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What’s on the horizon? New PrEP options presented at CROI 2016

, by Emily Newman

BETA is reporting from the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Boston—bringing you the latest news, updates, and research on HIV treatment and prevention.

“Overwhelming” preference for an injectable PrEP over oral PrEP despite pain

Injectable long-acting cabotegravir: ÉCLAIR

Cabotegravir LA vial and syringe (Photo courtesy of David Margolis)

Cabotegravir LA vial and syringe (Photo courtesy of David Margolis)

Long-acting cabotegravir as PrEP is generating quite a lot of buzz among researchers and other conference attendees. It’s exciting not just because it’s a new drug, but because the long-acting formulation could provide freedom from a daily pill regimen. Cabotegravir is an integrase inhibitor similar to dolutegravir, and it has been formulated as a nanosuspension that can be injected intramuscularly. The ÉCLAIR study, presented by Martin Markowitz, MD, from the Aaron Diamond AIDS Research Center, assessed safety and tolerability of a long-acting cabotegravir injection.

The study lasted for 81 weeks, and included an oral run-in phase (to test for adverse reactions to cabotegravir before the injection was given); an injection phase where three injections were given 12 weeks apart; and a follow-up phase. A total of 106 participants received cabotegravir and 21 received placebo.

Ouch! Study injections were painful

Pain from the injection (which was administered in the gluteal region) was the most frequently reported adverse effect in the study—in both the placebo and cabotegravir groups.

“As far as safety goes, it was relatively well tolerated both orally and as an injectable,” said Markowitz during a press conference.  All of the adverse events revolved around injection site pain. 92% of the injections of cabotegravir were associated with pain that lasted about 5 days on average. Half of the participants experienced mild pain, 40% moderate, and 10% described it as severe.”

Number of doses needed will likely increase from four to six times a year

The drug was absorbed faster than anticipated—leading to higher drug “peak” concentrations and lower drug “trough” concentrations.

Martin Markowitz

Martin Markowitz, MD

“Approximately 70% of subjects had trough levels below the predicted 4 x PA-IC90 [a measure of drug concentration] during the injection phase. And 15% to 31% of the cabotegravir subjects had trough concentrations less than 1x PA-IC90, a concentration that will not afford protection, based on previous studies,” said Markowitz.

Because of this faster drug absorption rate, Markowitz reported that the team is evaluating the possibility of changing the dosing schedule to once every 8 weeks, instead of once every 12 weeks.

Two HIV infections occurred

There were two seroconversions during the study: one in a person receiving placebo, and the other during the follow-up phase (24 weeks after the last injection).

Participants liked the delivery method, despite injection pain

Overall, participants were satisfied with the injections, and preferred the injections to the once-daily oral cabotegravir tablets.

“During the course of the study, participants were asked to compare their daily oral therapy to their injectable therapy. The results were overwhelmingly in favor of the injections,” said Markowitz.

A possible oral PrEP drug alternative to Truvada?

Maraviroc: HPTN 069 / ACTG A5305                             

Maraviroc is a CCR5 antagonist that blocks a receptor on the outside of immune cells—preventing HIV from entering and infecting them. The drug is licensed for HIV treatment (Selzentry) and its oral formulation is currently being tested as an alternative to Truvada-based PrEP. Results from a Phase 2 study, testing the safety and tolerability of maraviroc as PrEP, were presented by Roy Gulick, MD, MPH from the Weill Medical College of Cornell University.

Overall, the three maraviroc-based regimens tested were as safe and well-tolerated as the Truvada comparison. While the study was not designed to assess HIV prevention efficacy, the researchers reported a total of five HIV infections during the study with 406 participants—four of which may have been due to poor adherence to the study drug.

Study details

The 48-week study enrolled 406 HIV-negative people assigned male at birth (2% transgender women) with a history of recent condomless anal sex. The study randomized participants to receive either maraviroc alone; maraviroc plus emtricitabine; maraviroc plus tenofovir; or, tenofovir plus emtricitabine (Truvada).

STIs

At screening, 31 participants (8%) were diagnosed with an STI: 4% chlamydia; 1% gonorrhea; and 3% syphilis. An additional 115 STIs (among 90 participants) were diagnosed during study follow up.

Adverse Events

During the study, there were 67 adverse events that were rated as higher than “moderate,” with no differences in rate between the study arms. The most common reported events were diarrhea (5%), nausea (2%), vomiting (0.5%), and unintentional weight loss (1%).

Drug pharmacology

The study drug was detected in the majority of participants: with study drug detectable in 83% of participants at week 24 and 77% at week 48.

HIV infections

Although the study was not designed to assess efficacy, the researchers reported that there were five HIV seroconversions during the study, for annual incidence rate of 1.4%. Four occurred in participants who were only taking maraviroc; one occurred in someone taking maraviroc plus tenofovir. None of the participants developed a drug-resistant mutation. Only one participant (taking only maraviroc) had plasma drug concentration at a level indicating adherence to study drug on the seroconverstion visit—the remaining four had low or no drug detected.

“None [of the people who seroconverted] showed evidence of genotypic resistance mutations. One can see that participants 1 and 3 had no detectable levels of study drugs, and in fact, neither one had detectable study drug at any study visit. Of note, the expected pre-dose steady-state concentration of maraviroc given at a dose of 300 mg once a day is 32 ng/mL, so participants 4 and 5 were below that expected concentration.

Study drug concentrations in participants who seroconverted during the study. Slide: Roy Gulick, MD

Study drug concentrations in participants who seroconverted during the study. Slide: Roy Gulick, MD

“To take a closer look at this, we took a look at drug concentrations over time. You can see study weeks here on the X axis and maraviroc concentration on the Y axis. The dotted horizontal line is the maraviroc expected steady state concentration at the dose we used. That’s 32 ng/mL. I’ll remind you that two of our participants do not appear on this curve because they had no detectable study drug levels at any visit. What you see here in the squares is detectable HIV RNA and in the dots are detectable HIV antibodies. And each of the three colors represents the three individuals. Around the time of probable HIV infection, the maraviroc levels are either low or very low.”

Next steps

Overall, the researchers concluded that the maraviroc-containing regimens were as safe and well-tolerated as the Truvada-based regimen, so they will pursue further research with the drug. An upcoming study with maraviroc will include both men and women, collect behavioral and quality of life data and assess the impact of the drug on bone mineral density.

“We feel that maraviroc-containing regimens based on this study should be considered for testing in clinical efficacy trials,” said Gulick.

People prefer—and are more likely to use—a rectal gel when it’s used around the time of sex versus every day

Rectal Tenofovir Gel: MTN-017

“Rectal microbicides have been in development for approximately 10 years,” said Ross Cranston, MB, ChB, MD, FRCP from the University of Pittsburgh School of Medicine. “We know that individuals who practice receptive anal sex are very commonly using lubricants to facilitate receptive anal intercourse. We also know that incorporating an antiretroviral gel into a rectal product, a gel, has been shown to demonstrate potential in non-human primates after exposure to virus,” said Cranston.

A rectal microbicide—applied daily or before and/or after sex to prevent HIV—has potential to be a useful, practical prevention product that replaces personal lubricants. Cranston presented the results from a Phase 2 safety and acceptability study of a reduced-glycerin 1% tenofovir gel with men who have sex with men and transgender women having receptive anal sex.

The open-label, cross-over study randomized participants (195 total) to all of the three study regimens for eight weeks (with a one-week washout period between each regimen). The study treatments were: tenofovir gel used daily; tenofovir gel used before and after anal sex; oral Truvada daily. Participants using the product before and after sex were instructed to use only a max of two doses per day, and use the product at least once per week.

Safety

The rectal gel was safe whether it was used daily or before and after sex.  “There was no real difference in the percentages of grade 2 adverse events between either of the arms—the two rectal arms and the oral arms,” said Cranston.

Acceptability – ease of use, likability, and if participants would use it again

“Clearly, there was an overall preference for the oral product compared to the rectal product. But I do want to step back a little bit and look at the percentages of individuals who liked the product. 90% of individuals liked the oral product. 80% of individuals liked the RAI [rectal anal intercourse]-associated product, and 70% of individuals liked the daily product,” said Cranston.

Participants did not rate the rectal gels as difficult to use—with no significant differences found in ease of use between the rectal gels and the daily oral PrEP option.

When asked about intention to use the product, if it were commercially available, participants reported not preferring the daily rectal gel to the daily oral PrEP. There was no statistically significant difference, however, in intention to use between the rectal gel used with sex and daily oral PrEP.

Adherence and use of the rectal gel

Adherence to the daily regimens was high. “Almost 90% in the daily rectal, and in the daily oral, had detectable tenofovir when we expected it to be there,” said Cranston.

Every day, study staff sent a text message to ask participants about product use. Research staff also assessed adherence by looking at the number of unused gel applicators returned at each visit. “When we looked at adherence simply based on the SMS and product return, we set the bar quite high. So we looked at either less than 80% or greater than 80% adherence,” said Cranston.

There was no difference in adherence between the daily oral PrEP and sex-based rectal gel use. However, participants were less likely to adhere to the daily rectal gel use compared to the daily oral PrEP.

Moving forward

“These results support further study of 1% reduced glycerin tenofovir gel as a rectal microbicide for HIV prevention in men who have sex with men and transgender women,” Cranston concluded.

A new form of tenofovir in oral PrEP 

Tenofovir Alafenamide (TAF) protects macaque from rectal infection   

Tenofovir alafenamide (TAF) is a newer form of tenofovir disoproxil fumarate (TDF, one of the components of Truvada) that provides the same drug coverage with a lower dose. The FTC/TAF combination pill is being developed for treatment, but it’s not yet known if the same combination works as PrEP.  Ivana Massud, PhD, from the Centers for Disease Control, presented results from a study showing that FTC/TAF prevents rectal infections in a monkey animal model.

Finding the right dose

Three different doses (0.5, 1.5 and 4.5 mg/kg) were tested in 4 macaques per dose, and drug concentrations were measured in plasma, PBMCs (a type of cell of the immune system) and rectal biopsies. The 1.5mg/kg dose achieved target drug concentrations in PBMCs, plasma and in 3 out of 4 rectal biopsies.

The researchers also tested if FTC/TAF could prevent rectal infection in macaque animal models. 6 macaques were given the FTC/TAF medication and 6 were given placebo, and all were exposed to SHIV (a virus similar to HIV) once per week. After 14 weeks, all 6 macaques on active drug remained free of infection.

“Findings suggest that FTC/TAF may be a feasible alternative to FTC/TDF for PrEP against rectal HIV infection, and support the clinical development of FTC/TAF as a PrEP agent. While these data show that FTC/TAF protects against macaques against rectal SHIV infection, it should not be used in humans as a PrEP agent until clinical studies are complete and it is approved for a PrEP indication,” said Massud.

For full details of the TAF study including results from a second study showing lower-than-expected levels of TAF in human tissue samples, see Liz Highleyman’s article on HIV and Hepatitis.

Sources:

Cranston, R., and others. MTN-017: Rectal phase 2 extended safety and acceptability study of 1% tenofovir gel. CROI 2016. Abstract 108LB.

Gulick, R., and others. HPTN 069/ACTG5305: Phase II study of maraviroc-based regimens for HIV PrEP in MSM. CROI 2016. Abstract 103.

McGowan, I., and others. PrEP Impact on T-cell activation and explants infection: HPTN 069/ACTG 5305 substudy. CROI 2016. Session 0-9 Oral Abstracts. CROI 2016. Abstract 104.

Markowitz, M. and others. ÉCLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. CROI 2016. Abstract 106.

Massud, I., and others. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. CROI 2016. Abstract 107.

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