The CDC announced on 15 December 2009 that, due to unanticipated challenges, it is now revising the protocol of the TDF2 Botswana Study, one of several clinical trials around the world studying Pre-Exposure Prophylaxis. This trial is being conducted by BOTUSA, a partnership between the Botswana Ministry of Health and the U.S. Centers for Disease Control and Prevention.

The trial was designed to show whether taking an anti-retroviral drug (ARV) pill daily could reduce HIV negative participants’ risk of acquiring HIV. To test a combination tenofovir-emtricitabine pill (brand name Truvada®), the trial enrolled heterosexual men and women volunteers between the ages of 18 and 39.

Researchers concluded however, that the study would not be able to determine efficacy (whether the strategy works for HIV prevention or not) due to two significant challenges.  First, the HIV incidence rate proved  to be lower than expected in this study population. This is in part due to declining HIV rates in the nation overall. Since the trial began, Botswana has experienced a 25% drop in HIV prevalence among this age group – which is certainly good news. The low rate of infection observed among trial participants is also due in part to extensive HIV prevention counseling, condoms and other services provided by the trial to all participants.

The second factor is low retention rates among this highly mobile population of young adults.  If a significant number of participants drop out, the effect of the intervention cannot be correctly calculated.  Factors contributing to the low retention rates in this trial included pregnancy, participants moving out of the area, and the amount of time required for study visits. BOTUSA attempted to overcome this problem by adding weekend clinic hours, increasing participant reimbursements, and strengthening their participant retention procedures. While these steps resulted in improved retention, it was not enough to assure that the trial would produce valid efficacy data.

The trial will, however, still be able to assess the safety of Truvada use among participants, any changes in risk behavior, and participants’ ability to adhere to the requirement of taking a daily pill . This information will help to guide planning for PrEP introduction if PrEP is proven effective in other trials.

BOTUSA’s plans for completing the safety and adherence portions of the trial and the necessary follow-up with all trial participants are currently being discussed and finalized with the Botswana Ministry of Health, as well as with participants and community advisory boards. Final plans will be submitted for approval to the scientific and ethical review boards in Botswana and the U.S. in January 2010. A final report of the study findings is expected later in 2010.

For more information on the status of the Botswana TDF2 PrEP Study, click on the following link: http://www.cdc.gov/hiv/prep/resources/factsheets/botswanatdf2.htm 

Co-Principal Investigators Quarraisha and Salim Karim announced on 11 December 2009 that the CAPRISA 004 trial was closing one month ahead of schedule because it had met or exceeded its targets.

Designed as a Phase IIb trial to assess the safety and effectiveness of 1% tenofovir gel as a vaginal microbicide, the CAPRISA 004 study enrolled the first of its 900 participants in late May 2007 and the last participant in early January 2009. Conducted in the KwaZulu-Natal Province of South Africa, the trial retained 94% of its participants through trial completion (exceeding its goal of 90%). The final post-trial visits are scheduled to occur in the first quarter of 2010.

Since this is the first effectiveness study of an antiretroviral drug formulated as a microbicide, these post-trial visits are essential to determine whether any HIV infections could have been masked by use of the tenofovir gel. For example, the antibody response may appear muted, with a viral load below detection, making the person look as if they were not infected when in actuality they had seroconverted. At this time, it is only a theoretical possibility that infection could be masked by the presence of tenofovir—the purpose of the post-trial visits is to determine if there is any empiric evidence for this.

The study has also collected sufficient data to have the statistical power it needs to make a meaningful comparison between the effectiveness of tenofovir versus a placebo gel. Announcement of these results is expected in July at the Vienna AIDS 2010 Conference and are highly anticipated, especially in the wake of the MDP 301 PRO 2000 trial results announced in early December 2009.

Participants who became HIV positive, during the trial are receiving counseling and high-quality medical care and treatment, including antiretroviral therapy and psychological and social support, from CAPRISA’s AIDS Treatment Programme and other local AIDS treatment services

Like advocates everywhere, GCM would like to congratulate the CAPRISA 004 study teams for their hard work and, most of all, to the women who joined this trial. Each one of these volunteers has made a significant contribution to HIV prevention research.  In his announcement, Pro Vice-Chancellor (Research) at the University of KwaZulu-Natal and Principal Investigator, Dr. Salim Karim, stated that, “[w]e are crossing our fingers that we have a positive result - we are all painfully aware of how important this result could be to the future lives of hundreds of thousands of women, especially the most-disenfranchised young women at highest risk of HIV infection in Africa.”

The CAPRISA 004 study is a collaborative effort between the Centre for the AIDS Programme of Research in South Africa (CAPRISA), based at the University of KwaZulu-Natal in Durban, South Africa; Family Health International; and CONRAD. It is funded by the United States Agency for International Development and the South African Department of Science and Technology through LIFElab in South Africa.

On 14 December 2009, the Microbicides Development Programme (MDP) announced the results of the Phase III clinical trial of its candidate vaginal microbicide, PRO 2000. 

In anticipation of the trial results, the Global Campaign for Microbicides (GCM) had created an advocacy brief describing the trial and the issues raised by the research. Many of these issues relate to access and licensure and will hold true for any future product that shows safety and effectiveness.

Upon release of the study results, GCM organized a conference call for advocates to learn of the trial results and discuss their implications directly with researchers from MDP and peer advocates in the field.  

What did we learn from the trial?

The MDP 301 PRO 2000 trial showed that women who were assigned to use the microbicide candidate before sex, did not benefit from protection against HIV compared to those assigned to use a placebo gel. While this outcome is tremendously disappointing, we congratulate the MDP team on a well-organised study that incorporated robust clinical and social science analysis and community advocate perspectives.  Lessons from this trial, combined with those from the smaller HPTN 035 trial of PRO 2000 gel, will continue to inform the field. 

Although much of the reporting was responsible and well-balanced, a number of inaccurate reports emerged—particularly from Zambia—that were later picked up elsewhere and may have generated misunderstandings and concerns about the trial’s protocol and outcomes. GCM and members of the Microbicides Media and Communications Initiative (MMCI) have worked with stakeholders in Zambia and globally to correct these inaccuracies and prevent further confusion.                               

What’s next?

We believe that the HIV-prevention product development field—including pre-exposure prophylaxis (PrEP) and ARV-based and non-ARV-based microbicides—offer tremendous promise. As part of our role to increase understanding of and support for HIV-prevention research and advocacy, GCM continues to work closely with trial sites, study sponsors, government agencies, and advocacy organizations. The current pipeline includes the testing of tenofovir disoproxil fumarate (TDF) and also TDF combined with emtricitabine (Truvada) as oral PrEP, as well as  TDF as a topical microbicide. Results from these trials should be announced over the next two years.