Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV

Abstract

Roughly one-third of individuals living with the human immunodeficiency virus (HIV) are coinfected with the hepatitis C virus (HCV) due to shared routes of transmission. HIV accelerates the progression of HCV disease; thus, coinfected individuals are at high priority for HCV treatment. Several new HCV therapies, called direct-acting antiviral agents (DAAs), are available that achieve cure rates of >90% in many patient populations including individuals with HIV. The primary consideration in treating HCV in HIV-infected persons is the potential for drug interactions. We describe the clinical pharmacology and drug interaction potential of the DAAs, review the interaction data with DAAs and antiretroviral agents, and identify the knowledge gaps in the pharmacologic aspects of treating HCV in individuals with HIV coinfection. This review will focus on DAAs that have received regulatory approval in the United States and Europe and agents in late stages of clinical development.

Keywords: coinfection; direct-acting antivirals; drug interactions; hepatitis C virus; human immunodeficiency virus.

Figure 1.

The hepatitis C virus (HCV) life cycle. Reprinted with permission from [9]. A, The virus gains entry by receptor-mediated endocytosis. B, Fusion and uncoating occur and the HCV genomic RNA is released from the nucleocapsid into the cytoplasm. C, Translation into a single large polyprotein occurs in the endoplasmic reticulum. D, This polyprotein is then cleaved by viral and host proteases into 10 mature HCV proteins, including structural proteins (HCV core protein and envelope proteins E1 and E2) and nonstructural proteins (P7, NS4A, NS4B, NS5A, and NS5B). E, These viral and host proteins form a membrane-bound replication complex. F, Transcription takes place, dependent upon the RNA helicase (RNA-dependent RNA polymerase or NS5B polymerase) where the positive-strand RNA serves as a template for transcription. G, Virion assembly occurs in the Golgi apparatus when viral glycoproteins combine with newly produced RNA. H, Virion maturation, budding, and release from the hepatocyte occurs. The site of action of current direct-acting antiviral agents are listed at each step in the HCV life cycle. Abbreviation: siRNA, small interfering RNA.

Figure 2.

Drug interactions between direct-acting antivirals and antiretroviral drugs. Red, combination should not be used; yellow, use with caution or increased monitoring; and green, suitable for coadministration [7]. ^aWatch renal function, tenofovir levels increased; ^bDecrease daclatasvir (DCV) dose to 30 mg QD, increase DCV dose to 90 mg QD. Up arrow is an increase in the concentration, down arrow is a decrease in the concentration, and a horizontal arrow means no change in the concentration. Abbreviations: TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.