POSITIVELY AWARE NOVEMBER/DECEMBER 2010

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pills spillingHIV meds as HIV prevention

PrEP may be emerging as a viable form of prevention. But will people be willing to take HIV medication to avoid getting HIV?
by Jeff McConnell

An excited murmur had bubbled up through the audience and then washed back and forth across the auditorium like waves across sand. It was February 2006 at the Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. Previously, the CDC had presented data showing that Viread (tenofovir), a drug then commonly used against HIV infection, could prevent new infections by 70% in monkeys.1 Walid Heneine from the CDC had just told us that the combination formulation of tenofovir and FTC (Truvada) had been 100% effective against infection despite repeated exposure in the monkey model.2, 3

“What do you think, Javier?” I said to the principal investigator of the Peruvian sites of the HIV prevention clinical trial that would be called “iPrEx” and would test this idea in men who have sex with men (MSM). “I think that I want Truvada for our trial,” he replied, although planning for the trial with just tenofovir alone was well under way. In 2005 fundraising had failed to support the idea of a design to test tenofovir vs. Truvada vs. placebo, so we had held to the original plan of tenofovir vs. placebo. That is, until this new data on Truvada was presented.

“Well, Javier,” I said with certainty, “then you should have it!” Hours later, when a collection of researchers was sitting down to dinner at a restaurant on Denver’s 16th Street Mall, the iPrEx’s protocol chair and mastermind, Bob Grant, received a call on his cell.

Covering the mouthpiece he quipped, “It’s Jim Rooney!” Jim, who was also there for the presentation on Truvada, was vice president of medical affairs at Gilead Sciences, the company that made the combination drug. By the time appetizers were arriving, Bob ended the call with Jim and announced to the suddenly silent group, “I think we have Truvada for the trial!” Glasses rose in toast after toast to Jim Rooney and the drugs at Gilead, to Walid Heneine, and the monkeys at the CDC, and to us—a skeleton of the group that would grow over the next three years into 41 researchers on four continents making up the iPrEX study team. iPrEx is one trial in the “pre-exposure prophylaxis” (PrEP) research portfolio testing whether once-daily oral dosing of Truvada prevents HIV infection in high-risk HIV-negative individuals.

Over the four years since Denver, the murmur of excitement that grew in that convention hall has risen to a drumbeat of anticipation among some researchers and activists. Still, so many men and women who are already HIV-positive, or who are at considerable risk of getting there soon, have simply not heard of PrEP, and the same goes for HIV-affected individuals who serve our communities.

It is as if the second coming is upon us, but like that other second coming, if it arrives to find an unprepared mass, no salvation will ensue. And that is why I write today.

The Second Coming: Anti-Retroviral Treatment as HIV Prevention

The advent of combination anti-retroviral therapy (ART) for HIV infection around 1996 was a profound turning point in the epidemic. I could throw that reality at you with so many numbers you wouldn’t see straight for days, but I won’t, and you already know it anyway.

Is ART prevention the second coming in this pandemic?
The trials cannot tell us that. That is a question only
communities threatened by HIV can answer.

Instead, I will tell you that in the fall of 1995, just two months after I tested positive, I found out I had just 130 T-cells, and I was prescribed AZT and Bactrim. I refused the AZT.

“Jesus, man, you have AIDS. You need to be on something…at least a double combination, probably triple,” John said to me a month later, very quietly and calmly so as not to scare me, I suppose, all the while holding me in his blue gaze over a table in the Long Island diner where we regularly ate after the HIV-positive support group where we had met. John was gay, so hot I could hardly look at him even if he wasn’t looking back, HIV-positive for at least eight years, and a drywall contractor by trade. It would take a couple of months more to find a doctor who would equal John’s sage medical advice and several months more for ADAP to catch up. John’s advice had become “standard-of-care” treatment for us long before many medical practitioners got it.

Meanwhile, I eventually confessed my condition to a graduate school friend who cried herself asleep in my arms and, a few weeks later, passed on a fistful of HIV journals that her mother, top administrator at Boston’s Fenway Community Health Center (with a legendary HIV treatment program), “had around the house.” It was by pouring over these journals that I began my HIV education so that, by the time I was prescribed AZT monotherapy, I knew enough to reject it and the prescribing physician. Soon after I told my mother about my HIV, she discovered TPAN—I don’t know how, she lived in Colorado—and subscribed me to Positively Aware. This magazine immediately became a lifeline in a world suddenly seemingly filled with HIV-negatives who, however well-intentioned (or not), were of little help in learning how to live with HIV.

Although the ART drugs have been credited with changing the shape and experience of the epidemic, they were a necessary, but insufficient, cause of those changes. It took peer support, increasingly sophisticated activists, social networks, political organizing, policy changes, and, eventually, a little help from our friends to save our lives.

And this insight is perhaps even more important for HIV prevention, where the biggest miracles happened long before the drugs. The most effective examples of HIV prevention have been demonstrated by grassroots community action starting in the 1980s.4 While the popularity of condoms has waned, sero-adaptive tactics arising from the bottom up among affected communities are increasingly credited with keeping rates of infection stable in some U.S. MSM populations since the mid-1990s and through the last decade.5, 6

But HIV incidence that is stable in some communities of MSM is stable at rates that are too high. In women and among the poor in the U.S., even stability has not been achieved, and worldwide, nearly three million new infections every year convince us that we are losing the battle to beat HIV. A scramble for new options to prevent HIV infection has ensued, but there have been disappointments with vaccines, microbicides, other biomedical interventions, and behavioral interventions.

HIV prevention has seemed dead in the water for some time.

Perhaps, we will soon be finding out if ARVs (anti-retrovirals) work to prevent HIV infection in clinical trials among MSM, women at high risk, heterosexual couples, and injection drug users. But it is most important that we are not deluded about why the drugs worked so dramatically for treatment; they were the icing on an already baked cake, even if it was the icing that would make the cake.

Can Jim Rooney and the drugs from Gilead, Walid Heneine and the monkeys at the CDC, and investigators Javier Lama, Bob Grant, and the clinical trials of PrEP in people turn the tide on HIV?

Is ART prevention the second coming in this pandemic? The trials cannot tell us that. That is a question only communities threatened by HIV can answer.

ARVs as Prevention

When ARV therapy drove our viral loads to undetectable levels, many of us wondered if it must not also be making us less infectious. It has long been a controversial idea, but the idea’s time has come.

Observational studies of sero-discordant couples in Rakai, Uganda a decade ago discovered that no HIV-negative partners of persons living with HIV/AIDS (PLWHAs) who had low viral loads became infected.7 More recently, health records of PLWHA have been used to calculate “community viral load.” The idea is that widespread ARV treatment effectively suppresses viral load in positive individuals and therefore lowers the overall “community viral load” and must also curb the spread of the epidemic in the community. Lowering community viral load as an activity accomplished among PLWHAs is now being pursued as an HIV prevention strategy aimed at the HIV-negative community.8 The new HIV management strategy called “Test and Treat” (or now TLC-Plus—test, link to care, plus treatment) that has emanated from the U.S. Centers for Disease Control and Prevention (CDC) and the Obama administration is not just about identifying and caring for PLWHAs, it is a structural HIV prevention strategy: the more HIV-positive people on treatment, the fewer new infections.9-12 Finally, just this summer, a study in Africa reported that in sero-discordant heterosexual couples ARV treatment that suppressed viral load in the HIV-positive partner reduced infections in their partners by 92%.13

Our decision to start antiretroviral therapy and stick with it is no longer a PLWHA SOS (save our souls). It has become a way of caring for the health of our HIV-negative brothers and sisters too.

ART for prophylaxis against infection in HIV-negative individuals is not a new idea. Some had proposed it back when the drug options included ddI, AZT, and the first of the protease inhibitors. Besides making us feel miserable when we took them, however, those drugs preserved life long enough to reveal they also had long-term adverse health outcomes. When HIV-positive individuals began taking treatment interruptions to get a break from the daily side effects and possibly to stave off the longer term ones, it was evident that the drugs themselves were perceived to pose a health threat that, if not quite as severe a threat as HIV itself, clearly had to be measured and balanced against it.

No one really knows if HIV-negative individuals
will take to the idea of pills for prevention
or if they, their insurers, and their
governments will pay for this kind of prevention.

Newer generations of ARV medications have been remarkably kinder and gentler, so much so that the idea of the treatment interruptions, structured or otherwise, has somewhat faded from the culture and from research.

Gilead and Tenofovir

By 1995 the molecule (yup, that’s where our drugs start) that Gilead Sciences turned into the ARV they named Viread (tenofovir) was already generating some evidence that it might protect against getting HIV.14 As far as I can tell, Gilead simply did not know what to do with this information.

They did, however, know what to do with the other potential of Viread; it was soon approved by the FDA (2001) and became our first choice for both initial (or front-line) and salvage therapy. Compared to what we started with, Gilead (other companies have done likewise to be sure) has helped to make HIV treatment tolerable and simple enough for PLWHAs that we were given to revisit the question: instead of waiting to treat individuals who become infected, why not use simple and tolerable ARV drugs to prevent infections in the first place?

As the results of tenofovir and Truvada trials are reported, we will learn more about whether the idea of ART pre-exposure prophylaxis works at all. Still, Gilead has played an historical role in biomedical HIV prevention. Though it has sponsored none of the current human HIV-prevention trials using their drug, it has donated the drugs, and provided expert logistical support. Gilead is an example that we can point to when we find other promising PrEP drugs at other HIV ARV-producing companies.

Walid Heneine and the Monkeys at the CDC

Sometimes science proceeds in a fashion that you can really admire. A variety of researchers have conducted experiments in animal “models” to explore whether tenofovir and/or FTC can be effective at preventing infection. Many had positive results, but the models were so different it was difficult to make general conclusions even for the animals, which were most often monkeys (some great studies have been done in mice too).3 Among others, the research has been led by Walid Heneine and Geraldo Garcia-Lerma. They used oral doses of the drug comparable to once-daily dosing in humans (and apparently the monkeys pose their own challenges about certainty of adherence), concentrations of virus comparable to what one would get from sex, and administered it through a rectal or vaginal exposure procedure that’s more like sex than injection through a needle.

At last, the results from the animal model studies began to add up in ways that might apply to people and inform the design of randomized clinical trials.15

During his talk in one smallish conference, the charming Spaniard Garcia-Lerma offered to “jump up and down like a monkey” in excitement about not just what happened in the labs, but also because study sponsors, such as the U.S. National Institutes of Health, the CDC, and Family Health International; co-funders like the Bill and Melinda Gates Foundation; scientific investigators such as Javier Lama and Bob Grant; drug companies like Gilead, often represented by Jim Rooney; activist organizations such as the AVAC and Project Inform; and many others are at last all at the table planning these investigations together. However, when clinical PrEP trials reach their end points and report their results, the question of whether PrEP is a safe and effective alternative for HIV prevention will only just have been posed, a question that can ultimately only be answered by those at risk of contracting HIV.

ARVs for Negatives: Variations on a Theme

There are several ways in which ARVs may contribute to HIV prevention among HIV-negative folks. Biomedical effectiveness is but one measure of how useful drugs might be in preventing new infections. Here is what you need to know about various strategies under consideration.

Post-exposure Prophylaxis (PEP)

The idea of administering one month of combination ARV therapy as soon as possible after a possible high-risk exposure to HIV has been in practice for several years. Studies have shown that PEP decreases the chance of sero-conversion in medical settings where exposures occur from accidents like needle-sticks. Observational studies have examined humans after sexual exposure, but we do not have good evidence that PEP is effective in these situations. In places such as San Francisco, while PEP may be considered the standard of care for individuals who report high-risk sexual exposure to their physicians soon after it occurs, it appears that use or “uptake” in the community is low. PEP is infrequently requested, and in one Brazilian study, even when individuals were provided with a PEP starter pack (a few days’ supply of ARVs) to begin once exposed, participants sero-converted who never actually started the pills.16 In developing countries, where the expense of ARVs remains a barrier, the lack of evidence that PEP actually works has precluded widespread use. Even in the U.S., outside of urban centers with highly developed HIV treatment and prevention programs, it is unclear how many individuals at risk for HIV, and the physicians that they might consult, really know about PEP.

ARV Topical Microbicides

Unlike condoms, which require the active cooperation of male partners, topical microbicides or gels that can be inserted in the vagina or rectum before and after sexual intercourse present the opportunity for women and men to protect themselves without their partner’s cooperation or even knowledge. Several formulas that killed HIV under laboratory conditions have been tested in randomized clinical trials in women. Until this summer, none had been proven to work. In fact, in clinical trials, the once popular nonoxynol-9 spermicide was shown to actually increase risk of infection by as much as 50% in women.17

Interest in the idea of using ARVs formulated into gels as microbicides has been growing for some time. In his address at CROI last February, NIAID Director Anthony Fauci made it clear that while other possible microbicide agents were not off the table, the idea of using ARVs in gels would receive priority in trials until their effectiveness could be rigorously tested in people. (Again, the results in animal models, both monkeys and mice, are promising.)

The first great breakthrough in the microbicide field was announced this summer at the International AIDS Society (IAS) Conference in Vienna. The CAPRISA study showed that 1% tenofovir in a gel that was to be inserted in the vagina one hour before and again after sexual intercourse decreased HIV infection by 39%. As it turns out, few women in the trial consistently used the gel as directed, but among those who used it at least 80% of the time as directed, HIV infections were reduced by 54%!18

The story of ARVs used in gels as topical microbicides is still being written (see “Let the Sun Shine In,” page 26). It will be important to understand whether increased concentrations of the gel, or increased adherence to using the gels as directed, might be more effective. Finally, expect a rush toward formulation, and hopefully clinical trials, of ARV gels that can be safely used in the rectum during anal intercourse.

Oral Pre-exposure Prophylaxis (PrEP)

Once-daily dosing of tenofovir (Viread) has proven safe and tolerable in PLWHAs, and effective against HIV infection in monkeys and mice. Compelling ideas for oral PrEP are that, like microbicides, it can be used regardless of a partner’s knowledge or cooperation and, unlike PEP, it can be taken routinely without regard to whether a possible exposure will happen and without having to come to the conclusion that what did happen was a risky exposure.

Clinical trials among women in West Africa and MSM in the U.S. have been completed and reported no adverse safety concerns, but the studies were not designed to show if PrEP effectively prevented infection and caused some controversy.19 iPrEx, a study of 2,499 MSM on four continents, is designed to show whether PrEP can prevent infections in this population. The first results from this trial will likely be reported soon after this article goes to press. A CDC study of injection drug users in Thailand may be able to report on efficacy before the end of the year or soon after, too.

Intermittent Pre-exposure Prophylaxis (iPrEP)

As nearly as we can tell, one of the most consistent questions about daily PrEP from communities at risk is based on the following logic: “If I don’t have sex every day, at least not risky sex, why should I take a pill every day?” Researchers and activists have been posing the same question. Less frequent dosing would be less expensive, any side effects would be milder, and the more sense the idea makes to folks at risk, the higher uptake is likely to be. Well, Garcia-Lerma and those monkeys have been at work on that one too. Indeed, in monkeys, a variety of intermittent strategies have been highly effective against infection, the most effective always including at least one dose before exposure and another after.

Sponsors have warmed up to the idea. Family Health International is conducting a small trial in Africa. The NIH HIV Prevention Trials Network is planning two small trials in MSM and women. None of these will tell us if iPrEP is effective, but rather if it is feasible. I would bet that if daily PrEP trials show some efficacy, the idea of iPrEP will receive a great deal more attention and funding.

Back to John, ARVs for Prevention, and Community

No one really knows if HIV-negative individuals will take to the idea of pills for prevention or if they, their insurers, and their governments will pay for this kind of prevention even if it works in human trials like it works in the monkeys and mice.20

Remember my friend John, the guy who had the guts to tell me I had AIDS to my face and then what I needed to do about it when my doctor didn’t? I try to picture John across the table from some guy in a Long Island diner saying something like this.

“Jesus man, again? That’s three times in the last month without a condom. You need to change something…you need to think about PrEP.” Would John say something like that? You know, if he knew it was effective, even partially, and John would know this, I think he might.

Would you?

J. Jeff McConnell is a sociologist who began his career studying suburban homelessness on New York’s Long Island and in Westchester County. For 10 years, he has conducted studies of HIV superinfection and sexual sero-adaptation among HIV-positive couples and singles at the Gladstone Institute of Virology and the University of California in San Francisco. He is currently co-investigator on the HIV prevention clinical trial “iPrEx,” focusing on the social and behavioral impact of PrEP among men who have sex with men.

References

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  17. D'Cruz, O.J. and F.M. Uckun, Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des, 2004. 10(3): p. 315-36.
  18. Abdool Karim, Q., et al., Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science, 2010. 329(5996): p. 1168-74.
  19. Grant, R.M., et al., AIDS. Promote HIV chemoprophylaxis research, don't prevent it. Science, 2005. 309(5744): p. 2170-1.
  20. Underhill, K., et al., Implementation science of pre-exposure prophylaxis: preparing for public use. Curr HIV/AIDS Rep, 2010. 7(4): p. 210-9.

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