AIDS in the U.S. has changed dramatically since the epidemic began 30 years ago. The advent of HIV combination therapy was a game changer for everyone living with the virus, turning what was once a fatal disease into a manageable condition. And now, signs are pointing to these same drugs as a way to bolster HIV prevention.
HIV medications have been used for some time to prevent HIV transmission, including the prevention of mother-to-child transmission and post-exposure prophylaxis (PEP, giving HIV meds after exposure to the virus). Studies have also shown that the likelihood of transmitting HIV to someone else decreases in people whose viral load has been suppressed by HIV treatment. Research is under way to expand this list further. For example, microbicides that contain HIV drugs and pre-exposure prophylaxis (PrEP) have both recently shown promising results in clinical trials.
Twenty years ago, these prevention strategies were merely a wish list based on the scientific logic that a drug that can lower the viral load of HIV in the body should also be able to reduce transmission of the virus. Slowly, these wishes are becoming realities.
Microbicides
Microbicides are gels or creams used in the vagina or rectum that are designed to prevent or reduce the sexual transmission of HIV and other sexually transmitted infections (STIs). Last July, the long-awaited results of the CAPRISA 004 trial were finally reported. This trial studied the safety and effectiveness of a gel containing Viread. It studied 889 women, aged 18-40, in South Africa who were advised to use the gel within the 12 hours before sex, and within 12 hours after sex.
Results from the study found there were 39% fewer new HIV infections in women who used the gel compared with those who used a placebo (dummy) gel. In women who used the gel more regularly, infections were reduced by 54%. Further, the study found that there was no resistance to Viread among women who used the gel and acquired HIV during the study. The gel also appeared to lower the transmission of herpes virus.
It is important to note that the CAPRISA results are only the first step toward an effective microbicide. The trial was done in a specific population, and the small number of participants limits the ability to apply the results to the general population. Furthermore, questions remain about the timing in applying microbicides. Can it be taken immediately before sex? Due to the dosing strategy of the study, no conclusions can be made about how the timing of use affects its effectiveness. More studies are being conducted to confirm and expand on the CAPRISA findings. These studies will also provide further information on the use of a daily gel and the rectal use of the gel.
PrEP
In November 2010, results of the first study looking at the safety and effectiveness of a daily oral dose of Truvada to prevent HIV infection were reported. The study, known as "iPrEx," was done from 2007 and 2010, and included 2,499 HIV-negative men who have sex with men (MSM) and transgender women who have sex with men. Participants were from Peru, Ecuador, Brazil, the U.S., South Africa, and Thailand.
People in the study took either a daily Truvada pill or a placebo. Everyone was interviewed once a month, tested for HIV, and counseled on adherence. They were given a physical exam every three months and tested for other STIs, receiving treatment if needed.
In addition to finding daily Truvada safe, the study found about 44% fewer infections in those taking it. Further, it found that PrEP reduced HIV infection by 58% among participants at higher risk for HIV (those who reported having unprotected receptive anal intercourse). This is a major step forward, as it is the first study to show the effectiveness of PrEP. Once again, the effectiveness of the drug was linked to adherence. Almost all of the men in the study who got HIV even though they were assigned to take Truvada didn't have any Truvada in their blood -- meaning they most likely were not taking it at all.
The other interesting finding was that adherence was not only lower than expected, it was also lower than people reported or than was shown by pill counts. Participants claimed at least 90% adherence, but measuring drug levels in their blood found that in reality it was about 50%. Based on pill counts and self-reports, the effectiveness of PrEP in people who took more than half their doses was 50%, and it was 73% in people who took more than 90% of their doses. People who took less than 90% of their doses showed only a 21% reduction in HIV infection. But the significantly lower actual adherence levels make analyses based on pill counts unreliable.
More data and results are expected in the months to come, and a rollover study is under way. This study offers Truvada to all HIV-negative iPrEx participants, and will provide important information on any changes in adherence and risk behavior when people know they are using a partially effective prevention strategy.
Several other PrEP trials are under way in African and Asian countries, in heterosexuals and drug users. PrEP is also being studied for different routes of HIV transmission, including vaginal intercourse and intravenous drug use. One study is comparing daily Truvada with or without a Viread microbicide, to look for differences in effectiveness, drug resistance risk, costs, and tolerance. Results are expected in early 2013, but we can expect to receive information on some of the studies later this year.
The Future
There are important questions to answer about the use of these new tools. With current ADAP waiting lists at 6,000 in the U.S., there must be careful planning as to how these methods would be used in the areas they are most needed. It is estimated that as many as half of all HIV-positive people in the U.S. are not currently receiving treatment. Black men, who are among the most vulnerable to HIV, show even lower rates of treatment. Efforts must be made to ensure that those at highest risk for infection are able to use the most up-to-date prevention methods.
Data suggest that PrEP can have a huge impact on the epidemic in the U.S. and be cost-effective if the following conditions are met: reaching MSM at highest risk for infection; providing PrEP along with other prevention tools, including condoms and risk-reduction counseling; and ensuring high levels of adherence among those taking the meds.
The target population for a vaginal microbicide will most likely be women in Africa. Sex workers, women who are unable to ensure monogamy, or those who are unable to use condoms for a variety of reasons, will also be targeted. Further, should microbicides prove effective in preventing HIV through anal sex, MSM would also be a target population.
People will need to come forward and identify themselves as part of the groups described above, so the success of a microbicide will depend heavily on community education. The gel will also need to be readily available and offered with confidential counseling services. But it should not replace condoms since it will not offer 100% protection. It must be explained to users that microbicides are part of a package, not a single magic bullet.
PrEP will likely be given to those most at risk. One group would be HIV-negative people with partners who have HIV. This means there will need to be increased counseling of people with HIV about disclosure. PrEP may also be recommended for people who have sex with someone who is at high risk for HIV. This includes sex workers and their clients, certain MSM, intravenous drug users, and men with more than one partner. PrEP will have to be stopped in people who become HIV positive or have severe side effects. This shows the need for regular follow-up, including HIV testing.
Risks
Since Truvada is already available by prescription, the CDC and other public health agencies are developing guidelines on its use as PrEP. Without this guidance, unsafe and ineffective use may occur. Among these concerns are the use of other HIV meds not used in the study and not proven safe for HIV-negative people; using a dosing schedule not proven effective (such as just before sex or only after sex); not screening for HIV before starting PrEP or waiting long periods of time before retesting for HIV; and providing prescriptions for PrEP without other HIV prevention support, such as condoms and risk-reduction counseling.
Additionally, reports suggest that some people are already using HIV meds not prescribed to them, following unapproved PrEP regimens. Studies of how they get the meds, and from whom, may help to eliminate a black market that could undermine any benefits of PrEP. A critical concern is that people who sell their HIV meds will miss their own doses, leading to drug resistance. This puts their health at risk and could increase community viral load.
The New York State AIDS Institute is currently seeking advice from an advisory group of clinicians to determine next steps, but it will take several months before guidelines are published. The AI is urging providers and patients to wait for guidelines to be released before using PrEP. The CDC recently released interim guidelines for use of PrEP for MSM. The guidelines specifically discourage anyone other than high-risk, HIV-negative MSM from using it (since there are no data in other groups), and instruct users to follow the regimen used in the iPrEx study. This includes daily dosing of Truvada, regular HIV testing, treatment of other STIs, and risk-reduction counseling and condoms. The interim guidelines also provide information on how best to discontinue PrEP.
The Cost
The retail price of Truvada is $14,000 a year in the U.S., and even though insurers and Medicaid pay less than that, the price to them is still in the thousands. If it is approved for PrEP, some have asked how a "chemical condom" that costs $38 a day could be justified when condoms themselves cost a few cents each. In the U.S., we would need cost-effectiveness analyses, perhaps calculating the cost of PrEP per infection avoided, to convince insurers and Medicaid that it is worth the money.
In developing countries, where generic forms of Truvada are available for as low as $143 a year, the picture is very different. If PrEP is approved in these countries, the biggest dilemma may center on providing HIV drugs for prevention when only 36% of people with HIV have access to these same drugs to save their lives. This lack of access to treatment makes justifying funding for PrEP challenging. Treatment alone, however, is not enough to stop the epidemic. With 56,000 new HIV infections in the U.S. and 2.7 million new infections worldwide, it is imperative that we utilize every prevention option available.
The Way Forward
Education about these two prevention methods will most likely be centered in health care facilities. This will require that they have enough personnel and supplies to provide high-quality services that are available to the most vulnerable people. And before these new methods are widely used, the general community, and people with HIV, must be educated about them. Education needs to be correct, easily available, and constantly updated about new prevention methods. Both microbicides and PrEP are still in the development phase, and each new result will bring both new information and new questions.
Samuel Kalibala is a Senior Associate and Country Director (Kenya) at the Population Council. Sarah Littlefield is a Clinical Trial Specialist in the HIV/AIDS Program at the Population Council. Robert Valadéz is a Policy Analyst at GMHC.