Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Fumarate

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate has the following uses:

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is a four-drug combination of darunavir (DRV), an HIV-1 protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 NRTIs, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. 1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Co-administration of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate components. Consult the full prescribing information prior to and during treatment for potential drug interactions.1

Mechanism of Action

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is a fixed-dose combination of antiretroviral drugs darunavir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide.1

Darunavir: Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.1

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of CYP-P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.1

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, ε, and mitochondrial DNA polymerase γ.1

Tenofovir Alafenamide: TAF is a phosphonamidate 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-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. 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.1

Spectrum

Darunavir: Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human PBMCs, and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum.1

Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1.1

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary PBMCs. The EC50 values for emtricitabine were in the range of 0.0013–0.64 µM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).1

Tenofovir Alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), primary monocyte/macrophage cells, and CD4+ T lymphocytes. The EC50 values for TAF ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).1

The combination of darunavir, emtricitabine, and tenofovir alafenamide was not antagonistic in cell culture combination antiviral activity assays. In addition, darunavir, emtricitabine, and tenofovir alafenamide were not antagonistic with a panel of representative agents from the major classes of approved HIV antivirals (PIs, NRTIs, NNRTIs, and INSTIs). The antiviral activity of approved HIV antivirals was not antagonized by cobicistat.1

Resistance

Darunavir in Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected and obtained from subjects treated with darunavir co-administered with ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated substitutions resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.1

Emtricitabine in Cell Culture: HIV-1 isolates with reduced susceptibility to emtricitabine were selected in cell culture and in subjects treated with emtricitabine. Reduced susceptibility to emtricitabine was associated with M184V or I substitutions in HIV-1 RT.1

Tenofovir Alafenamide in Cell Culture: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions. In addition, a K70E substitution in HIV-1 RT was observed.1

Individuals with Prior Antiretroviral Treatment in Clinical Trials: Darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) in HIV-1 protease were derived from clinical trial data of antiretroviral therapy experienced patients, which were all protease inhibitor-experienced patients. Baseline International AIDS Society-USA (IAS-USA)-defined PI resistance substitutions confer reduced virologic response to darunavir.

Individuals with No Prior Antiretroviral Treatment History in Clinical Trials: In the AMBER clinical trial of subjects with no prior antiretroviral treatment history, there were 7 subjects with protocol-defined virologic failure and with HIV-1 RNA ≥400 copies/mL at failure or later timepoints who had post-baseline resistance data in the darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate arm. None of the subjects had detectable emergent darunavir resistance-associated substitutions or other primary protease inhibitor resistance substitutions and only one subject had emergent M184M/I/V, which confers resistance to emtricitabine and lamivudine. In the comparative PREZCOBIX + emtricitabine/tenofovir disoproxil fumarate arm, there were 2 protocol-defined virologic failures with post-baseline resistance data and neither had detectable resistance emergence.

Virologically Suppressed Individuals in Clinical Trials: In the EMERALD clinical trial of virologically-suppressed subjects who switched to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, 1 subject who rebounded and 2 subjects who discontinued early from the study had post-baseline resistance genotypes. None of the subjects had darunavir, primary protease inhibitor, emtricitabine, or tenofovir resistance substitutions. In the control arm, there were 3 subjects who rebounded with post-baseline genotypes and no resistance substitutions were observed.

Cross-Resistance

Darunavir: Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir. A less than 10-fold decreased susceptibility was observed for the other PIs in 26% to 96% of these PI resistant clinical isolates [nelfinavir (26%), ritonavir (34%), lopinavir (46%), indinavir (57%), atazanavir (59%), saquinavir (64%), amprenavir (70%), and tipranavir (96%)].1 Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, gp41 fusion inhibitors, CCR5 co-receptor antagonists, or integrase strand transfer inhibitors is unlikely because the viral targets are different.1

Emtricitabine: Emtricitabine-resistant viruses with the M184V or I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.1

Tenofovir Alafenamide: Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.1

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Instructions for Use

Advise patients to take darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate with food every day on a regular dosing schedule, as missed doses can result in development of resistance. Inform patients not to alter the dose of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate or discontinue therapy without consulting their physician. For patients who are unable to swallow tablets whole, darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate may be split using a tablet-cutter, and the entire dose should be consumed immediately after splitting.1

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or TDF, and may likewise occur with discontinuation of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise the patient to not discontinue darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate without first informing their healthcare provider.1

Hepatotoxicity

Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop.1

Severe Skin Reactions

Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, could potentially occur with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop, including but not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis.1

Pregnancy

Advise patients that darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate.1

Lactation

Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.1

Drug Interactions

Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate may interact with many drugs; therefore, inform patients of the potential serious drug interactions with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and that some drugs are contraindicated with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate and other drugs may require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.1

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.1

Renal Impairment

Advise patients to avoid taking darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.1

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate. Advise patients that they should stop darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.1

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, and that the cause and long-term health effects of these conditions are not known at this time.1

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.