FDA approves new treatment for HIV

November 5, 2015

The U.S. Food and Drug Administration approved Genvoya (a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Genvoya is approved for use in HIV-infected adults and children ages 12 years and older weighing at least 35 kilograms (77 pounds) who have never taken HIV therapy (treatment-naïve) and HIV-infected adults whose HIV-1 virus is currently suppressed.

Genvoya

DESCRIPTION

GENVOYA is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for oral administration.

Elvitegravir is an HIV-1 integrase strand transfer inhibitor.

Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.

Emtricitabine is a synthetic nucleoside analog of cytidine.

Tenofovir alafenamide is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Genvoya contains a new form of tenofovir that has not been previously approved. This new form of tenofovir provides lower levels of drug in the bloodstream, but higher levels within the cells where HIV-1 replicates. It was developed to help reduce some drug side effects. Genvoya appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir containing regimens based on laboratory measures.

Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (equivalent to 11.2 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate.

Mechanism of Action

Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide (TAF): TAF is a phosphonoamidate prodrug of tenofovir (2’- deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.

Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both emtricitabine and tenofovir can be full phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

INDICATIONS AND USAGE

GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.

DOSAGE AND ADMINISTRATION

  • Testing: Prior to initiation of GENVOYA, patients should be tested for hepatitis B infection.
  • Recommended dosage: One tablet taken orally once daily with food.
  • Renal impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
  • Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment.
  • Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide

CONTRAINDICATIONS

Coadministration of GENVOYA is contraindicated with drugs that:

  • Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events.
  • Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of GENVOYA and possible resistance.

SAFETY & EFFICACY

Genvoya’s safety and efficacy in adults were evaluated in 3,171 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Genvoya or another FDA approved HIV treatment. Results showed Genvoya was effective in reducing viral loads and comparable to the other treatment regimens

WARNINGS AND PRECAUTIONS

Avoid coadministration with other antiretroviral products: Do not use with drugs containing elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate, lamivudine, ritonavir, or adefovir dipivoxil.

Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of GENVOYA and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of GENVOYA and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs.

Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

Immune reconstitution syndrome: May necessitate further evaluation and treatment.

New onset or worsening renal impairment: Assess creatinine clearance, urine glucose, and urine protein in all patients before initiating GENVOYA therapy and monitor during therapy. Monitor serum phosphorus in patients with chronic kidney disease.

Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss.

ADVERSE REACTIONS

Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea.

Reference:

FDA News

Prescribing Information