Top HIV/AIDS-Related Clinical Developments of 2010
December 8, 2010
Table of Contents
As an action-packed year for the HIV/AIDS community draws to a close, TheBody.com takes stock of 2010 in a new series of articles, "HIV/AIDS Year in Review: Looking Back on 2010 (and Ahead to 2011)." Read the entire series here.
The first year of a new decade, 2010 could have been the year of hope. Political spin masters dangled it before our eyes -- luring us, a divided nation, to come to their side -- only to cause more division. As the economic crisis continues to put the hammer to life as we know it, hope is all that many of us feel we have left as we try to make do with less.
In HIV-land, we also hope -- for better therapies for those living with HIV and for the beginning of the end of an epidemic that is just getting old. This past year, we saw some bright glimmers of success where before there was stagnation. A series of remarkably positive results in HIV prevention promises to move us into a new era of interventions designed to stop people from giving each other HIV. In HIV therapeutics, the pipeline of new antiretrovirals has spurted again and additional coformulation of these and older medications will mean even more convenient choices for patients.
Such developments made for a better year in HIV than many could have expected given the grim headlines. They signal, as we move through the tweens to the teens of this decade, that the prevention of new infections and the care for those who acquire HIV will continue to advance; that HIV research will continue to be a marvel of medicine; that there is good reason to hope.
A review of:
Controlling the spread of HIV has been a vexing and complex public health challenge. The physical mechanics are really not the problem: Keeping one person's virus-laden fluids away from the vulnerable cells of another is something most with a well-developed frontal cortex can figure out how to do, technically speaking. But latex barriers -- despite their colorful names, choices of textures, and fruit-inspired flavors -- have just not cut it, and efforts that rely heavily on getting men to put on condoms can be summed up with a word: failed.
There have been a number of different creative approaches to the whole keep-your-virus-off-my-cells approach, including protective and therapeutic vaccines, male circumcision, pre- and post-exposure prophylactic treatment and microbicides. However, with the important exception of circumcision -- which has demonstrated modest success in preventing HIV transmission, but has its own drawbacks and limitations -- these strategies have had poor efficacy, leading to much head hanging and dour faces at HIV prevention conferences.
One can therefore understand the ebullient and triumphant response that greeted the first public report of the results of a Centre for the AIDS Programme of Research in South Africa (CAPRISA) trial this year at the XVIII International AIDS Conference held in Vienna.
CAPRISA 004 was a South Africa-led trial of a 1% tenofovir (Viread) vaginal gel that enrolled HIV-uninfected women 18 to 40 years of age at two clinical sites in that country, one urban and the other rural. The trial was a double-blind study. Participants were provided with pre-filled vaginal applicators (those that contained the study gel were indistinguishable from those that contained a placebo gel) and instructed to insert the assigned gel within 12 hours before sex and a second dose of gel as soon as possible within 12 hours after sex (the so-called "BAT24" approach, short for "before and after sex within 24 hours"). All participants received HIV counseling services, condoms and sexually transmitted disease screening and treatment at entry and each subsequent study visit. The enrolled women also received assistance in learning to use the gel to increase comfort and adherence.
During a maximum of 30 months of follow-up (mean was 18 months), 38 of the 445 women assigned to the active gel versus 60 of the 444 assigned placebo became infected with HIV. The HIV incidence rate in the tenofovir gel arm was 5.6 per 100 women-years (confidence interval [CI], 4.0 and 7.7) compared with 9.1 per 100 women-years (CI, 6.9 and 11.7) in the placebo gel arm (IRR = 0.61; CI, 0.40 and 0.94; P = .017). Therefore, at the primary endpoint of 30 months follow-up, the incidence rate for women receiving tenofovir gel was 39% lower than for the placebo-assigned women.
Adherence to the gels was assessed carefully; the investigators even requested that women return used applicators, which were then inspected for signs of use. Remarkably, over 95% of applicators were returned. Women in both study groups reported a mean of approximately 5 sex acts per month. Self-reported condom use was high at around 80%. When looking at adherence and efficacy, it was observed that among those with greater adherence, the effect size increased: Even fewer women in the tenofovir arm acquired HIV relative to the control arm. Elegant studies led by Dr. Angela Kashuba looking at levels of tenofovir in the cervical-vaginal fluid corroborated this finding. Interestingly, the effectiveness of the tenofovir gel seemed to wane over time, with a greater effect observed early in the study. However, this may reflect a decrease in adherence to the gel over time, rather than a flaw with the gel itself.
Overall, the gel was found to be safe, although there were some complaints of the compound being a bit on the messy side. There was more diarrhea reported among those on the active gel, but otherwise tolerability was no different between the study arms. For those who did seroconvert while receiving active tenofovir gel, there was no impact seen on plasma viral load or demonstration of tenofovir resistance.
A fascinating aspect of the trial was the observation that the rate of herpes simplex virus (HSV) type 2 seroconversion during the study was less among those assigned to the tenofovir gel. A lesser-known fact is that tenofovir has activity against HSV, but only at high concentrations of the drug. It is possible that the gel achieved high enough levels in the genital tract to protect some women against HSV acquisition.
The Bottom Line
The cheers that greeted the CAPRISA trial findings were not for the modest 40% reduction in infection with tenofovir gel -- a result that would send a vaccine back to the drawing board. It was a response by a community of researchers and advocates hungry for any success of a microbicide. Prior studies of earlier compounds found not only a lack of effect but, in the case of nonoxynol-9, what actually appeared to be an increased susceptibility to HIV.
The triumph of CAPRISA 004 is a starting point. There are aspects to tweak, including the timing of applications and formulation. In addition, the trial was rigorous in describing the association between adherence and efficacy of the gel and the need to develop interventions to support women using this compound. Lastly, it is unclear whether a combination of antiretrovirals (for instance, a gel containing tenofovir plus emtricitabine [FTC, Emtriva]) would offer better protection.
There are additional studies underway and planned. Meanwhile, the prospects of a woman-controlled HIV prevention method seem much closer now than just a few months ago. Score!
This article was provided by TheBody.
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