What to know about new PrEP drugs

The drug maraviroc is safe and well-tolerated as pre-exposure prophylaxis for women

Maraviroc, a drug that is already on the market to treat HIV (brand name, Selzentry), is a CCR5 antagonist that concentrates in the genital tract and rectum, and selects for drug resistance uncommonly—making it a desirable product for PrEP, if it works.

The HPTN 069 study, which previously reported findings for men who have sex with men at CROI 2016, presented findings for women at AIDS 2016. HPTN 069 compared maraviroc-containing regiments to Truvada, making it the first randomized study of HIV PrEP regimens in U.S. women.

The study included 188 people born female over the age of 18. Participants, in the last three months, had  condomless vaginal or anal sex with at least one HIV-positive or unknown status man. The median age of participants was 35, and most were Black (65%).

People in the study received either maraviroc 300 mg; maraviroc 300 mg plus emtricitabine (FTC) 200 mg; maraviroc 300 mg plus tenofovir disoproxil fumarate (TDF) 300mg; or, Truvada (TDF 300 mg + FTC 200 mg). The study lasted 48 weeks.

Study participants were, overall, moderately adherent to the study drug regimen. At week 24, 65% of the sample had detectable study drug in their system; at week 48, 60% of the sample did. There were no new HIV infections during the study. (This study did not assess efficacy, however, so no conclusions can be made yet about how well maraviroc works to prevent HIV in women.)

All of the maraviroc-containing regimens were safe and well-tolerated, as compared to Truvada.



.Benefits of PrEP far outweigh the risks of drug resistance

One concern about PrEP is the potential for drug resistance mutations to develop if HIV infection happens during PrEP delivery (or if PrEP is given to a person who is unknowingly already HIV-positive). People with HIV who develop drug resistant mutations may be effectively limited in their future HIV treatment options. Can the risk of drug resistance be weighed against the HIV prevention benefits of PrEP—as this strategy is provided to an ever-increasing number of people all over the world?

“Resistance infections during PrEP should be weighed against the numbers of infections averted,” said Robert Grant, MD, MPH of the Gladstone Institutes and San Francisco AIDS Foundation. “Each of [these] will require life-long therapy with the attendant risk of virological treatment failure with drug resistance.”

“The risk of drug resistance during PrEP use is rare. It is very low risk,” emphasized Grant. In one review of six PrEP studies by Fonner and colleagues, out of the over 9,000 people took TDF/FTC PrEP only five drug resistant infections emerged, for an overall risk of developing FTC or TDF resistance of 0.05%.

A closer analysis of drug resistant infections in three oral TDF PrEP studies, said Grant, found that there was only one case of TDF resistance—for 53 infections that were averted overall by PrEP use. This one case of resistance that occurred happened because PrEP was give to someone in the acute (early) phase of HIV infection.

Out of five studies of oral FTC/TDF (Truvada), there were eight infections averted for every one drug resistant infection that occurred. Excluding cases of drug resistance that occurred because PrEP was given during early HIV infection, 22 infections were averted for every one case of drug resistant infection.

“Drug resistance risk during PrEP use has been low. And it mostly occurs when starting PrEP during acute HIV infection. Screening for acute infection would increase the benefits relative to drug resistance risk, by more than two-fold,” concluded Grant.

PrEP taken before and after sex—instead of daily—works well to prevent HIV

Jean-Michel Molina, of University of Paris Diderot, first presented the much-anticipated results from the IPERGAY randomized-controlled portion of the study at CROI in 2015 of “on-demand” PrEP use (i.e., PrEP taken around the times of sex, instead of once per day). Yesterday, he shared final results from the open-label portion of the study, which lasted from A total of 362 men who have sex with men participated in the open-label portion of the study. At the start of the study, men reported an average of 9.5 sex acts in the prior four weeks and seven sexual partners in the prior two months. The median follow-up time was 18.4 months with a total of 515 patient follow-up years in the study.

The HIV incidence per 100 patient-years was 0.19 during the study, for an estimated 97% relative risk reduction compared to placebo.

There was one HIV infection during the study, in a participant who was found to not have used PrEP for months. TDF/FTC were not detectable in his system at the time that he was diagnosed, and he did not develop a drug resistant mutation.

“As you may know, PrEP on-demand is recommended in France as an alternative to daily PrEP for MSM. That’s also the case in the UK, in Europe, and soon in Canada,” said Molina. (The PrEP on-demand regimen is not recommended in the United States.)

Injectable and long-acting PrEP testing is underway—with three different drugs  November 2014 to June of 2016.

Three drugs are being tested as possible long-acting PrEP agents, said Myron Cohen, MD, from the University of North Carolina School of Medicine. The first is rilpivarine, a widely available pill that is currently used to treat HIV. It has been formulated as a long-acting nanosuspension that can be injected into the muscle for long-acting PrEP.

Cohen clarified drugs formulated as nanosuspensions aren’t inherently long-acting. “It’s rather that the suspension, once injected into the muscle, is distributed into the tissues very slowly over a long period of time.”

The HPTN 076 study is currently testing the safety and acceptability of injectable rilpivarine for PrEP in 136 HIV-negative women at sites in the United States and sub-Saharan Africa.

A second possible injectable PrEP options Cohen discussed is cabotegravir (or GSK126744 LA), an antiviral similar in structure to dolutegravir. A variety of studies are currently underway to test the safety and efficacy of the cabotegravir in men and women—including the Éclair study, HPTN 077 and HPTN 083. Cohen reported that a possible future study, called HPTN 084, is “heavily in the discussion phase,” and could be an open-label study for women in sub-Saharan Africa.

Efda (MK-8591) is a new drug that is also being tested as a long-acting PrEP injection. Cohen described this agent, being developed by the pharmaceutical company Merck, as something that is “still in progress,” but so far an “exceptional agent.”

Efda is a very potent NNRTI with a long half life. Cohen said that in pill form, the antiviral is something that could be given once per week for HIV treatment. The company is currently working on how to develop it for HIV treatment and/or prevention. Cohen said that the drug’s potency would make it ideal as a the drug used in an implant—and possibly even combined with a contraceptive drug in an implant for women.

“An implant would be a whole new ball game for HIV prevention or treatment,” said Cohen. “This drug could offer something really terrific in this field.”

Rilpivarine injections have an extremely long “tail”—carrying implications for drug resistance

One new method for PrEP that is currently being investigated are long-acting injections—that might provide HIV protection for two months or more. One concern about long-acting antiretroviral injections are the drug “tails,” or how long the drug persists in the body—at levels that are below the level to be therapeutic—after an injection if a follow-up injection is not given on schedule.

Rilpivarine was detectable in plasma samples of all seven of the participants a mean of 541 days after a single dose of 1200 rilpivarine, and the drug was also detected in cervical and vaginal fluid.

“It’s clear, I think, that as we move forward with this exciting field of long-acting injectables, we really need to better characterize the terminal half-life of these products, the “tail,” so that we can better inform the management of this and avoid the potential for antiretroviral drug resistance.”

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AVAC 2017 Advocacy Fellows Program OPEN

The Advocacy Fellows Program

AVAC recently announced the call for applications for the 2017 Advocacy Fellows Program. This update serves as a reminder that Monday, 15 August 2016 is the submission deadline for this eighth year of the Advocacy Fellows Program application process. 

To read more about the Advocacy Fellows Program, the 2017 application process and required documents, please download application materials atwww.avac.org/fellows-application-materials.

HIV Treatment + PrEP Virtually Eliminates HIV Transmission

Integrating antiretroviral therapy (ART) for HIV-positive partners and Truvada pre-exposure prophylaxis (PrEP) for HIV-negative partners can nearly eliminate the risk of HIV transmission in serodiscordant couples, researchers reported at the 21st International AIDS Conference (AIDS 2016) taking place this week in Durban, South Africa.

Several studies have shown that effective antiretroviral treatment dramatically lowers the risk of onward HIV transmission—a concept known as “treatment-as-prevention”—- while PrEP taken consistently reduces the risk of infection by more than 90%. Putting the two approaches together may fill any gaps that could occur, for example, if a person has recently started ART and not yet achieved an undetectable viral load. In this strategy, PrEP serves as a “bridge” until treatment is fully effective.

Jared Baeten, MD, from the University of Washington in Seattle presented findings from the Partners PrEP Demonstration Project, which looked at the real-world feasibility of ART plus PrEP for serodiscordant (mixed HIV status) heterosexual couples in Kenya and Uganda.

In the original Partners PrEP study, HIV-negative partners were randomly assigned to take tenofovir/emtricitabine (the drugs in Truvada), tenofovir alone, or a placebo. At the time World Health Organization and country guidelines recommended ART initiation based on CD4 cell count, so some of the HIV-positive partners did not start treatment.

Baeten first presented the study results at the International AIDS Society conference in 2011, showing that Truvada and tenofovir alone reduced the risk of HIV transmission by 73% and 62%, respectively.

The follow-up Partners PrEP Demonstration Project aimed to show whether integrating PrEP for negative partners plus ART for positive partners could further lower the risk. By the time this study started in November 2012 there was clear evidence that both PrEP and treatment-as-prevention worked, so all participants received ART and PrEP on an open-label (non-randomized) basis.

The demonstration project enrolled a new cohort of 1,013 serodiscordant heterosexual couples in which neither partner had ever taken antiretroviral drugs. Couples were selected using a risk algorithm that gave scores based on predictors including younger age, recent unprotected sex, male partners not being circumcised, and positive partners having a high viral load.

In two-thirds of couples, the woman was HIV-positive. Positive partners had a median CD4 count of around 400 cells/mm3 and a median viral load over 37,000 copies/mL. A majority (65%) said they’d had unprotected sex during the past month.

Upon enrollment, HIV-positive partners were offered combination ART (recommended for all positive partners in serodiscordant couples regardless of CD4 count) and HIV-negative partners were offered daily Truvada. PrEP was continued if the positive partner delayed treatment or for the first six months after ART initiation, giving time for viral load to become undetectable.

At the 2015 Conference on Retroviruses and Opportunistic Infections Baeten reported interim results, showing that two HIV-negative partners had seroconverted. Based on the HIV incidence rate in the placebo arm of the original Partners PrEP trial, the researchers estimated that 40 new infections would have been expected without ART and PrEP—a  risk reduction of 96%.

This week Baeten gave final updated results with data through June 2016. By this time 91% of positive partners had started ART, almost all of those had achieved viral suppression, and 97% of negative partners offered PrEP had accepted it. By the end of follow-up four new HIV infections had occurred, compared with 83 expected without ART or PrEP—a risk reduction of 95%.

Adherence to both ART and PrEP was found to be good during the demonstration project. A subset of HIV-negative partners on PrEP were randomly selected for drug level testing, and 82% of blood samples showed detectable tenofovir.

However, Baeten reported, none of the people who became infected used PrEP consistently, and in fact were in couples that used neither ART nor PrEP.

One negative woman had broken up with her positive partner and stopped PrEP, while a second woman had a partner who did not yet want to start treatment and she also stopped PrEP. A third woman was a sex worker who used PrEP inconsistently. The only newly infected man declined PrEP and had multiple sex partners.

“In this open-label demonstration project of integrated delivery of ART and PrEP for prevention in HIV serodiscordant couples, we observed virtual elimination of incident HIV,” the researchers concluded.

“Interventions like this could have a substantial effect on the HIV epidemic,” Baeten said at an AIDS 2016 press conference. “Both PrEP and ART are extremely important interventions that can virtually eliminate HIV transmission.”

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