Hepatitis B and C Pharmacology

Hepatitis B virus (HBV) is a partially double-stranded DNA virus of the Hepadnaviridae family that maintains a stable nuclear reservoir of covalently closed circular DNA (cccDNA) that persists despite antiviral therapy. This intranuclear reservoir is the fundamental pharmacological barrier to HBV cure and explains why antiviral therapy suppresses but does not eradicate infection in most patients.

Current antiviral therapy targets the HBV reverse transcriptase step; no approved agent directly degrades cccDNA, which is why therapy is indefinite in most patients.

Serological markers provide both a roadmap of infection phase and endpoints for treatment monitoring. Hepatitis B surface antigen (HBsAg) is present in all phases of active infection; its loss with or without development of hepatitis B surface antibody (anti-HBs) represents functional cure — the highest achievable therapeutic endpoint, occurring spontaneously in fewer than 1% of chronically infected adults per year and rarely in response to antiviral therapy. Hepatitis B e antigen (HBeAg) presence indicates high-level viral replication and high infectivity; seroconversion to anti-HBe marks a transition to lower-replication phases in many patients. HBV DNA quantification by polymerase chain reaction (PCR) is the primary measure of viral replication and treatment response, with treatment targets of undetectable or below the lower limit of quantification (generally below 10–20 international units per milliliter [IU/mL]). Hepatitis B core antibody (anti-HBc) IgM indicates acute infection; anti-HBc IgG persists lifelong and marks past or current HBV exposure.

HBV infection phases determine treatment eligibility. The immune-tolerant phase features high HBV DNA, HBeAg positivity, normal alanine aminotransferase (ALT), and minimal hepatic inflammation — antiviral therapy is generally not indicated because immune-mediated hepatocyte injury is absent and treatment response is poor. The immune-active phase features elevated ALT, active hepatic inflammation, and variable HBV DNA — treatment is indicated. HBeAg-negative chronic hepatitis B, which predominates in Mediterranean and Asian regions due to precore mutant strains, represents a distinct treatment-requiring phase with low-to-intermediate HBV DNA and fluctuating ALT. Most guidelines recommend treatment for all patients with compensated or decompensated cirrhosis regardless of HBV DNA level, and for patients with HBV DNA above 2,000 IU/mL and ALT above the upper limit of normal.

Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus of the Flaviviridae family. Unlike HBV, HCV does not integrate into the host genome and lacks a nuclear cccDNA reservoir, making pharmacological cure achievable with finite antiviral therapy. Current direct-acting antiviral (DAA) regimens achieve sustained virological response at 12 weeks post-treatment (SVR12) — operationally equivalent to cure — in more than 95% of treatment-naive patients across all genotypes.

The HCV genome encodes a large polyprotein cleaved into structural proteins and non-structural proteins. Three non-structural proteins are the targets of all approved DAAs. NS3/4A is a serine protease that cleaves the HCV polyprotein; its inhibition blocks polyprotein processing and halts viral replication. NS5A is a multifunctional phosphoprotein essential for viral RNA replication and virion assembly; its inhibition makes it the most potent target in the HCV drug armamentarium. NS5B is the RNA-dependent RNA polymerase (RdRp) responsible for copying the HCV genome; it is targeted by nucleotide analogues (which act as obligate chain terminators after incorporation) and non-nucleoside inhibitors. HCV exists in seven major genotypes (GT1 through GT7) with multiple subtypes. The advent of pangenotypic DAA regimens — those active against all genotypes — has substantially simplified treatment by obviating genotype testing before therapy in most clinical settings.

The pharmacological basis of HCV cure with finite therapy rests on four properties of current DAA regimens: extremely high antiviral potency (reducing HCV RNA by 4–6 log10 within days of initiation), combinational targeting of three non-overlapping mechanisms (preventing resistance emergence through single mutations), high resistance barrier for newer agents (particularly sofosbuvir, for which resistance requires multiple simultaneous mutations), and the absence of a persistent nuclear reservoir unlike HBV cccDNA. SVR12 is considered durable and equivalent to cure because HCV RNA levels do not rebound after sustained suppression in the absence of reinfection. Large prospective cohort studies demonstrate fewer than 1% of patients with SVR12 experience viral relapse.

DAA therapy achieves high SVR12 rates across most patient populations, but cirrhosis, advanced renal impairment, HIV co-infection, prior DAA experience, and baseline resistance-associated substitutions (RASs) require tailored regimen selection and in some cases extended treatment duration.

Compensated cirrhosis (Child-Pugh A) does not substantially reduce SVR12 rates with pangenotypic regimens, but does influence treatment duration. Glecaprevir/pibrentasvir for 12 weeks (rather than 8 weeks) is used in treatment-naive patients with compensated cirrhosis; sofosbuvir/velpatasvir for 12 weeks is similarly used. Genotype 3 (GT3)-infected patients with cirrhosis are the most challenging scenario in contemporary HCV practice — SVR12 rates with sofosbuvir/velpatasvir are approximately 88–91%, below the greater-than-95% threshold achieved in other populations; sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is the preferred approach in NS5A-naive GT3 cirrhotic patients. Decompensated cirrhosis (Child-Pugh B or C) is a contraindication to NS3/4A protease inhibitor-containing regimens because protease inhibitor concentrations increase dramatically in hepatic impairment, increasing toxicity. Sofosbuvir/velpatasvir with or without ribavirin for 12–24 weeks is the preferred approach in decompensated cirrhosis.

Severe renal impairment (eGFR below 30 mL/min/1.73m²) requires careful DAA selection because sofosbuvir accumulation is not well characterized at low eGFR levels. The preferred regimen in this setting is glecaprevir/pibrentasvir, which has no renal elimination pathway and is approved at standard doses including in patients on hemodialysis, achieving SVR12 rates above 98%. HIV/HCV co-infection was historically associated with accelerated hepatic fibrosis progression and lower interferon response rates. With DAA therapy, SVR12 rates in HIV/HCV co-infected patients are equivalent to those in HCV monoinfected patients across all approved regimens, provided HIV is virologically suppressed and the ARV regimen is compatible with the chosen DAA. NS3/4A protease inhibitors (glecaprevir, voxilaprevir, grazoprevir) are sensitive CYP3A4 substrates; ritonavir- and cobicistat-boosted ARV regimens raise NS3/4A inhibitor concentrations substantially — atazanavir/ritonavir raises glecaprevir exposure approximately 6-fold and is contraindicated; sofosbuvir/velpatasvir has a favorable interaction profile with most INSTIs and NNRTIs.

NS5A resistance-associated substitutions (RASs) can reduce SVR12 rates with specific regimens when present at baseline. Baseline NS5A RAS testing is recommended before elbasvir/grazoprevir in genotype 1a-infected patients (where NS5A resistance-associated substitutions predict reduced efficacy and mandate 16-week treatment with ribavirin), before sofosbuvir/velpatasvir/voxilaprevir in genotype 1a treatment-experienced patients, and before re-treatment after prior DAA failure involving NS5A inhibitors. For modern pangenotypic regimens such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, baseline RAS testing is not routinely required because SVR12 rates exceed 95% even in the presence of known baseline RASs for most patient populations — sofosbuvir's exceptional resistance barrier anchors these combinations against NS5A or NS3 RAS-mediated failures.