What we’re learning about new PrEP drugs and delivery methods at AIDS 2016
BETA is reporting from the 21st International AIDS Conference this week in Durban, South Africa—bringing you the latest news, updates, and research on HIV treatment and prevention.
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.
“Maraviroc-containing regiments could be considered for testing in HIV PrEP clinical efficacy trials,” concluded Roy Gulick, MD, MPH of Weill Cornell Medicine.
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.
Vaginal dapivirine ring reduces HIV infection by more than 75% in women
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 November 2014 to June of 2016.
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
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.
Ian McGowan, MD, PhD, of the University of Pittsburgh, presented data from the MWRI-01 study, a Phase 1 safety and acceptability study of injectable rilpivarine (1200 mg of TMC278 LA). Researchers followed up with participants (5 women and 2 men) after their last 1200 mg dose of the study drug, to determine how long the drug was detectable at sub-therapeutic levels after the single injection.
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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