Microbicide Field Wrestles With the Implications of Success

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:

• MDP 302 is a confirmatory study to be led by the MRC Microbicides Development Programme that will take place across sub-Saharan Africa. This trial will differ from CAPRISA 004: the dosing regimen will be one of single use before sexual intercourse. The trial is estimated to cost US$40 million and there is approximately $7 million from the UK government believed to be allocated for this trial. It is possible that the funding gap will be reduced after a full spending review by the new UK government in late October or early November 2010. Nonetheless, there will be a considerable shortfall that will need to be addressed before the trial can move forward.
• FACTS001 is another confirmatory trial in South Africa, which is in a draft protocol stage. In addition to a study arm to confirm efficacy of tenofovir-based gel as prevention for HIV, another arm will study the effects on HSV-2 prevention. A subgroup will undergo an intensive safety study in 16- and 17-year-old girls. The South African Ministry of Health and its Ministry of Science and Technology, as well as assistance from USAID, will fund the trial. CONRAD is providing tenofovir gel for the study. While the draft budget has not yet been finalized and is likely to change in the review process, if all donors make good on provisional commitments, funding is likely to come up short by roughly $3-$5 million.
• CAPRISA 008 will study the effective-ness of using family planning clinics as a method for distributing tenofovir gel in communities where the trial took place. The control arm will use the same protocol as CAPRISA 004 and provide tenofovir gel to participants who did not seroconvert during the trial; the intervention arm will use trained nurses to provide counseling and gel distribution in family planning clinics. The study is designed to help determine effective ways of implementing programs to distribute the microbicide once licensure is secured.
• CAPRISA 009 will follow all trial participants who became HIV infected during CAPRISA 004 and will test the effectiveness of tenofovir- and non-tenofovir-based first-line treatment for HIV. The study will monitor the evolution of the disease to see if there are differences among women who took part in the trial and to ensure that these volunteers receive appropriate care and treatment. This data will contribute to design of future trials and to the safe and proper use of microbicides if licensure becomes a reality. It's important to note that all women who became HIV-positive during CAPRISA 004 will receive care and treatment for HIV whether or not they participate in CAPRISA 009. The two additional CAPRISA studies will cost, collectively, an estimated $19 million in total over three years. CAPRISA 008 is in draft protocol and is provisionally funded by the South African Government and USAID. CAPRISA 009 is very early in development, but is estimated at $4.5 million for three years.

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.