HBsAg: present in all active infection phases. Loss = functional cure (rare, <1%/year spontaneously). HBeAg: indicates high-level replication and infectivity. Seroconversion to anti-HBe = lower replication. HBV DNA: primary measure of viral replication; treatment target = undetectable. Anti-HBc IgM: acute infection. Anti-HBc IgG: lifelong marker of past or current exposure.
HBV maintains cccDNA as a stable minichromosome in the hepatocyte nucleus. No approved agent degrades cccDNA. This is why HBV therapy is indefinite in most patients — discontinuing NAs in HBsAg-positive patients causes HBV DNA rebound in the majority. Functional cure (HBsAg loss) is the highest achievable endpoint but occurs in <1% per year even with therapy.
Nucleotide analogues. Chain terminators after RT incorporation. No confirmed resistance in naive patients through 8+ years. TDF: preferred in decompensated cirrhosis and HIV/HBV. TAF: preferred if CKD or osteoporosis risk. Both also suppress HIV if used alone — must be part of full ARV regimen in HIV-positive patients.
Guanosine analogue. Inhibits 3 steps of HBV RT. Very high resistance barrier in naive patients (<1% at 5 years). CRITICAL: substantially higher resistance in lamivudine-resistant patients — avoid if prior lamivudine failure. Has anti-HIV activity — selects M184V in HIV without suppressive ARV regimen.
Immune-based therapy — only agent capable of off-treatment responses (HBeAg seroconversion, rarely HBsAg loss). 180 mcg SQ weekly for 48 weeks. HBeAg seroconversion: ~27–32%. Contraindicated: decompensated cirrhosis, psychiatric disorders. Predictors of response: genotype A/B, high ALT, low HBV DNA.
Screen all patients for HBsAg and anti-HBc before any immunosuppression (rituximab, steroids, chemotherapy). HBsAg-positive: start TDF or TAF 1–2 weeks before immunosuppression; continue 6–12 months after. Anti-HBc positive/HBsAg negative: monitor HBV DNA or prophylax depending on immunosuppression intensity. Reactivation can cause acute liver failure.
Serine protease inhibitors — block HCV polyprotein processing. Genotype-specific (1st gen) or pangenotypic (glecaprevir, voxilaprevir, grazoprevir). CYP3A4-sensitive substrates — raised by boosted PI regimens. Contraindicated in decompensated cirrhosis (Child-Pugh B/C) — concentrations rise dramatically.
Most potent HCV target — picomolar to femtomolar inhibitory concentrations. Essential for RNA replication and virion assembly. Velpatasvir, pibrentasvir: pangenotypic. Ledipasvir, elbasvir: genotype-specific. Low genetic resistance barrier individually — must be combined with sofosbuvir or NS3 inhibitor. RASs at positions 28, 30, 31, 93 reduce susceptibility.
Sofosbuvir: nucleotide analogue chain terminator. Essentially absolute resistance barrier (S282T causes severe fitness loss — never seen clinically). The pharmacological anchor of modern HCV therapy. Renally eliminated — avoid if eGFR <30 mL/min. P-gp/BCRP substrate — rifampin and carbamazepine contraindicated.
12 weeks all genotypes. SVR12 >95% across all GTs. PPIs: max omeprazole 20 mg simultaneously (not at other times). Rifampin/carbamazepine/St. John's Wort: contraindicated (reduce sofosbuvir). Add voxilaprevir for NS5A-experienced patients (SOF/VEL/VOX, Vosevi). Preferred for GT3 with cirrhosis: SOF/VEL/VOX 12 weeks.
8 weeks naive, no cirrhosis (all GTs). 12 weeks with compensated cirrhosis. PREFERRED IN DIALYSIS — no renal elimination (biliary excretion only). Rosuvastatin: contraindicated (OATP1B1/1B3 inhibition). Atazanavir: contraindicated (6-fold rise in glecaprevir). Efavirenz: contraindicated (reduces levels). SVR12 >98% in dialysis patients.
SVR12 (undetectable HCV RNA 12 weeks post-treatment) represents durable HCV eradication in >99% of patients. Benefits: fibrosis regression, reduced HCC risk, reduced liver-related mortality. However: patients with advanced fibrosis or cirrhosis require lifelong HCC surveillance (ultrasound every 6 months) — SVR12 reduces but does not eliminate HCC risk in established cirrhosis.
Mechanism: HCV suppresses HBV via interferon-stimulated gene signaling. When HCV is eliminated by DAAs, that suppression is lost → HBV reactivates. Occurs in 1–2% of HBsAg-positive patients receiving DAAs — rare cases of acute liver failure documented. Rule: Check HBsAg and anti-HBc before every HCV DAA course. HBsAg-positive: start TDF or TAF simultaneously with HCV DAAs; continue for ≥12 weeks post-HCV treatment. Anti-HBc positive/HBsAg negative: monitor HBV DNA throughout.