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By Jeannie Wraight & Mariel Selbovitz

JeannieWraight_ViroChannelJeannie Wraight is a contributing writer and columnist for A&U Magazine and a blogger and writer for TheBody.com and The Body Pro. She is a member of the Board of Directors of Health People (a community-based organization in the South Bronx) and an advisor to TRW (Teach me to Read and Write, a community-based organization in Kampala, Uganda).

Ms. Wraight has attended over 100 HIV scientific conferences and has sat on numerous Board of Directors and Community Advisory Boards over the past 16 years.

 

Mariel_Selbovitz_ViroChannel

Mariel Selbovitz, MPH is Senior Research Program Coordinator at Johns Hopkins School of Medicine and President at The Bio Diversity Group.

She is also a member of the International AIDS Society (IAS), American Public Health Assocciation (APHA) and Campaign to End AIDS (C2EA) and serves as Co-Chair of the Cornell AIDS Clinical Trials Group Community Advisory Board.

She received her BA from Cornell University and her Master in Public Health from the Johns Hopkins School of Public Health.

As efforts to roll out the use of Pre Exposure Prophylaxis (PrEP) take center stage in many high-risk communities, we are tasked with the complex undertaking of sorting out how best to utilize this biomedical intervention. If taken properly, PrEP can provide a high level of protection against HIV. However, studies show a lack of adherence greatly diminishes the benefit of PrEP and this lack of adherence is relatively common in certain individuals and populations, leaving us with many questions on how to effectively implement this prevention method.

Several studies were presented on the use of PrEP at CROI 2014. Described below are two thought provoking presentations that address some of the outstanding dilemmas we face in optimally utilizing PrEP as an effective prevention methodology.

The Partners PrEP study was one of four studies that evaluated the use of TDF (tenofovir disoproxil fumarate) alone or FTC/TDF (emtricitabine and tenofovir disoproxil fumarate) for use as PrEP. The Partners PrEP study was the only study of the four presented to measure the effects of both single agent TDF as well as combination FTC/TDF in the same clinical trial. Jared Baeten of the University of Washington presented on a review of this data to ascertain whether there was a greater degree of efficacy in either the single drug TDF or combination drug regimen FTC/TDF in this trial.

The Partners PrEP study was a phase III, randomized, double-blind, placebo-controlled, three-arm trial which measured tenofovir (TDF) and emtricitabine and tenofovir PrEP against placebo in 4427 heterosexual couples throughout nine sites in Uganda and Kenya where one partner was HIV-positive and the other was HIV-negative. The study began in July of 2008. In July of 2011, the placebo arm was discontinued due to the definitive rate of protection seen in the two drug arms. Those in the placebo arm were offered re-randomization to one of the two existing arms. The study concluded in December of 2012.

Data showed a total of 52 seroconversions: 31 from the FTC/TDF arm and 21 in the TDF arm. An average 75% risk reduction was seen with the use of FTC/TDF and 67% in the TDF arm. HIV incidence in both arms was less then 1% per year and HIV protection when comparing FTC/TDF to TDF was 0.67 with a p-value of 1.6, which equaled a 33% reduction in HIV for FTC/TDF verses TDF alone. The difference was not statistically significant.

No differences were seen in TDF versus FTC/TDF by sex, age, country, sexual behavior, male circumcision, or CD4 or viral load of the HIV-positive partner.

Serious side effects were rare and didn’t differ by single or combination agent.

Of the 22 individuals who tested positive for HIV, after July2011 when the placebo arm was discontinued, none of the 19 who had resistance testing were found to be resistant to either TDF or FTC. When a sample of this group was taken, 36% had detectable levels of drug from the TDF arm and 15% from the FTC/TDF arm. A sample from the group that did not seroconvert showed that 82% from the TDF arm had detectable levels of drug in their blood verses 75% from the FTC/TDF arm. The relative risk reduction of those with detectable levels of drug was 85% in the TDF arm and 90% in the FTC/TDF arm.

Overall, data from this analysis showed no significant difference in FTC/TDF combination ARV therapy over single agent TDF for use as PrEP against HIV infection. The CDC and WHO PrEP guidelines presently recommend the use of FTC/TDF for PrEP, which, according to these study results, is an unnecessary use of limited funds and additional risk of harsh side effects and possible drug resistance with long term use.

Adherence issues the Achile heels for PREP

Differences in population, HIV exposure routes (i.e., anal sex, vaginal sex, and injecting drugs), biological factors, and rates of participant drop-out are potential sources for the “heterogeneity,” or diversity, in estimates of PrEP efficacy noted David Bangsberg from the Massachusetts General Hospital Center for Global Health. According to him, the most likely explanation is that this wide heterogeneity in efficacy estimates is due to differences in adherence between these studies.” The lower the proportion of trial participants with detectable levels of the study drug in their blood, the lower the efficacy estimate for the trial.

Bangsberg added. “How do we understand adherence so we can, going forward, improve adherence to not only get better efficacy estimates but also better effectiveness?”
Given that using a study drug or product is clearly culturally loaded, Bangsberg advocated for greater attention to evidence-based approaches to monitoring and supporting adherence. Self-reported data on adherence is the measure most commonly employed, but as shown by comparisons against drug levels in blood, self report can dramatically overestimate adherence. Bangsberg also proposed conducting small-group studies to understand pill-taking behavior and anticipate adherence issues before launching large and costly randomized controlled trials

In a separate session, Christopher Balthazer, Program Coordination for the Project Prepare II in Chicago, Illinois, spoke about the challenges his team confronted while accruing for Project Prepare II and the iPREX Open Label Phase and how they addressed those challenges. This presentation suggested approaches, which could not only apply to clinical trials but also to the over all use of PrEP by following the recruiters lead of discarding rigidity in patient care for innovation, flexibility and ideas that would create better chances of the successful inclusion and retention of individuals in utilizing preventative methods such as PrEP.

PREP study for YMSM

In recruiting young gay male participants, primarily between the ages of 15-17, the study recruiters found a great deal of difficulty in accessing and successfully approaching, recruiting and retaining this population.

Many of the issues revolved around a lack of information and education in the community about PrEP. A large majority of the potential participants, organizations and other identities they confronted had never heard of PrEP or had what recruiters felt were misconceptions of PrEP. This lack of knowledge took form in several ways.

Trial recruiters confronted an absence of community support. This was due to a concern on the part of community organizations and leaders who feared PrEP sent a message that gave permission to young gay men to have more condomless sex. The study recruiters also had difficulty in gaining support for the study from schools and Gay Straight Alliance’s (GSA) within schools that were concerned with upsetting parents with their support for the PrEP initiative.

Recruiters confronted these issues with creating opportunities for education such as arranging meetings with community leaders and organizations on the issue of PrEP, by attending meetings and events in the community at which they discussed PrEP and by distributing information on PrEP through additional outreach.

The study recruiters addressed other barriers with adjustability and modification. Additional barriers they encountered were transportation issues which were resolved with the use of the study paying for cabs to study visits, clinic hours conflicting with school hours which were addressed by keeping the clinic open later and asking Radiology and the lab to stay open later and difficulties of reaching participants and potential participants via telephone calls which was addressed with the utilization of Facebook messaging and text messages.

Much of the trial recruitment was performed through social media outlets such as Facebook and through apps like Grinder. Recruiters found that the young men they encountered changed their cell phone numbers frequently but never changed their Facebook page, making Facebook a more secure means of communication.

Interesting insights were obtained through the use of questionaries on reasons why young gay males were interested in the use of PrEP/participating in the trial. Reasons included: wanting back up protection for when condoms were not used; wanting intimacy in sero discordant relationships; fear of partner infidelity; unsuccessful use of condoms from start to finish of intercourse; partners unwilling to use condoms; power differential in relationships; multiple partners; transient housing and the use of trade sex for resources; being less likely to use condoms while intoxicated and utilizing the trial for healthcare.

Next generation PREP : Monkey Studies Confirm Validity of Injectable PrEP

In another session, several preliminary data were presented from CDC studies to evaluate the next generation of PrEP options, including injectable delivery methods and vaginal gels. According to Dr. Gerardo Garcia-Lerma (CDC Atlanta), monthly injections with a long-acting formulation of the HIV integrase inhibitor GSK744 completely prevented vaginal simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. More precisely, in one of these 2 studies, they gave 6 monkeys 3 injections of GSK744LA a month apart, while giving them frequent low-dose challenges of SHIV (22 in 12 weeks) to mimic sex more closely. These results have strengthened the evidence that it may work as pre-exposure prophylaxis (PrEP) in humans PrEP with long-acting drug formulations has the potential to overcome challenges of adherence associated with taking a pill daily. They concluded that the data show promise for advancement to human trials of the long lasting formulation of GSK744. –

These presentations provide an informative look into some of the existing variations with PrEP and further studies are needed to better ascertain additional information in regards to specific populations, regimens and methods to garner the highest level of protection against HIV possible with PrEP.

REFERENCES
David R. Bangsberg. Adherence: The Achilles Heel for Trial Interventions. 21st Conference on Retroviruses and Opportunistic Infections. Boston, March 3¬–6, 2014. Abstract 7.

CD Andrews, W Spreen, YL Yueh, et al. Correlating GSK1265744 Plasma Levels To Prevention of Rectal SHIV Transmission in Macaques. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 39.

J Radzio, W Spreen, YL Yueh, JG Garcia-Lerma, et al. Monthly GSK744 Long-Acting Injections Protect Macaques Against Repeated Vaginal SHIV Exposures. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 40LB.