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Pre-exposure Prophylaxis (PrEP)

IAS 2015: Gay Youth PrEP Study Finds Good Retention and Reasonable Adherence

A U.S. study of Truvada pre-exposure prophylaxis (PrEP) looking at 200 young gay and bisexual men aged 18-22 in a dozen cities found reasonable levels of adherence, researchers reported at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention last week in Vancouver. Adherence was highest among those with the highest risk of HIV. However, adherence dropped off considerably after study visits changed from monthly to quarterly, suggesting that gay youth starting PrEP would benefit from more intensive support than older participants. The study also found considerably lower adherence among young black and mixed-race men.


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IAS 2015: U.S. PrEP Demo Project Finds People at Highest HIV Risk Take PrEP Most Consistently

An open-label demonstration project of Truvada pre-exposure prophylaxis (PrEP) in the U.S. has found generally high retention and adherence rates, with the highest adherence among people at the highest risk of HIV infection, researchers reported at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) last week in Vancouver. However, some groups appeared to have more difficulty taking PrEP -- most notably young people and black people, and it proved difficult to recruit black men and transgender women -- to the project.


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IAS 2015: Non-Daily PrEP Provides Extra Options, But Adherence Often Better with Daily Dosing

For some people in some settings, less frequent pre-exposure prophylaxis (PrEP) regimens with doses linked to sexual activity are feasible, with high numbers of sexual acts protected by PrEP, according to studies presented Monday at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Vancouver. This may give people who want to use PrEP and their doctors additional options, allowing people to find a pattern of taking PrEP that best suits them. But the studies also found that more people are able to adhere to daily PrEP than non-daily regimens. Further, the actual effectiveness of non-daily regimens remains uncertain.



The studies presented Monday were in part inspired by the French Ipergay study, so far the only study to demonstrate that a schedule of non-daily PrEP, with Truvada (tenofovir/emtricitabine) doses taken before and after sex, could be effective (there were 86% fewer infections). However, Ipergay was conducted in a population of gay men who tended to have sex quite frequently. To prevent transmission during anal sex, 4 doses a week appear to be almost equivalent to 7 doses. But it's possible that people who have sex less frequently -- and so take pills less frequently -- will have lower levels of the drug in the body that are not protective.

Presented in Vancouver in a late-breaker session on Monday afternoon, HPTN 067/ADAPT is a trio of 3 randomized trials investigating the feasibility and acceptability of different PrEP regimens with 3 distinct populations in Bangkok, Harlem (New York City), and Cape Town. The studies give insights into patterns of PrEP use and adherence, but were not designed to answer questions about effectiveness. Larger Phase 3 trials would be needed to do that.

The researchers found that in a group of well-educated, motivated Thai gay men, each of the 3 PrEP regimens tested were feasible, acceptable, and likely to protect against most exposures to HIV. The non-daily regimens required far fewer pills to be taken.

Challenging social circumstances were more commonly experienced by participants in Harlem and Cape Town. Adherence was generally not as good in these 2 locations. Moreover, the daily regimen resulted in better adherence and likely protection against HIV than the non-daily options.

The HPTN 067 Studies

In each city, around 180 participants were recruited and randomly allocated to receive 3 TruvadaPrEP regimens:

  • Daily dosing;
  • Twice-weekly dosing + an extra dose after sex;
  • Event-driven dosing (1 dose up to 48 hours before sex, another 2 hours after sex).

Follow up continued for 6 months. Adherence was measured by providing PrEP in pill bottles, which send an electronic signal when they are opened. Weekly phone calls to the participants collected information about recent sexual activity, which was correlated with the data on when pills were taken.

The populations in the 3 cities had different social, cultural, and demographic characteristics. The researchers expected these to influence the acceptability of different regimens -- they did not expect to find one regimen that would be appropriate everywhere.

  • Bangkok, Thailand: 176 men who have sex with men and 2 transgender women. Most were university educated, few were unemployed, and the average age was 31. Participants had sex an average of once a week.
  • Harlem, New York City: 176 men who have sex with men and 3 transgender women. Over two-thirds were unemployed and over two-thirds were black. Average age was 30. Participants had sex an average of once a week.
  • Cape Town, South Africa: 179 women. Four-fifths were unemployed, a similar proportion were unmarried, and the average age was 26.


Across all sites, adherence was somewhat higher for the daily rather than the non-daily Truvada doses. For example, in Bangkok, 85% of daily doses, 79% of twice-weekly doses, and 65% of event-driven doses were taken as prescribed. In Harlem, the respective figures were 65%, 46%, and 41%.

The primary analysis was of the percentage of reported sexual acts which were protected by PrEP, with doses taken both before and after sex.

  • In Bangkok, the daily regimen protected 85% of sexual acts, the twice-weekly regimen protected 84%, and the event-driven regimen protected 74%.
  • In Harlem, the daily regimen protected 66% of sexual acts, the twice-weekly regimen protected 47%, and the event-driven regimen protected 52%.
  • In Cape Town, the daily regimen protected 75% of sexual acts, the twice-weekly regimen protected 56%, and the event-driven regimen protected 52%.

The missed doses were most often those that were meant to be taken after sex, both in the twice-weekly and event-driven regimensA. Participants often found it difficult to take this dose when they were still with a sexual partner or were away from home.

The researchers also tested blood samples twice during the study to see if tenofovir could be detected, restricting the analysis to those participants who reported having sex in the previous week. In Bangkok, over 90% of participants in each arm had detectable drug, with no significant differences between arms.

In contrast, Harlem and Cape Town participants were more likely to have detectable drug if they had been asked to take PrEP daily.

A total of 6 people prescribed PrEP became HIV positive -- 5 in Cape Town, 1 in Harlem -- but each had low or negligible levels of drug in their body.

One hoped-for advantage with non-daily regimens is that by reducing the number of pills, side effects may be less frequent. However, the data so far do not show statistically significant differences in the experience of side effects between arms. This may be partly due to the limited number of people in each arm and the short period of follow up. The side effects that were reported (dizziness, headaches, nausea, diarrhea etc.) were mild and mostly experienced during the first 2 months of taking PrEP.

But the non-daily regimens did require considerably fewer Truvada tablets, which could make providing PrEP more affordable. Sexual behavior did not differ between PrEP regimens.


Presenting the Bangkok data, Timothy Holtz summed up several advantages of daily regimens: clearly proven to be effective, likely to offer more protection, more forgiving of missed doses, and helping people develop habits of daily pill-taking.

But he said that non-daily PrEP could be an option for those men who have sex somewhat infrequently and know in advance when they are likely to do so. The findings suggest some flexibility in the way in which PrEP can be prescribed.

Robert Grant, who led the HPTN 067/ADAPT studies, told a press conference that PrEP needs to be adaptable to the different circumstances of people’s lives. And non-daily use is happening anyway: "People do choose how to use PrEP, when to take it and when not to take it," he said.



T Holtz, Achitwarakor, ME Curlin,et al. HPTN 067/ADAPT study: a comparison of daily and non-daily pre-exposure prophylaxis dosing in Thai men who have sex with men, Bangkok, Thailand. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015.Abstract MOAC0306LB.

S Mannheimer, Y Hirsch-Moverman, A Loquere, et al. HPTN 067/ADAPT study: a comparison of daily and intermittent pre-exposure prophylaxis (PrEP) dosing for HIV prevention in men who have sex with men and transgender women in New York City. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract MOAC0305LB.

R Grant et al. HPTN 067 ADAPT methods and results from women in Cape Town. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. MOSY0103.

IAS 2015: Intermittent PrEP May Be Robust Strategy for Anal Sex -- Vaginal Protection Less Certain

The pharmacodynamics (drug absorption and elimination rates) of the 2 drugs that comprise Truvada may favor the efficacy of intermittent pre-exposure prophylaxis (PrEP) more than previously thought, at least when it comes to protection from transmission via anal sex, according to a presentation at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this week in Vancouver.


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Study Sheds Light on How Tenofovir is Processed in Different Body Tissues

Tenofovir, which is widely used for HIV treatment and prevention, is activated in a tissue-specific manner, being processed by different enzymes in immune cells, the vagina, and the colon, according to a study published in the July 19 advance edition of EBioMedicine. These findings have implications for the effectiveness of tenofovir for pre-exposure prophylaxis (PrEP).


Tenofovir disoproxil fumarate or TDF (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs for HIV treatment. A new formulation under development, tenofovir alafenamide or TAF, reaches higher levels in HIV-susceptible immune cells when taken at lower doses that are easier on the kidneys and bones.

Oral Truvada is the only agent currently approved for HIV PrEP. Other tenofovir formulations are under study including gels and vaginal rings. The iPrEx trial of mostly gayand bisexual men showed that once-daily Truvada reduced the risk of HIV infection by 44% overall, rising to 92% among participants with blood drug levels indicating consistent use.

Truvada PrEP also performed well in the Partners PrEP and TDF2 studies of heterosexual couples in Africa. But the Fem-PrEP and VOICE trials of young women were unable to show a protective effect of Truvada or tenofovir vaginal gel. This has primarily been attributed to poor adherence, but animal and human studies suggest that there are also physiological reasons why tenofovir may be less effective against vaginal compared to rectal HIV exposure.

Julie Lade and colleagues fromJohns Hopkins University School of Medicine performed a laboratory study to analyze the chemical processing required to convert tenofovir to its pharmacologically active form in the body.

Tenofovir requires 2 phosphorylation steps (addition of phosphate groups), being converted first to tenofovir monophosphate then to the active form tenofovir diphosphate. But the specific kinase enzymes that activate tenofovir in cells and tissues susceptible to HIV infection have not yet been identified, the study authors noted as background.

In this study the researchers examined peripheral blood mononuclear cells (PBMC) and vaginal and colon-rectal tissue samples that were transfected with siRNA targeting nucleotide kinases and incubated with tenofovir in the laboratory. As explained in a Johns Hopkins press release, this had the effect of "knock[ing] out genes for phosphate-adding enzymes one by one."

They also genetically sequenced clinical samples from 142 women who participated in Microbicide Trials Network study MTN-001, which tested oral tenofovir and 1% tenofovir vaginal gel.


  • Adenylate kinase 2 (AK2) performed the first phosphorylation step -- converting tenofovir to tenofovir monophosphate-- in PBMCs, vaginal tissue, and colon tissue.
  • Both pyruvate kinase isoenzymes -- muscle (PKM) and liver/red blood cell (PKLR) versions -- were able to phosphorylate tenofovir monophosphateto tenofovir diphosphatein PBMCs and vaginal tissue.
  • However, the creatine kinase muscle isoenzyme (CKM) performed this conversion in colon tissue.
  • Sequencing of MTN-001 clinical samples detected 71 previously unreported variants in the genes encoding these kinases, several of which could make the enzymes ineffective.
  • 8% of the women had genetic variants that would likely to make them unable to convert tenofovir to its activated form.

"[O]ur results demonstrate that tenofovir is activated in a compartment-specific manner," the authors concluded. "Further, genetic variants have been identified that could negatively impact tenofovir activation, thereby compromising tenofovir efficacy in HIV treatment and prevention."

"Because these enzymes are polymorphic and may be dysfunctional in some individuals, these findings suggest that tenofovir-based HIV PrEP may not be protective for all individuals," they added.

"Tenofovir has been shown in trials to be very effective, so when it doesn’t work, researchers and clinicians tend to assume the individual just wasn’t taking the drug as directed," coauthor Namandje Bumpus explained in the press release. "That is probably true in most cases, but in others, it’s possible that genetic variation is actually at fault."

"If confirmed by further studies, our results suggest that in the future, before prescribing tenofovir to a patient, a doctor could order genetic testing and know in advance if it works, and prescribe a different drug if it won’t," she added.



JM Lade, EE To, CW Hendrix, and NN Bumpus. Discovery of Genetic Variants of the Kinases That Activate Tenofovir in a Compartment-specific Manner. EBioMedicine. July 10, 2015 (Epub).

Other Source

Johns Hopkins. New Evidence that Genetic Differences May Help Explain Inconsistent Effectiveness of Anti-HIV Drug. Press release. July 9, 2015.