6. HIV Drugs: Few New Approvals, but Pipeline Looks Promising

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HIV drug development news in 2014 included approval of a new single-tablet regimen and 2 more components of antiretroviral therapy (ART). Promising candidates in the pipeline include a better-tolerated version of tenofovir, a NNRTI with fewer neuropsychiatric side effects, and potential long-acting injectables that may be useful for treatment or pre-exposure prophylaxis.

In August the U.S. Food and Drug Administration (FDA) approved ViiV's Triumeq combination pill containing the integrase inhibitor dolutegravir (marketed alone as Tivicay) plus abacavir and lamivudine -- the first single-tablet regimen that does not contain tenofovir and emtricitabine, making it an option for people with impaired kidney function. Triumeq is now a recommended first-line option in the DHHS antiretroviral therapy guidelines.

In September the FDA granted approval of Gilead Science's integrase inhibitor elvitegravir (Vitekta) and booster cobicistat (Tybost) -- both components of the Stribild single-tablet regimen -- as stand-alone agents. The European Commission also approved Janssen's Rezolsta fixed-dose coformulation containing the HIV protease inhibitor darunavir (marketed alone as Prezista) plus cobicistat; this combination is currently awaiting U.S. approval.

Next in line may be Gilead's tenofovir alafenamide, or TAF, a new formulation designed to produce higher levels of the active drug in HIV-infected cells than the original tenofovir disoproxil fumarate formulation (TDF, marketed as Viread), which allows for lower dosing. Studies have shown that TAF works as well as TDF in combination ART regimens but has less effect on kidney and bone biomarkers. Gilead and Janssen are developing coformulations containing TAF plus darunavir or rilpivirine (Edurant).

Further back in the pipeline, Merck's next-generation NNRTI doravirine (MK-1439) works as well efavirenz in combination ART but is associated with fewer central nervous system side effects, and Bristol-Myers Squibb's HIV attachment inhibitor fostemsavir (BMS-663068) demonstrated good virological efficacy and safety in a Phase 2 study.

Long-acting injectable drugs that could potentially be administered monthly or quarterly continue to generate interest. The LATTE trial showed that an oral combination of the NNRTI rilpivirine and the new integrase inhibitor cabotegravir (GSK1265744) kept viral load in check when used as HIV maintenance therapy, supporting further study of the long-acting injectable versions of these 2 drugs, either for maintenance therapy or pre-exposure prophylaxis (PrEP).

At the HIV Research for Prevention meeting in Cape Town researchers reported that long-acting cabotegravir reaches adequate blood levels in humans with intramuscular injections given once every 3 months, setting the stage for PrEP efficacy trials. But animal studies suggest that injected rilpivirine (also known as RMC278-LA) loses its protective effect after about 20 days.

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