Preparing for PrEP
We know it works. But how do you get people to take it?
By Regina McEnery
Clinics in Southern California will, in the next few months, begin enrolling 400 volunteers for a study examining a particularly troublesome aspect of pre-exposure prophylaxis (PrEP) against HIV. PrEP trials have, of course, been done before. But the focus of the study this time around is somewhat different—reminiscent of nothing quite so much as mom begging you to, please, eat your peas. In this case, however, it won’t be moms doing the cajoling but HIV prevention researchers. The folks getting cajoled, meanwhile, will be men who have sex with men (MSM) in a pattern and manner that puts them at great risk of HIV infection.
Turns out the Southern Californian researchers won’t be the only ones doing this routine. Nearly two dozen similar studies examining adherence are either already up and running or about to start. Their ultimate aim is to figure out how to translate PrEP into a practical public health intervention. Large-scale trials have now established that PrEP using the antiretroviral drugs tenofovir and a tenofovir/emtricitabine combo called Truvada can dramatically lower the risk of transmission in high-risk men and women. But to do so, they have to be taken faithfully, and they often are not. And most studies have not been designed to vet possible solutions to that fundamental problem.
To be sure, the problem is not, well, easy-peasy. Researchers would like to make PrEP as attractive to adults as a gummy-bear multivitamin is to toddlers (and some adults). But even in the context of a clinical trial, where volunteers are monitored regularly by researchers, getting people to take pills faithfully has been an uphill battle.
The results were mixed. The international iPrEX study found, for instance, that daily Truvada lowered HIV risk among MSM by 54%. Similarly, Partners PrEP established that a single dose of tenofovir (TDF) reduced the risk of infection by 62% among a cohort of 4,758 serodiscordant couples (SDCs), while daily Truvada reduced HIV infection risk by 73%.
Most recently, a daily dose of oral tenofovir lowered HIV incidence by as much as 50% in a study of 2,413 injection drug users in Thailand. Yet other studies, such as VOICE and FemPrEP, which both happened to focus on high-risk heterosexual women in Africa, didn’t show any efficacy. (VOICE evaluated topical and oral tenofovir as well as Truvada, while FemPrEP only focused on Truvada.)
In all of these studies, adherence was found to be the primary—perhaps sole—determinant of PrEP efficacy. “We must never forget that PrEP is not just a pill,” says Mitchell Warren, executive director of AVAC, the HIV prevention advocacy group based in New York. “It is a program, a new intervention that includes an antiretroviral pill. We know the pill can work. But we have not systematically designed or assessed the programs that might best translate that ability to work into public health and prevention.”
Hence, this new phase of PrEP research—a collection of demonstration projects, off-label studies and pilot studies that are all, to one degree or another, searching for ways to make PrEP practical.
Demonstration projects are designed to focus more on program design for new interventions than on assessing efficacy. As such, they can be helpful to the rollout of novel interventions in the real world. Open label studies describe a type of clinical trial where both the investigator and the study participant know the treatment being administered. In the case of PrEP, the approach is being used to examine and improve compliance.
Warren says these studies and others will be crucial to the future of PrEP. “We need to determine who really wants it, who needs it, who gets it, how do we help them get it, who pays, and who decides,” says Warren. “None of these questions got answered in the efficacy studies.”
The solution could lie, in part, in the ubiquitous cellphone. The Southern California demonstration project will try and boost adherence to Truvada by texting MSM volunteers a daily reminder. The drug was initially developed by Gilead Sciences to treat HIV, but a year ago the US Food and Drug Administration granted the biotech approval to market once-daily Truvada for reducing the risk of acquiring HIV in high-risk adults on the strength of the efficacy data (see FDA approves Truvada for use in PrEP, IAVI Report Blog, July 16, 2012).
The study will enroll men at clinical sites in San Diego, Long Beach and Los Angeles and is to be conducted jointly by the California Collaborative Treatment Group (CCTG) consortium, which includes the Harbor-University of California-Los Angeles, University of Southern California and University of San Diego (UCSD). It will not include any HIV-uninfected MSM who took Truvada as part of an earlier trial, says Richard Haubrich, professor of medicine in the Division of Infectious Diseases at UCSD, who heads the CCTG demonstration projects, known as ALERT.
Haubrich says half of the MSM will be randomized to a group that will receive safe sex counseling along with their Truvada. The other half will, in addition, get daily texts. The study was designed to test the benefit of using a text message intervention called iTAB (Individualized Texting for Adherence Building), which was developed by David Moore, an associate professor of psychiatry at UCSD.
The phrasing of the text messages can be deliberately generic—something like ‘Take your blue pill and stay healthy’—or more specific, such as, ‘Did you take your Truvada today?’ To keep them motivated, the men will also receive an accompanying “fun fact” from a pre-selected list of topics that are tailored to their specific interests and tastes. These might be fun facts about music, movies, sports, nutrition, and other topics. (Here’s one example: “In ‘Terminator 2: Judgment Day,’ Arnold Schwarzenegger received a salary of US$15 million; the 700 words he spoke translate to $21,429 per word”.)
“We all understand that the biggest challenge [in PrEP] is adherence to therapy,” says Haubrich. “So we chose to design a randomized study to use text messaging to augment [adherence]. The beauty of this system is that the men can control the wording of the message and they can respond that they took their medicine with a single key stroke.”
The hope, of course, is that the men will answer every day in the affirmative. If they do, they’ll get a reply, such as “Good job.” But the study participants also have the option of ignoring the texts, or ’fessing up and saying, “No, I haven’t.”
“There is a lot of interest in cellular and mobile technologies for health uses,” says Haubrich. “It’s really a burgeoning field.” Haubrich says one of his colleagues is using a sensor that records ingestion of medicine and then wirelessly transmits the data to a clinician of the patient’s choosing, so that the clinician can keep track of the patient’s adherence.
Location, location, location
Another demonstration project involving MSM is looking at the acceptability, feasibility and safety of administering PrEP in different real-world clinical settings. The study, known as the Demo Project, is offering daily oral Truvada to 600 HIV-uninfected MSM and transgender women in San Francisco, Miami, and Washington, D.C. The cities were chosen because they are heavily impacted by HIV and have large MSM epidemics. In San Francisco and Miami, men are being recruited from sexually transmitted disease (STD) clinics, while men from Washington, D.C. are being recruited from a community health center. As adherence is critical to the effectiveness of PrEP, the primary goals of the Demo Project are to evaluate PrEP adherence among MSM and transgender women in real-world clinical settings and to determine factors related to adherence.
“We initially started with STD clinics, given the substantial proportion of MSM patients at risk of acquiring HIV in these settings, and subsequently added a community health center site as well,” says Albert Liu, director of HIV Prevention Intervention Studies at the San Francisco Department of Public Health and the lead investigator in the Demo Project. This diversity of sites will provide important information on staffing and space for effective delivery of PrEP in different care delivery systems, he says. “Typically, STD clinics aren’t set up to see people in an ongoing fashion in terms of longitudinal care, whereas community health centers are.”
Participants in the Demo Project will visit the clinic one month after initiating PrEP, and then every three months for clinical monitoring. While follow-up visits were monthly in PrEP clinical trials, PrEP demonstration projects will help determine whether less frequent clinical monitoring can provide adequate support and safety monitoring to PrEP users. This question is important, he says, because otherwise healthy individuals may not be inclined to visit the doctor all that often. Frequent clinic visits may also burden the healthcare system, so finding strategies to streamline PrEP delivery will be important in the scale-up of PrEP, he added.
“We want to see what the interest level in PrEP is and who will want to take it,” says Liu. “We will also be looking closely at patterns of adherence over time and, importantly, whether and how their sexual behaviors and practices change while using PrEP.”
|The pharmacokinetic factor|
Adherence appears to be the primary determinant of PrEP efficacy, but could differences in drug levels in tissues also play a role?
The answer: Sort of.
According to Craig Hendrix, director of the Drug Development Unit at Johns Hopkins University, concentrations of tenofovir disoproxil fumarate (TDF) and tenofovir diphosphate—the active form of TDF—are much higher in homogenized colon tissue than in homogenized vaginal tissue 24 hours after dosing. The differences are not so striking, however, in CD4+ T cells extracted from tissue. Hendrix, who has extensively studied chemoprevention of HIV, made this observation with colleagues in a recently published study of six healthy women who were administered a single oral dose of TDF and then tested for drug concentrations in blood and colon and vaginal tissue (AIDS Res. Hum. Retroviruses 2013, doi: 10.1089/aid.2013.0044). Samples were taken up to 15 days after the dose was administered.
The study sought to answer questions about dosing frequency in PrEP regimens. But the higher drug concentrations in colon tissue could also, perhaps, explain why less than perfect PrEP adherence is less detrimental to men who have sex with men, who primarily transmit and acquire HIV through anal intercourse. High-risk heterosexual women, on the other hand, are primarily exposed to HIV through vaginal intercourse. “The risk of receptive anal intercourse is roughly 20 times higher than receptive vaginal intercourse,” notes Hendrix. “So if the concentration of [TDF] is 100 times higher in colon tissue, there may be a net benefit.”
But Hendrix says this initial benefit subsides in the first week after dosing because the half-life of the drug is shorter in rectal tissue than in vaginal tissue. “The critical issue going forward is how much drug has to be present for PrEP to be effective,” says Hendrix. “In other words, if one did take the drug reliably on a less than daily schedule, how well would that work? If one could take a smaller amount of drug a day, might that reduce cost and side effects?’’ —RM
Revisiting a success
While most of the demonstration projects focus to one degree or another on the MSM community, a project launched last year in Kenya and Uganda is following up on results of the Partners PrEP study of SDCs. This demonstration project will be enrolling 1,000 SDCs in which HIV-infected partners are not yet on antiretroviral therapy (ART) because they either do not meet the treatment guidelines, only recently discovered they were HIV-infected or treatment-eligible, or because they have chosen to opt out of therapy. The project will explore how couples use ART and PrEP to reduce HIV risk: uninfected partners will be offered PrEP as a bridge to ART use in the infected partner, with PrEP discontinued once the infected partner initiates and sustains adherence to ART.
Jared Baeten, a University of Washington associate professor of global health who was a co-investigator in the Partners PrEP study, says SDCs in Africa are a priority for public health interventions because the risk of transmission is high in that population. While PrEP clearly works in a controlled setting, such as a clinical trial, Baeten says it is still not clear whether the HIV-infected partners would initiate ART to reduce the risk of transmitting virus, or whether the uninfected partner would use PrEP diligently.
The Partners Demonstration Project is searching for answers to questions that were not asked in the efficacy trial that preceded it—such as what factors influence adherence to ART and PrEP, and the decision processes that couples follow in making HIV prevention choices.
A tough group to crack
While the data from SDCs will almost certainly be useful, the work being done among younger, high-risk heterosexual women from Africa is likely to be even more informative. Not only are HIV incidence rates dramatically higher among this demographic, but engaging them in PrEP studies has proved difficult as well.
“How do you figure out how to make PrEP feasible in this group? It’s a million dollar question,” says Jeanne Marrazzo, a professor of medicine at the University of Washington and the principal investigator in the VOICE trial, which ended on a disappointing note. “Why didn’t the women use it? And among the women who did it, what were they like and what motivated them? That is the conundrum—where we are right now.”
The VOICE study—which was conducted in South Africa, Zimbabwe and Uganda—showed adherence differed geographically. “We are still trying to figure out who took the product,” says Marrazzo. “What we do know is that, in general, women who were older, married, and who had more children were more likely to have taken the product. That played out in terms of countries. In Zimbabwe and Uganda, the women were more likely to be married. In South Africa, a minority were married. So the question becomes: what was it about those [married] women that facilitated taking the product? Is it because they had control, that they were in more stable relationships?”
Because VOICE did not find PrEP to be effective in the evaluated population, a demonstration project would be fruitless. But Marrazzo says researchers are planning to follow up on the results to try and get a better handle on why adherence in this group proved so difficult. They will be meeting with women in the study, their male partners, and community leaders to determine whether particular perceptions about PrEP might have persuaded women to stop taking the study drug.
“Some of the stuff will be pretty important,” says Marrazzo. “We are learning, I think, that we may not have appreciated how much the concept of using ARVs as prevention was really new and not necessarily well understood among the women.”
Marrazzo says discussions with the women revealed distrust about the use of ARVs to prevent HIV. “When we talked to them about why women didn’t use the product, they said, ‘Why would I want to take that drug that people take when they are sick?’ Maybe we were not attentive enough to the concerns these women may have had about taking products that are clearly associated with HIV infection.”
Marrazzo says members of the VOICE team also plan to hold focus groups with women from the VOICE study. Women will be placed in groups according to how adherent they were with the study drug, says Marrazzo. “Am I sure we will get answers? No. The barriers to disclosure can be huge. I just don’t think we really appreciated how challenging that was.”
PROUD of PrEP
As researchers begin to sort out why PrEP failed to work in high-risk women in Africa, another pilot study in the UK known as PROUD is trying to determine if it might be feasible to study the impact of PrEP effectiveness—in this case Truvada—and its impact on risk behaviors and STDs among MSM in a real-world setting.
Sheena McCormack, a professor of clinical epidemiology at UK’s Medical Research Council Clinical Trials Unit (MRC CTU) and a principal investigator of the study, says it is still unclear whether taking a pill that they now know reduces their risk of acquiring HIV will prompt gay men to use condoms less frequently with a larger number of sexual partners, and thereby increase their risk of STDs. “To make a measurable difference to the HIV epidemic in the UK, we would probably need a large number of gay men to take PrEP,” McCormack says. “This is why it is unclear whether offering PrEP for free to the entire MSM community would be cost-effective overall in the UK.”
Focusing on high incidence groups makes sense, but these populations might be the least likely to take the regimen, as was seen in the clinical trials with younger participants. These uncertainties, and lack of UK-specific data, explain why the UK has a position statement recommending that PrEP be used only in the context of a clinical research study, says McCormack.
To try and answer these questions, the MRC CTU and Public Health England (PHE) proposed a study of 5,000 MSM—half randomized to the immediate offer of daily oral Truavda in the combination prevention package and the other half to a deferred offer of Truvada after 12 months follow-up—to measure the effectiveness of PrEP and impact on risk behaviors and STDs. To determine whether this would be feasible, a pilot study called PROUD has been initiated. If it is possible to enroll 500 gay men to the study design in a timely manner and retain both groups, then the collaborators will reapply for funding—an initial request by collaborators was declined—for a trial that is large enough to address the question of effectiveness.
McCormack was optimistic that volunteers could be quickly recruited from participating publicly funded sexual health clinics, as this is where the majority of gay men are tested for HIV and STDs, and where HIV treatment is provided. “Having HIV prevention and treatment under one roof ensures excellent linkage to care, and we are lucky to have had this network since the start of the epidemic,” says McCormack. “In spite of this, we still have rising numbers of new infections in gay men.”
In reality, the PROUD study has recruited more slowly than anticipated. First, it took longer than expected to obtain the local approvals for each clinic, and so the study has only been at full capacity since July. Second, there is very little awareness of PrEP in the community and it has been difficult for community organizations and clinics to promote it, as PrEP is not currently available in the UK.
“I worry that we will end up concluding PrEP is a tool of no interest when we haven’t given it a fair shot,” McCormack told Baseline, a community magazine for people living with or affected by HIV and hepatitis. “I firmly believe we can promote condoms and PrEP together in a responsible way, and if we don’t rise to this challenge, we are failing the breadth of the sexually active community in the long term, but especially gay men right now.”
Working with sex workers in Africa
Another real-world PrEP experiment will include commercial sex workers (CSWs) from Johannesburg and from a rural community six hours from the South African city. The study, which researchers hope to continue over three years, will evaluate the uptake, acceptability and adherence to a proven PrEP regimen.
Professor Helen Rees, executive director of the Wits Reproductive Health and HIV Institute of the University of the Witwatersrand in Johannesburg says her research group proposed the study to address questions about PrEP acceptability. “We have learned a lot from the efficacy trials but more needs to be understood about the feasibility and acceptability of introducing PrEP,” says Rees. “And it will be difficult to roll out PrEP to a general population, so we are looking instead at targeted populations. Here in South Africa, modeling suggests that 20% of new infections are associated with CSWs and their clients.”
Rees says CSWs present particular challenges, their mobility being one, and their long-term commitment to daily PrEP another. Fortunately, says Rees, her group has established longstanding relationships with many CSW cohorts throughout the region.
Countries will have to figure out how to put research into practice, she says, or risk delaying the rollout of a proven intervention that could save thousands of lives.
The PrEP forecast
Warren of AVAC agrees that the public health community is still grappling with PrEP delivery. Even in the US, he says, where PrEP is recommended for high-risk populations, medical providers lack awareness about current protocols. “There was a young man at a leading university [in the US] who went into the student health services and said he is at risk for HIV, that he had had unprotected sex, and that he would like to get on PrEP,” says Warren. “He was told, ‘Oh, you have to go to an infectious disease doctor. And the infectious disease doctor says, ‘No. That is only for sero-discordant couples.’ This guy was a perfect candidate for PrEP.”
Warren says this anecdote is Exhibit A for why well-designed demonstration projects are needed to make the PrEP program work. The good news, he says, is that there is no shortage of such projects. In fact, the field is littered with them. What is missing, he says, is leadership and an overarching strategy. “There need to be some common elements, answering a core set of questions in a systematic fashion. We need some sense of shared vision, a common play book. If not, at the end of the day, we run the risk of having random acts of demonstration-project goodness that answer a bunch of questions.” Except, that is, the one that matters most: how to make PrEP work in the real world.