CROI 2016: On-Demand Rectal Microbicide Gel Has Reasonable Acceptability -- Daily Less So

Results from the MTN-017 study of 1% tenofovir gel as a rectal microbicide were presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston. The study compares the safety and acceptability of oral tenofovir/emtricitabine (Truvada) PrEP with the rectal gel either in daily use or used before and after the participant has anal sex as the receptive partner.

[Produced in collaboration with Aidsmap.com]

The study found that the rate of adverse events of any severity was exactly the same as for oral PrEP for daily use, and somewhat lower during occasional use. However, though participants rated the gel as almost as easy to use as oral PrEP, and said that they would be willing to use the gel again during sex (though not daily), there was no disguising the fact that, if offered the choice between the gel and the pill as the one PrEP method they could use, most participants would choose the pill.

The encouraging safety and adherence results, however, may help this product move further towards a full acceptability study.

The MTN-017 Study

MTN017 was conducted between 2013 and 2015 at 8 sites in 4 countries: Pittsburgh, Boston, and San Francisco, as well as San Juan, Puerto Rico, in the U.S.; Bangkok and Chiang Mai in Thailand; Lima, Peru; and Cape Town, South Africa.

The study had a so-called crossover design, meaning that every participant used all 3 PrEP regimens in turn. After a screening visit, participants used one of the 3 methods (oral PrEP, daily gel, or gel before and after sex) for 8 weeks, with clinic visits on day 1, after 4 weeks, and after 8 weeks. They then waited for a week before using the second method for 8 weeks, then waited another week and used the third method.

The researchers selected 195 participants from 349 who were screened for the study. The most common reason for not being selected were ineligible lab results (such as poor kidney function), but 8 people were found to already have HIV (2.3%) and 3 were screened out for possible acute HIV symptoms.

Adherence was measured by product returns and by participants responding to SMS text reminders, but free drug levels were also measured in blood, rectal fluid, and rectal biopsies, and intracellular drug levels were assessed in rectal tissue and in T-lymphocytes.

The average age of the 195 participants was 31.1 years, and the average age at individual sites ranged from 22.8 in Cape Town to 35.9 in San Francisco. On average 80% had a college education or were attending college (apart from at Cape Town, where it was 27%).

Notably, this study managed to enroll a significant proportion of trans women. While 73% of participants defined themselves as gay or bisexual men, there were 4 cisgender women (2%), 19 people who defined themselves as trans women, and another 30 who described themselves as "other" or declined to define their gender. So this study included somewhere between 10% and 25% trans people.

Safety, Acceptability, Adherence, and HIV Infections

In terms of safety, the rectal gels were at least as safe as the Truvada pill. The percentage of participants who experienced adverse events of grade 2 or above (i.e., more than "mild") was 34% among oral pill users, 33% among daily rectal gel users, and 30% among sex-associated gel users.

In terms of subjective acceptability, however, the oral pill was more popular than the gel. Scores from 1 (dislike) to 10 (like) for general impression of the product, ease of use, and intention to use it again if it became available were added up. If the score for oral Truvada was regarded as 100%, then the score for generally liking the product was only 28% for daily-use gel and 37% for before-and-after sex gel.

The gel’s scores for ease of use were better, with a score of 56% for the daily gel (again compared with 100% for oral Truvada) and 76% for before-and-after sex use. For intention to use in the future, the score was 38% for daily gel and 70% for before-and-after sex. The 70% and 76% scores did not differ, statistically speaking, from the Truvada scores.

Adherence was defined as the proportion of participants who used the pill or gel more than 80% of the time. In terms of self-report and product returns, 94% of pill users and 93% of before-and-after sex gel users achieved at least 80% adherence, but only 83% of those using gel daily.

Drug level measurements confirmed the self-reports: the percentage of participants with detectable tenofovir in plasma and issues was 94% for oral Truvada and 80% for the daily gel. Levels were not given for the before-and-after-sex gel, as these would vary with use.

There were 4 HIV infections during the study, 3 of them in Cape Town, though 1 of these was diagnosed 82 days after his last product use. The other 3 infections were distributed 1:1:1 in terms of the regimen the participant was allocated to at the probable time of infection. Of these, 2 participants had HIV resistance mutations to the NNRTI class of drugs, which could not be PrEP-related as the PrEP regimen did not include NNRTIs.

Tenofovir gel is not the only one being evaluated as a possible rectal microbicide. A study of gel containing the drug dapivirine, which was also used in the vaginal ring studies presented at CROI, is underway.

Presenter Ross Cranston of the University of Pittsburgh told the conference, "These results support further study of 1% rectal gel tenofovir as a microbicide for HIV prevention in men who have sex with men and transgender women."

2/29/16

Reference

R Cranston, J Lama, BA Richardson, et al. MTN-017: Rectal Phase 2 Extended Safety and Acceptability Study of 1% Tenofovir Gel
.Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 108LB.

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.

Results

• 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.

7/16/15

Reference

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.

ICAAC 2015: Combination Vaginal Ring May Be Able to Prevent Both HIV and Herpes

An experimental silicone vaginal ring with separate compartments may be able to deliver both tenofovir for prevention of HIV infection and acyclovir for prevention of genital herpes and potentially other sexually transmitted infections (STIs), according to a report at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last weekin San Diego.

Read more:

Drug Levels Are Key to Effectiveness of Tenofovir Vaginal Gel for HIV Prevention

Although the VOICE study failed to show an overall protective effect for tenofovir vaginal gel, further analysis suggests that women who had detectable blood drug levels were at lower risk of HIV infection, according to an analysis described in the June 29 advance edition of Journal of Infectious Diseases. Another recent analysis from the CAPRISA 004 trial showed that higher levels of tenofovir in the genital tract were associated with greater reduction in risk.

Read more: