the efficacy phase in October this year, with primary effectiveness results expected by early 2009.
• Microbicides Development Programme (MDP) 301, is a study funded by United Kingdom's medical research council and DFID looking at two strengths of PRO 2000 (0.5%, and 2.0%) versus placebo at six sites in South Africa, Uganda and Tanzania. The trial is expected to continue until March 2009 with results due later than year.
• Methods for Reproductive Health in Africa (MIRA) is conducting a study of the Ortho All-Flex diaphragm containing Replens gel (an acidifying buffer) in Harare, Zimbabwe, and in Soweto and Durban, South Africa. The study is fully enrolled, and final results are projected for the fall of 2007.
• Two trials of Savvy, a surface active agent formulated as a gel that provides a protective coating within the vagina, have begun: Savvy Nigeria, conducted in Lagos and Ibadan, Nigeria, began in October 2004 and is expected to continue until May 2007. Savvy Ghana was discontinued when it was discovered that the HIV incidence among trial participants (in both placebo and microbicide arm) would be too low to reach any clear conclusion about the effectiveness (or lack of effect) of Savvy.

As the latter example attests, the fact that so many studies have begun is no guarantee that they will conclude successfully. Researchers at the meeting discussed various challenges with conducting these trials, some anticipated and some not, including:

• Problems of study design and size — especially in light of lower than expected incidence rates.
• Recruitment of high risk women.
• How to provide a high standard of HIV care to women who test HIV positive at screening or during these clinical trials?
• What to do when women in microbicide trials become pregnant?
• The benefits and challenges involved in measuring a microbicide's effect on other sexually transmitted infections.
• Poor adherence to the studies’ experimental arms.
• Finally, if a somewhat effective microbicide is identified, approved and makes it to the market, how will this affect other ongoing or planned clinical trials?

Yet, perhaps because these products are being developed first for the public sector in resource-limited settings, there was a stronger spirit of collaboration at the Microbicides 2006 Conference than seen at many medical conferences. Researchers devoted much time describing their experiences and strategies for dealing with these challenges, and sharing ideas to make each study more successful and ultimately provide women with a variety of options to protect themselves from HIV.