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Genvoya Pill with Tenofovir Alafenamide Added to Recommended HIV Regimens

The Department of Health and Human (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents has added the recently approved Genvoya single-tablet regimen containing elvitegravir and the new tenofovir alafenamide to its list of recommended regimens for initial HIV treatment.

Genvoya, developed by Gilead Sciences, is a fixed-dose combination pill containing the integrase inhibitor elvitegravir (sold separately as Vitekta), a cobicistat booster, emtricitabine (Emtriva), and tenofovir alafenamide (TAF). TAF is a new pro-drug formulation that reaches higher levels in HIV-infected cells, but lower levels in the blood, making it easier on the kidneys and bones than the older tenofovir disoproxil fumarate (TDF).

Food and Drug Administration (FDA) approval of Genvoya was based on data from Phase 3 randomized clinical trials showing that the new coformulation works as well as the current TDF-containing Stribild coformulation for first-line treatment -- and as well as various TDF-containing regimens for people switching therapy -- but with less kidney and bone toxicity.

Below is an edited excerpt from an AIDSinfo announcement of the DHHS panel's revised recommendation.

HHS Panel on Antiretroviral Guidelines for Adults and Adolescents Includes a Fixed-Dose Combination of Elvitegravir/ Cobicistat/Emtricitabine/Tenofovir Alafenamide Among the Recommended Regimens for Antiretroviral Treatment-Naive Individuals with HIV-1 Infection

Tenofovir alafenamide (TAF), an oral prodrug of tenofovir (TFV), was recently approved by the U.S. Food and Drug Administration as a component of a fixed-dose combination tablet consisting of elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) (EVG/c/FTC/TAF). This new combination product is approved for antiretroviral treatment (ART)-naive HIV-infected individuals 12 years or older with estimated creatinine clearance >30 mL/min. The combination drug is also approved for some ART-experienced patients, as discussed below.

Panel’s Recommendation

Based on efficacy and safety data from phase 3 randomized clinical trials, EVG/c/FTC/TAF will be added as one of the Recommended Initial Regimens for ART-naive adults and adolescents with estimated creatinine clearance >30 mL/min (AI).

See Table 6 in the current guidelines for a list of the Panel's Recommended and Alternative regimens for treatment-naive patients.

Tenofovir Alafenamide (TAF)

TAF is an oral prodrug of TFV. TAF is converted to TFV and then to TFV-diphosphate intracellularly, where it exerts its activity as a reverse transcriptase inhibitor. Unlike tenofovir disoproxil fumerate (TDF), which readily converts to TFV in plasma after oral absorption, TAF remains stable in plasma resulting in lower plasma and higher intracellular TFV concentrations. When orally administered TAF (10 mg) and TDF (300 mg) were compared, plasma TFV concentrations were 90% lower in participants who received TAF than in those who received TDF. Because of the lower plasma TFV concentration, the potential for adverse kidney and bone effects is less with TAF than with TDF.

Clinical Trials of EVG/c/FTC/TAF

Two randomized, double-blind phase 3 clinical trials compared the safety and efficacy of EVG/c/FTC/TDF and EVG/c/FTC/TAF in ART-naive HIV-infected adults with estimated glomerular filtration rate (eGFR) >50 mL/min. At 48 weeks, 800 of 866 (92%) participants randomized to TAF and 784 of 867 (90%) participants to TDF achieved plasma HIV RNA <50 copies/mL, demonstrating that TAF was non-inferior to TDF when combined with EVG/c/FTC (95% CI, 0.7%-4.7%). Both regimens were well tolerated. Participants in the TAF arm had significantly smaller decline in eGFR, less proteinuria, and smaller reductions in bone mineral density at the spine and the hip. The studies did not have adequate power to assess whether renal failure and fracture rates were different between the TAF and TDF groups. Fasting lipid levels, including both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, increased more in the TAF group than in the TDF group. Similar safety and efficacy results were reported at 96 weeks.

A separate open-label study of EVG/c/FTC/TAF in virologically-suppressed patients with mild-moderate renal insufficiency (eGFR 30-69 mL/min) supported the safety and efficacy of this combination in patients with eGFR >30 mL/min.

In addition to its approval for initial treatment of HIV-1 infection, based on the results from an open-label randomized switch study, EVG/c/FTC/TAF is also approved to replace an ART regimen in patients who are virologically suppressed for at least 6 months and who do not have a history of treatment failure or known resistance to the individual agents in the combination drug.

Other Considerations

Like other cobicistat-containing regimens, EVG/c/FTC/TAF may interact with medications that are metabolized by CYP3A (see the tables in the Drug Interactions section of the guidelines). The combination product is not recommended in patients with severe liver impairment (i.e., Child-Pugh Class C).

This new combination product is approved for antiretroviral treatment (ART)-naive HIV-infected individuals 12 years or older with estimated creatinine clearance >30 mL/min. The combination drug is also approved for some ART-experienced patients, as discussed below.

11/23/15

Source

AIDSinfo. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents Includes a Fixed-Dose Combination of Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Alafenamide Among the Recommended Regimens for Antiretroviral Treatment-Naive Individuals with HIV-1 Infection. November 18, 2015.