Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Abstract

The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n ‫؍‬ 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (<32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen.

Hepatitis C guidance: AASLD‐IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus

“…When the regimen was combined with rilpivirine, exposures to rilpivirine were substantially increased. Therefore, rilpivirine and efavirenz should not be used with the PrOD regimen …”

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir: Drug Interactions With Antiretroviral Agents and Drugs for Substance Abuse

“…Phase 1 DDI studies have been conducted in healthy volunteers with the 3D regimen and 12 antiretrovirals . All studies were designed to assess the steady‐state pharmacokinetics of antiretrovirals alone and in the presence of the 3D regimen at steady state, and vice versa.…”

“…The 3D regimen was evaluated in combination with once‐daily abacavir 600 mg/lamivudine 300 mg or tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg . No significant changes in nucleos(t)ide reverse‐transcriptase inhibitor (NRTI) exposures were noted when combined with the 3D regimen except for a 29% increase in lamivudine C trough .…”

Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8‐Hydroxyefavirenz Exhibit Divergence in Activation

“…The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV; Figure 1) is a cornerstone of HIV therapy, and in fact is designated by the World Health Organization (www.who.int) as an essential medicine; however, EFV is also a PXR agonist [5] and as a result exhibits a high incidence rate of drug-drug interactions upon co-administration with other P450 substrates, including anti-hepatitis C viral agents, antifungals and oral contraceptives [6] . Further, EFV autoinduces the formation of its primary cytochrome P450-dependent metabolite, 8-hydroxyEFV (8-OHEFV).…”