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CROI 2016: Long-Acting Cabotegravir PrEP Injection Tolerable and Acceptable, but Dose Adjustment Needed

Attendees at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston heard results from the first Phase 2 (safety, acceptability, and dose-finding) study of a long-lasting injectable formulation of the integrase inhibitor drug cabotegravir for use as pre-exposure prophylaxis (PrEP) in HIV-negative people. The previous day researchers also presented a study of the same injectable drug, plus another injectable, rilpivirine, used as treatment for people with HIV.

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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.alt

[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.

CROI 2016: Botswana Close to Reaching 90-90-90 HIV Testing and Treatment Targets

Botswana is already close to reaching the 90-90-90 target for HIV testing, treatment, and viral suppression, and is ahead of the United States and most European countries in its efforts to improve treatment coverage, Tendani Gaolathe of the Botswana-Harvard AIDS Institute Partnership reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston.

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CROI 2016: Early Antiretroviral Therapy Reduces the Risk of Infection-Related Cancers

People who started antiretroviral therapy at a CD4 cell count above 500 had a significantly lower risk of developing a cancer with an infectious cause when compared to people who started treatment at a CD4 count of 350 or below, an analysis of the START study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston has shown.

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CROI 2016: People with HIV Considerably Overestimate Their Chances of Infecting Someone

Only a small proportion of HIV-positive people in a large U.S. treatment study, ACTG A5257, regarded themselves as non-infectious after up to 3 years on antiretroviral therapy (ART), and a third of participants regarded their chance of infecting a partner as still "high," even though only 10% of participants actually had a detectable viral load, according to a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.

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[Produced in collaboration with Aidsmap.com]

The study showed that there was no correlation between a person’s actual viral load and their belief about how infectious they were, Raphael Landovitz of the University of California in Los Angeles told the conference.

ACTG A5257 was a large drug-comparison study in which 1809 participants were randomized to receive either raltegravir (Isentress), boosted atazanavir (Reyataz), or boosted darunavir (Prezista), plus tenofovir/emtricitabine (Truvada). The 96-week results were presented at the CROI 2014 conference.

The trial enrolled participants between 2009 and 2011 and patients were asked about their infectiousness beliefs 1, 2, and 3 years after starting ART, so this study includes responses up to 2014.

A quarter of the study population was women, the mean age was 37, and ethnicity was distributed quite evenly, with 34% white, 42% African-American, and 22% Hispanic. The median viral load at baseline was 40,000 copies/mL, with 30% having a viral load over 100,000 copies/mL.

The participants were asked the question "How likely would you be to give someone HIV if you had unprotected sex with them today?"

They rated how infectious they thought they were on a visual analog scale, from "not infectious at all" (zero) to "highly infectious" (100). They were then divided into 4 categories: those who thought they were not infectious, and those who thought their risk of infecting another person was "low" (score 1-33), "medium" (34-66), or "high" (67-100).

As the start of the study, 58% of participants thought they were highly infectious and 26% placed themselves in the "medium" category. This left 16% who thought -- at this point inaccurately -- that their risk of infecting another person was "low" (10%) or zero (6%).

After a year on ART, a higher proportion -- just under one-third -- thought their risk of infecting someone was low. But 38% still thought their infectiousness was high. The percentage who thought they were not infectious at all had increased slightly to 10%. (Incidentally, 8.1% of this 10% -- just 8 individuals – were actually mistaken in their belief at this point, did have a detectable viral load, and were, to at least some extent, infectious.)

This hardly changed at all in the subsequent 2 years. At week 96, when 90% of trial participants were in fact virally suppressed, 36% still thought they were highly infectious and 19% were in the "medium" category. The proportion who thought their chance of infecting others was low had gone up just 1 point to 33%, and the proportion who thought they were not infectious to 12%.

By week 144, after 3 years on ART, 34% still thought they were highly infectious and a majority (52%) thought they were highly or somewhat infectious. The "low" category had increased by 2 points to 35%, and the non-infectious by 2 points to 14%.

In other words, after 3 years on largely suppressive antiretroviral therapy, the proportion who thought they were highly infectious had roughly halved and the proportion who believed they were not infectious had roughly doubled, but these figures in no way reflected the actual proportions who were infectious, and had no relationship with people’s actual viral load.

At week 48, young people under age 30 were somewhat more likely than average to regard their infectiousness as having fallen. Black people, people with lower educational attainment, and people who entered the study with a very low CD4 count were less likely to do so.

Women and Hispanic people were more likely to put themselves in the "not infectious" category at week 48, and users of recreational drugs and those who at baseline had seen themselves as highly infectious were less likely.

The study team will now analyze the data further to find if people’s beliefs about their infectiousness had any impact on their sexual risk behavior and choices of partners.

Given that people’s beliefs about their infectiousness, although changing somewhat after starting treatment, had little relationship to whether they were infectious, Landovitz was asked whether patients were taking over-cautious messages from healthcare professionals to heart, or felt, due to HIV stigma, that they still had to profess a belief in their own infectiousness.

Landovitz commented that ACTG A5257 spanned the period during which, in May 2011, the results were announced from the HPTN 052 study, which confirmed that people with HIV who were on ART were rarely infectious. This result appears to have had little impact on the ACTG A5257 participants.

However the trial finished around the time that the even more persuasive PARTNER study, which found no transmissions from anyone with an undetectable viral load, announced its interim findings. Landovitz commented that if this same sub-study was repeated today, people’s beliefs about their infectiousness might be different.

Asked what message we should give to patients about viral load and infectiousness, he commented: "Don’t give them a dumbed-down message and talk in absolutes. In my experience, people want nuanced information about their risk of infecting others and want to be able to make up their own minds."

2/26/16

Reference

RJ Landovitz, TT Tran, SE Cohn, et al. Perception of Infectiousness in HIV-Infected Persons After Initiating ART: ACTG A5257Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 55.

CROI 2016: Dolutegravir Is Safe and Highly Effective for Older Children with HIV

Dolutegravir (Tivicay) plus an optimized background regimen is safe, well tolerated, and provides virological efficacy in HIV-infected children from 6 to 12 years of age at 48 weeks, Andrew Wiznia, presenting on behalf of the IMPAACT1093 study group, told participants at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston.

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Coverage of the 2016 Conference on Retroviruses and Opportunistic Infections

HIVandHepatitis.com coverage of the 2016 Conference on Retroviruses and Opportunistic infections (CROI 2016), February 22-25, 2016, in Boston.

Conference highlights include PrEP and other HIV prevention innovations, new HIV treatment strategies, HIV cure research, the cascade of care, HIV-related conditions, and optimizing therapy for hepatitis C.

HIVandHepatitis.com coverage by topic

CROI website

2/26/16

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