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Microbicide Field Wrestles With the Implications of Success

By Richard Jefferys and Scott Morgan

Autumn 2010

In July of this year, the stubborn persistence and commitment of microbicide researchers, advocates, and trial participants was finally rewarded with positive results from a South African trial of the gel form of the antretroviral drug tenofovir (trade name Viread). The CAPRISA 004 study, led by the wife-and-husband investigator team of Quarraisha and Salim Abdool Karim, was relatively small (a total of 889 participants were included in the final analysis) but showed a statistically significant 39% reduction in risk of HIV infection. Unexpectedly, the microbicide also reduced the risk of acquiring herpes simplex virus type 2 (HSV-2) by 51%. Preliminary findings from studies looking at tenofovir levels in vaginal tissues (conducted by pharmacologist Angela Kashuba) are consistent with the efficacy results; there were statistically significant associations between higher drug levels and protection from both HIV and HSV-2. When these results were announced at the International AIDS Conference in Vienna, the presenters received a standing ovation. Since the conference presentations, a number of organizations have issued detailed descriptions of the findings and analyses of their implications, with AVAC's "Understanding the Results of CAPRISA 004" being the most comprehensive.

Charting the Route From Here

There is now an urgent need to confirm and extend the findings from CAPRISA 004 in larger trials, involving different populations and dosing strategies. There are currently four follow-on trials to CAPRISA 004 in various stages of design, protocol review, and funding:

In addition to these protocols, another ongoing trial being conducted by the Microbicide Trials Network, named VOICE or MTN-003, is comparing oral daily dosing of tenofovir or Truvada to daily application of the tenofovir gel; at the last update in July, close to 1,000 women out of a planned total of 4,200 had been enrolled.


Tradeoffs in a Complex Path to Licensure

Tenofovir gel is the first microbicide that has possibly demonstrated sufficient efficacy to bend the calculus of the epidemic. One of the principal investigators, Salim Abdool Karim, estimates there is potential to prevent 1.3 million new HIV infections and 800,000 deaths over a 20-year period in the country of South Africa alone. Yet the global economic environment has donors and foundations struggling to commit modest sums, in relative terms, to fund multiple trials. A presentation on September 27, 2010 in Atlanta by UNAIDS estimated a $42 million shortfall to fund these trials.1 Yet consider that over the past five years, more than $1 billion has been spent on microbicide research and, in 2009 alone, $868 million of the $1.65 billion invested in HIV prevention research and development was spent on vaccine research. In a global economic environment that is straining public-funder purses and influencing the politics of funding, how can more than one trial be justified? The results of CAPRISA 004 must be replicated for licensure, hopefully with higher levels of efficacy while still maintaining safety. Were only one confirmatory study to take place and not show efficacy with statistical significance, then the conundrum would be: of the two studies,which was flawed? This would compel another study, which would run out to at least 2017. Thus, to provide sufficient data by 2013 to unequivocally prove efficacy, a minimum of two confirmatory trials is required.

There is currently no certainty on which trials will go forward and which might end up on the scrap heap due to lack of funding. It seems likely that the trials with the smallest funding gap -- FACTS 001 and CAPRISA 008 -- will have the best opportunity to proceed. Stakeholders will soon be meeting with the U.S. Food and Drug Administration in order to discuss requirements for licensure, and this should help in the prioritization process.

The CAPRISA 004 results are an exhilarating breakthrough in biomedical prevention, a field that has been littered with disappointments over the years. Activists and researchers must capitalize on this breakthrough to secure small sums of money, relatively speaking, for the necessary confirmatory research. Cast under the shadow of the cost of lifelong treatment for women at the current level of HIV incidence, the funding requirements continue to diminish in relative terms. Most important, moving these confirmatory trials forward quickly has the potential to save millions of lives if the results support licensure.

UPDATE 10/25/2010: After this article went to press, CONRAD issued a press release summarizing the outcome of the meeting with the U.S. Food and Drug Administration (FDA). According to the release, FDA is willing to consider the VOICE trial as a second confirmatory study which could be used (along with the results of CAPRISA 004) as the basis for an application to license tenofovir gel. The FDA also granted tenofovir gel a Fast Track designation, which expedites the review of drugs which address serious life-threatening diseases and fill an unmet need.

CAPRISA 004 Resources

AVAC, "Understanding the Results of CAPRISA 004"

AVAC's CAPRISA 004 page

CAPRISA -- Centre for the AIDS Programme of Research in South Africa

Sean R. Hosein, Canadian AIDS Treatment Information Exchange, "PrEP -- Hope and Excitement Greet First Successful Microbicide"

Global Campaign for Microbicides: CAPRISA 004 Telebriefing and Satellite Meeting Webcast

Simon Collins, HIV i-Base, "Results from the Caprisa 004 Tenofovir Microbicide Trial"

Quarraisha Abdool Karim, Salim S. Abdool Karim, et al., "Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women"

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