Pharmacology · Antiviral Pharmacology

Hepatitis B and C Pharmacology

HBV serology, antiviral agents, HCV DAA regimens, and clinical decision rules

HBV therapy cannot achieve true virological cure because the virus maintains cccDNA as a stable minichromosome in the hepatocyte nucleus — no approved antiviral degrades this reservoir, which means that HBsAg-positive patients who discontinue nucleos(t)ide analogues experience HBV DNA rebound in the majority, making therapy indefinite for most; functional cure (HBsAg loss) occurs in less than 1% of patients per year even with treatment.
Entecavir carries a critical but frequently missed caveat: it has a very high resistance barrier in nucleoside-naive patients (less than 1% at five years), but in patients with prior lamivudine resistance the barrier collapses dramatically — lamivudine resistance mutations create a permissive background for entecavir resistance, making TDF or TAF the mandatory choice after lamivudine failure.
Sofosbuvir is the pharmacological anchor of modern HCV therapy because its resistance barrier is essentially absolute — the S282T resistance mutation causes severe viral fitness loss and has never been documented clinically — but it is renally eliminated and contraindicated when eGFR falls below 30 mL/min, which is where glecaprevir/pibrentasvir (biliary excretion only) becomes the preferred regimen.
SVR12 — undetectable HCV RNA 12 weeks after completing therapy — represents durable eradication in over 99% of patients and confers measurable fibrosis regression, reduced hepatocellular carcinoma risk, and reduced liver-related mortality; however, patients who have already developed advanced fibrosis or cirrhosis still require lifelong HCC surveillance with ultrasound every 6 months because SVR12 reduces but does not eliminate HCC risk in established cirrhosis.
HBV reactivation during HCV DAA therapy occurs because HCV actively suppresses HBV via interferon-stimulated gene signaling — when DAAs eliminate HCV, that immune-mediated suppression is lost and HBV rebounds; every patient receiving HCV DAA therapy must be screened for HBsAg and anti-HBc beforehand, and HBsAg-positive patients must start TDF or TAF simultaneously with DAA initiation.

Abbreviations: HBV = hepatitis B virus · HCV = hepatitis C virus · cccDNA = covalently closed circular DNA · DAA = direct-acting antiviral · SVR12 = sustained virological response at 12 weeks · RAS = resistance-associated substitution · GT = genotype · HCC = hepatocellular carcinoma · NA = nucleos(t)ide analogue · eGFR = estimated glomerular filtration rate

HBV Serology — Quick Reference

Interpretation Guide

Key Serological Markers

HBsAgPresent in all active infection phases — loss of HBsAg = functional cure (rare, <1%/year spontaneously)
HBeAgIndicates high-level replication and infectivity; seroconversion to anti-HBe marks lower replication state
HBV DNAPrimary measure of viral replication — treatment target is undetectable
Anti-HBc IgMAcute infection marker
Anti-HBc IgGLifelong marker of past or current HBV exposure — does not distinguish active from resolved infection

Barrier to Cure

cccDNA — Why HBV Is Not Curable

HBV maintains cccDNA as a stable minichromosome in the hepatocyte nucleus — independent of the viral replication cycle
No approved agent degrades cccDNA — all current NAs suppress replication but do not eliminate the reservoir
Discontinuing NAs in HBsAg-positive patients causes HBV DNA rebound in the majority of patients
Functional cure (HBsAg loss) is the highest achievable endpoint — occurs in less than 1% per year even with therapy
Peginterferon is the only agent capable of inducing off-treatment immune control (HBeAg seroconversion)

HBV Antiviral Agents

Preferred NAs

TDF / TAF

Nucleotide analogues — chain terminators after incorporation by HBV reverse transcriptase
No confirmed resistance in treatment-naive patients through 8+ years of follow-up
TDF: preferred in decompensated cirrhosis and HIV/HBV co-infection
TAF: preferred when CKD or osteoporosis risk — same efficacy, lower renal/bone toxicity
Both also suppress HIV — must be part of a full ARV regimen in HIV-positive patients; monotherapy selects HIV resistance

Alternative NA

Entecavir

Guanosine analogue; inhibits three steps of HBV reverse transcription
Very high resistance barrier in naive patients — less than 1% at 5 years
Lamivudine-resistant patients: resistance barrier collapses substantially — avoid after prior lamivudine failure; use TDF or TAF instead
Has anti-HIV activity — selects M184V if used without a suppressive ARV regimen in HIV-positive patients

Immune-Based Therapy

Peginterferon alfa-2a

Only HBV agent capable of inducing off-treatment responses — 180 mcg subcutaneously weekly for 48 weeks
HBeAg seroconversion rate: ~27–32%; HBsAg loss: rare
Predictors of response: genotype A or B, elevated ALT, low HBV DNA at baseline
Contraindicated: decompensated cirrhosis, autoimmune disease, severe psychiatric disorders

HBV Reactivation During Immunosuppression

Screen all patients for HBsAg and anti-HBc before initiating any immunosuppressive therapy — including rituximab, high-dose corticosteroids, TNF inhibitors, and chemotherapy. HBsAg-positive patients: start TDF or TAF 1–2 weeks before immunosuppression and continue for 6–12 months after completion. Anti-HBc positive/HBsAg negative: monitor HBV DNA or provide prophylaxis depending on immunosuppression intensity. HBV reactivation can cause acute liver failure and death.

HCV Direct-Acting Antiviral Targets

NS3/4A

Protease Inhibitors

Serine protease inhibitors — block HCV polyprotein processing into functional viral proteins
First-generation: genotype-specific; newer agents (glecaprevir, voxilaprevir, grazoprevir): pangenotypic
CYP3A4 substrates — concentrations rise significantly with boosted PI co-administration
Contraindicated in decompensated cirrhosis (Child-Pugh B/C) — hepatic accumulation causes severe toxicity

NS5A

NS5A Inhibitors

Most potent HCV target — inhibitory concentrations in the picomolar to femtomolar range
Essential for HCV RNA replication and virion assembly
Pangenotypic agents: velpatasvir, pibrentasvir; genotype-specific: ledipasvir, elbasvir
Low individual resistance barrier — must always be combined with sofosbuvir or an NS3 inhibitor; RASs at positions 28, 30, 31, 93 reduce susceptibility

NS5B

Sofosbuvir — NS5B Inhibitor

Nucleotide analogue chain terminator — the pharmacological anchor of modern HCV therapy
Essentially absolute resistance barrier — S282T causes severe viral fitness loss and has never been documented clinically
Renally eliminated — avoid if eGFR <30 mL/min; use GLE/PIB instead
P-gp/BCRP substrate — rifampin, carbamazepine, and St. John's Wort are contraindicated

Preferred HCV Regimens

SOF/VEL — Pangenotypic

Sofosbuvir/Velpatasvir (Epclusa)

12 weeks for all genotypes (GT1–6); SVR12 >95% across all GTs in clinical trials
PPIs: take simultaneously at maximum omeprazole 20 mg equivalent — other timing intervals reduce velpatasvir absorption
Rifampin, carbamazepine, St. John's Wort: contraindicated — reduce sofosbuvir levels
NS5A-experienced patients: add voxilaprevir (SOF/VEL/VOX, Vosevi) to cover NS5A RASs
GT3 with cirrhosis: SOF/VEL/VOX 12 weeks is preferred — overcomes GT3 NS5A resistance

GLE/PIB — Pangenotypic

Glecaprevir/Pibrentasvir (Mavyret)

8 weeks in naive patients without cirrhosis (all GTs); 12 weeks with compensated cirrhosis
Preferred in advanced CKD and dialysis — biliary excretion only; no renal elimination; SVR12 >98% in dialysis patients
Rosuvastatin: contraindicated — OATP1B1/1B3 inhibition raises rosuvastatin levels dramatically
Atazanavir: contraindicated — 6-fold rise in glecaprevir concentrations
Efavirenz: contraindicated — reduces GLE/PIB levels below therapeutic threshold

SVR12 = Cure — but Surveillance Continues in Cirrhosis

SVR12 (undetectable HCV RNA at 12 weeks post-treatment) represents durable HCV eradication in over 99% of patients. Benefits include fibrosis regression, significantly reduced hepatocellular carcinoma risk, and reduced liver-related mortality. However, patients who already have advanced fibrosis (F3) or cirrhosis (F4) require lifelong HCC surveillance — ultrasound every 6 months — because SVR12 reduces but does not eliminate HCC risk once cirrhosis is established. Achieving SVR12 in cirrhosis does not end the obligation for surveillance.

HBV Reactivation During HCV DAA Therapy

Screen Before Treating HCV — HBV Reactivation Risk

Mechanism: HCV suppresses HBV replication via interferon-stimulated gene signaling. When HCV is eliminated by DAAs, that suppressive signaling is lost and HBV rebounds — including rare cases of acute liver failure. This occurs in approximately 1–2% of HBsAg-positive patients receiving DAAs.

Rule: Check HBsAg and anti-HBc before every HCV DAA course. HBsAg-positive patients: start TDF or TAF simultaneously with HCV DAA initiation and continue for at least 12 weeks after completing HCV treatment. Anti-HBc positive/HBsAg negative: monitor HBV DNA throughout the DAA course.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 49: Antiviral Agents	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 56: Antiviral Agents (Non-Retroviral)	McGraw-Hill; 2023
Seeger C, Mason WS	Molecular biology of hepatitis B virus infection	Virology. 2015
Terrault NA, Lok ASF, McMahon BJ et al.	Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance	Hepatology. 2018
Marcellin P et al.	Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B	Lancet. 2013
Perrillo RP et al.	AGA Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy	Gastroenterology. 2015
Lohmann V et al.	Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line	Science. 1999
Feld JJ, Jacobson IM, Hezode C et al.	Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection	N Engl J Med. 2015
Asselah T et al.	Efficacy of glecaprevir/pibrentasvir in patients with hepatitis C virus genotype 1–6 without cirrhosis	Clin Gastroenterol Hepatol. 2018
Foster GR et al.	Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection	N Engl J Med. 2015
Rockstroh JK et al.	Efficacy and safety of grazoprevir and elbasvir in patients with HCV and HIV co-infection	Lancet HIV. 2015
Bersoff-Matcha SJ et al.	Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic HCV	Ann Intern Med. 2017
Ioannou GN, Feld JJ	What are the benefits of a sustained virologic response to direct-acting antiviral therapy for HCV infection? Gastroenterology	2019