Long-awaited results were released today in the New England Journal of Medicine of a study on the effectiveness of a single daily tablet for preventing HIV transmission among those at high risk of infection. Findings from the iPrEx trial, conducted among HIV-negative gay men, transgender women, and other men who have sex with men (MSM), showed that individuals who took the oral therapy containing two widely-used HIV medications, emtricitabine and tenofovir (FTC/TDF), experienced an average of 43.8 percent fewer HIV infections than those who received placebos. The combined antiretroviral drug is known under its brand name as Truvada.
The trial, as summarized by Medscape and in a release from the AIDS Foundation of Chicago (AFC), included 2,499 participants, including individuals from Peru, Ecuador, Brazil, South Africa, Thailand and the United States.
Half the men were randomized into the active arm that received Truvada, which is currently approved by the US Food and Drug Administration for treatment of HIV infection, and the other half were randomized into the placebo arm and received a look-alike pill with no active ingredient. All the participants tested negative for HIV at the beginning of the trial, but reported engaging in sexual practices that put them at high risk for infection. Both groups in the study were followed up for over a year, also received HIV education, testing, and condoms. Neither the participants nor the researchers knew who was assigned to which arm (placebo or Truvada) of the study.
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Enrollment for the trial began in June 2007 and was completed in December 2009. The primary analysis of the results released today includes participants who were followed until May 1, 2010, or for an average of 14 months.
Each participant was tested for HIV at monthly trial visits and given intensive pre-and-post test counseling. Additionally, they were regularly screened for sexually transmitted infections and received condoms, making up a very robust prevention package.
Study materials note that while pill-taking measures that rely on self-reports are not objective, testing to measure levels of the PrEP drug in the blood of study participants — a more reliable measure of pill-taking — also indicated that those participants who were protected against HIV infection were likely taking the study drug more regularly. Among a subset of study participants who received the active drug, detectable levels of the PrEP drug combination were found in the blood of 51 percent (22 of 43) of a group that remained HIV-negative, but in only 9 percent (3 of 34) of participants who became HIV infected. Low or absent drug levels underlay all of the infections that occurred among those who received active PrEP, while those who used the drug more regularly had higher levels of protection against HIV infection.
At the end of the trial, there were 36 infections in participants who received Truvada and 64 in recipients who took the placebo. Researchers calculated that the use of Truvada reduced new HIV infections by an estimated 43.8 percent overall when compared to placebo. While there appeared to be few side effects reported by the men who were taking the Truvada tablet, researchers and advocates make clear that much more information is needed regarding long term safety of this drug.
Advocates and researchers alike expressed cautious excitement about the development.
“This discovery alters the HIV prevention landscape forever. While this level of efficacy is relatively strong, PrEP is not quite ready for prime time and work remains before this strategy is rolled out. However, we are thrilled to have a new prevention option beyond male and female condoms visible on the horizon,” said Jim Pickett, Director of Advocacy at (AFC) and Chair of IRMA – International Rectal Microbicide Advocates (IRMA). The full IRMA statement can be found here.
According to AFC: “It is important to emphasize the factors that led to successful use of Truvada to prevent HIV in iPrEx.” Adherence was a critical, so that taking the pill regularly was one of the most important factors in reducing the risk of infection. According to AFC, men who did not take the pill regularly did not see a protective benefit.
Regular HIV testing and ongoing monitoring by a physician was also critical. For this strategy to work, each of these pieces, including a doctor’s prescription, need to be in place.
“The study team found that about half of the men in the active arm of the trial were in fact not taking their pills regularly, if at all,” said Pickett of AFC. “It is not clear why this happened, but it certainly suggests that alternate means of using ARVs to prevent HIV infection may be more acceptable for these men. The primary means of transmission among gay men and other MSM is through unprotected anal intercourse. If we develop an ARV as a gel or lubricant applied rectally – a rectal microbicide – it could be more acceptable for some individuals who don’t like taking pills.”
Many gay men and other MSM already use lubricants for anal intercourse, notes Pickett, so they wouldn’t have to modify their behavior to achieve higher levels of protection with a rectal microbicide formulated as a lubricant. Adopting a new behavior—such as taking a pill every day—can be a considerable challenge for some.
A statement from The Global Forum on MSM & HIV (MSMGF) said that:
“These findings are promising and show that there is a potential role for PrEP to play in HIV prevention for MSM. However, with this new reality comes the fact that we, as a community of advocates, must now confront difficult questions about roll-out, cost, HIV-prevention messaging and the place PrEP takes in a broader continuum of prevention interventions.”
Today, said MSMGF, “Access to ARVs remains extremely difficult around the world. UNAIDS has estimated that only 36 percent of people living with HIV who need ARVs could access them just one year ago.”
Implementation of PrEP is highly unlikely in countries where access to ARVs is already seriously limited. Even in places where access to ARVs is more stable, PrEP will likely be targeted to groups most at risk for HIV, including MSM. This would in turn require disclosure of same-sex behavior, which could prove difficult or even dangerous in countries where violence, stigma and discrimination against MSM persists.
The iPrEx team has rightly noted that this is not a study of PrEP in a vacuum, but a study of PrEP when combined with a suite of other proven HIV prevention interventions – a state-of-the-art model of combination prevention, which may have been an important contributing factor underlying these encouraging results, continued the MSMGF statement.
However, the additional components of this intervention also remain out of reach for the vast majority of MSM; an estimated 90 percent of MSM globally lack access to even the most basic prevention services. To achieve true combination prevention, we must not only significantly expand access to ARVs, but also promote much greater access to condoms, lubricant and other basic sexual health services.
Another challenge of concern according to MSMGF and others is the question of adherence, especially outside a study context. Although study participants learned about PrEP and the importance of adherence as part of the trial protocol, researchers reported that only about half of study participants took the medication consistently. Compounding the problem of adherence is the challenge of developing communication strategies about an intervention that is just 44 percent effective – and only when taken in combination with a full complement of prevention services.
Dr. Ian McGowan, one of the principal investigators of the Microbicide Trials Network and Scientific Vice Chair of IRMA agreed.
“The data from the iPrEx study are encouraging but the less than ideal adherence rate to oral PrEP clearly show that we need additional prevention approaches such as rectal microbicides that could be used by men and women at risk of HIV infection through unprotected receptive anal intercourse,” he said.
The world’s third rectal microbicide trial is currently underway with sites in Pittsburgh, Pennsylvania; Boston, Massachusetts; and Birmingham, Alabama. Scientists are testing the rectal safety and acceptability of tenofovir gel, a microbicide developed for vaginal use that has shown promise for preventing HIV through vaginal intercourse. Depending on the outcome of this new study, tenofovir gel could be further evaluated to determine if it can reduce the risk of HIV among both men and women who engage in receptive anal intercourse.
According to IRMA’s Pickett, this new Phase I rectal microbicide study, known as MTN-007, aims to determine if rectal use of tenofovir gel is safe, and in particular, does not cause cells in the rectum to become more vulnerable to HIV. Investigators will also ask trial participants questions regarding the gel’s desirability. The trial is planning to recruit a total of 60 men and women.
While the rectal microbicide field has gained significant momentum, more focus and resources are needed. In 2010, U.S. $7.2 million is being spent globally on rectal microbicide research. IRMA has calculated that annual investments must increase by 40% from 2011 – 2014, to U.S. $10 million/year and must increase further to U.S. $44 million (a six-fold increase) in the years 2015 – 2020. These targets need to be met to ensure a minimum of candidate products are moving through the research pipeline into late stage testing for effectiveness.
As noted in Medscape, the iPrEX is the second major study this year demonstrating the efficacy of PrEP. In July, South African researchers in what is known as the CAPRISA 004 trial published an article in Science Express reporting how a vaginal gel containing tenofovir lowered the risk of HIV infection in sexually active women by 39 percent.
As these highly promising advances in both science and technological are being made, researchers and advocates both underscore again and again there is no silver bullet.
“PrEP is best conceived as a back-up [to more direct HIV prevention strategies],” said Robert Grant, MD, lead study author of an article published online today in the New England Journal of Medicine that reports the study findings.
Other PrEP trials are ongoing. Results from studies among heterosexuals in Africa and injection drug users in Thailand are expected next year.