Viral Hepatitis Treatment
Hepatitis A
Hepatitis A is self-limiting and does not require antiviral therapy. Management is entirely supportive, focusing on symptom relief and monitoring for the rare complication of fulminant hepatic failure. 1
- No antiviral agents are indicated for acute hepatitis A infection 1
- Supportive care includes rest, adequate hydration, and avoidance of hepatotoxic substances (especially alcohol) 1
- Hospitalization is reserved for patients with severe symptoms, dehydration, or signs of hepatic decompensation 1
Hepatitis B
Acute Hepatitis B
More than 95% of adults with acute HBV infection recover spontaneously without antiviral therapy. 1, 2
- Antiviral therapy with entecavir or tenofovir is indicated only for severe acute hepatitis B (defined by coagulopathy, severe jaundice, or impending liver failure) 1, 2
- For fulminant hepatitis B, immediate evaluation for liver transplantation and initiation of nucleos(t)ide analogues is mandatory 1, 2
- If treatment is started, continue for at least 3 months after anti-HBs seroconversion or at least 12 months after anti-HBe seroconversion if HBsAg loss has not occurred 1, 2
Chronic Hepatitis B
First-line treatment consists of nucleos(t)ide analogues with high genetic barriers to resistance: entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF). 1, 2
Treatment Indications
Immediate treatment is required for:
- All patients with cirrhosis (compensated or decompensated) and any detectable HBV DNA, regardless of ALT level 1, 2, 3
- Patients with decompensated cirrhosis require urgent treatment with entecavir or tenofovir AND simultaneous evaluation for liver transplantation 1, 2, 3
- HBV DNA ≥20,000 IU/mL AND ALT >2× upper limit of normal (ULN) in non-cirrhotic patients—treatment can be started without liver biopsy 1, 2, 3
- HBV DNA ≥2,000 IU/mL with elevated ALT (>40 IU/L) AND at least moderate fibrosis (demonstrated by biopsy or non-invasive markers such as liver stiffness ≥9 kPa with normal ALT or ≥12 kPa with ALT <5× ULN) 1, 2, 3
Treatment should be strongly considered for:
- HBeAg-positive patients >40 years with persistently high HBV DNA, even with normal ALT, due to increased risk of cirrhosis and hepatocellular carcinoma 2, 3
- Patients with HBV DNA ≥2,000 IU/mL and at least moderate fibrosis, even when ALT levels are normal 1, 2, 3
First-Line Agents
- Entecavir 0.5 mg once daily (oral) 1, 2, 4
- Tenofovir disoproxil fumarate (TDF) 300 mg once daily (oral) 1, 2, 4
- Tenofovir alafenamide (TAF) 25 mg once daily (oral)—demonstrates less renal tubular dysfunction and bone mineral density loss compared to TDF through 96 weeks 2
Avoid lamivudine due to high resistance rates (up to 70% at 5 years) 2, 3
Alternative Therapy
- Pegylated interferon alfa remains an option for finite-duration therapy (48 weeks) in selected patients with mild to moderate disease who desire a time-limited treatment course, though response is variable and side effects limit its use 1, 2, 3
- Pegylated interferon is absolutely contraindicated in decompensated cirrhosis and pregnancy 1, 2, 3
Treatment Goals and Duration
- The primary endpoint is long-term suppression of HBV DNA to undetectable levels by sensitive PCR assay 1, 2
- HBsAg loss (functional cure) is the optimal endpoint but is rarely achieved with current nucleos(t)ide analogue therapy 1, 2, 3
- Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues until HBsAg loss occurs 1, 2, 3
- Stopping therapy may be considered in HBeAg-positive patients who achieve HBeAg seroconversion with undetectable HBV DNA and have completed at least 12 months of consolidation therapy 2, 3
Monitoring During Treatment
- HBV DNA every 3 months until undetectable, then every 6 months 1, 2, 3
- Liver function tests (ALT/AST) every 3-6 months 1, 2, 3
- Annual quantitative HBsAg testing to assess for potential HBsAg loss 2, 3
- Renal function monitoring if on tenofovir 2, 3
Special Populations
Pregnancy:
- Tenofovir DF is the preferred agent during pregnancy due to its high potency, low resistance rates, and favorable safety profile 1, 2, 3
- Maternal antiviral prophylaxis is recommended when HBV DNA >200,000 IU/mL, initiated between 24-32 weeks gestation to prevent mother-to-child transmission 2, 3
- Continue maternal therapy for up to 4 weeks postpartum, with close monitoring for hepatic flares after discontinuation 2, 3
- All newborns of HBsAg-positive mothers must receive hepatitis B vaccine AND hepatitis B immune globulin (HBIG) within 12 hours of birth 2, 3
- Breastfeeding is generally not contraindicated even if tenofovir DF is being administered 3
Immunosuppression/Chemotherapy:
- All HBsAg-positive patients receiving immunosuppressive therapy or chemotherapy (including rituximab, anthracyclines, or anti-TNF agents) require prophylactic antiviral therapy to prevent HBV reactivation (risk 12-50%) 2, 3
- Start antiviral prophylaxis 2-4 weeks before immunosuppressive therapy 3
- Continue prophylaxis through treatment and for at least 12 months after completion (24 months for rituximab) 2, 3
HIV-HBV Coinfection:
- All HIV-HBV coinfected patients should start antiretroviral therapy (ART) regardless of CD4 count, with TDF- or TAF-based ART regimens being mandatory 2, 3
Liver Transplantation:
- All transplant candidates must receive nucleos(t)ide analogue therapy to achieve undetectable HBV DNA pre-transplant 2
- Post-transplant, combination of HBIG plus potent nucleos(t)ide analogue reduces graft infection to <5% 2
Hepatocellular Carcinoma (HCC) Surveillance
Ultrasound examination every 6 months is mandatory for: 1, 2, 3
- All patients with cirrhosis
- Asian men >40 years and Asian women >50 years
- First-generation African-American individuals >20 years
- Any chronic carrier >40 years with persistent ALT elevation and/or HBV DNA >2,000 IU/mL
- Persons with a family history of HCC
Surveillance must continue even while on potent nucleos(t)ide analogue therapy and after HBsAg loss if the patient is older than 40-50 years 2, 3
Hepatitis C
Acute Hepatitis C
Acute hepatitis C should be treated with the same direct-acting antiviral (DAA) regimens used for chronic infection. 1, 5
- Treatment can be initiated immediately or deferred for 8-12 weeks to allow for spontaneous clearance (occurs in 15-25% of cases) 1
- If treatment is pursued, use pangenotypic DAA regimens as outlined below 5
Chronic Hepatitis C
All patients with confirmed chronic hepatitis C should be treated with pangenotypic direct-acting antiviral (DAA) regimens that achieve cure rates exceeding 95-97%. 5
First-Line Treatment
Sofosbuvir/velpatasvir 400mg/100mg once daily for 12 weeks is the preferred option across all genotypes (SVR rate 98%). 5
Alternative option:
- Glecaprevir/pibrentasvir: three tablets (300mg/120mg total) once daily with food 5
These interferon-free regimens have revolutionized HCV therapy, as almost all patients can be cured with few, if any, side effects. 4
Pre-Treatment Assessment
Before initiating DAA therapy, obtain: 5
- HCV RNA quantitative testing
- HCV genotype determination
- Fibrosis staging using noninvasive methods (transient elastography, FibroScan, or serum biomarkers)
- Comprehensive drug-drug interaction screening
Treatment Modifications by Clinical Scenario
Compensated Cirrhosis (Child-Pugh A):
- Use the same pangenotypic regimens as non-cirrhotic patients 5
- Extend glecaprevir/pibrentasvir duration to 12 weeks 5
Decompensated Cirrhosis (Child-Pugh B and C):
- Patients with decompensated cirrhosis should be urgently treated with an interferon-free regimen 1
- Sofosbuvir/ledipasvir with ribavirin for 12-24 weeks (SVR rates 87-89% in Child-Pugh B and C cirrhosis) 5
- Treatment should only be attempted in experienced centers until further safety and efficacy data have accumulated, particularly in patients with Child-Pugh scores above 12 and MELD scores higher than 20 1
Treatment Prioritization
Immediate treatment priority for: 1, 5
- Patients with significant fibrosis or cirrhosis (METAVIR score F3 to F4)
- Patients with decompensated cirrhosis (Child-Pugh B and C)—urgent treatment required
- Pre- and post-liver transplant patients
- Patients with clinically significant extrahepatic manifestations (symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune complex-related nephropathy, non-Hodgkin B cell lymphoma)
- Patients with debilitating fatigue, regardless of fibrosis stage
- HIV or HBV coinfection
- Individuals at high risk of transmitting HCV (active injection drug users, men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, hemodialysis patients, incarcerated individuals)
- Hepatocellular carcinoma
Treatment is justified in patients with moderate fibrosis (METAVIR score F2). 1
In patients with no or mild disease (METAVIR score F0-F1) and none of the above-mentioned extrahepatic manifestations, the indication for and timing of therapy can be individualized, though informed deferral can be considered. 1
Treatment is not recommended in patients with limited life expectancy due to non-liver-related comorbidities. 1
Retreatment Strategies for DAA Failure
For patients who fail initial DAA therapy, retreatment with sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir/daclatasvir with ribavirin is recommended. 5
Post-SVR Follow-Up
Lifelong HCC surveillance for patients with advanced fibrosis or cirrhosis (F3-F4) even after achieving SVR: 5
- Ultrasound every 6 months indefinitely
- Fibrosis reassessment
- Monitoring for reinfection in at-risk patients (active injection drug users, men who have sex with men with high-risk sexual practices)
Expected Clinical Benefits of Achieving SVR
Achieving sustained virological response (SVR) provides: 5
- Prevention of cirrhosis complications, hepatocellular carcinoma, hepatic decompensation, and death
- Improvement in liver histology (fibrosis regression)
- Resolution of extrahepatic manifestations
- Improved quality of life and removal of stigma
The infection is cured in more than 99% of patients who achieve an SVR. 1
Hepatitis D
Hepatitis D (delta hepatitis) only occurs as a coinfection or superinfection in patients with hepatitis B. 6, 7, 4
- Treatment is based on pegylated interferon alfa, though the relapse rate is high 6
- Hepatitis D remains the most challenging type of chronic viral hepatitis to treat, with response rates less favorable compared to HBV and HCV even with novel therapeutic options 4
- All patients with HDV coinfection should have their HBV managed with nucleos(t)ide analogues (entecavir or tenofovir) to suppress HBV replication 7, 4
- Novel therapeutic options have recently been approved, but efficacy remains limited 4
Hepatitis E
Acute hepatitis E is usually self-limiting in immunocompetent individuals and does not require antiviral therapy. 6, 8
- In immunocompromised patients (e.g., after organ transplantation), hepatitis E can become chronic 6, 8
- Reduction of immunosuppression may clear HEV 6
- Ribavirin shows antiviral efficacy and is a promising off-label treatment option for chronic hepatitis E in immunocompromised patients 6, 8
Common Pitfalls
- Do not assume immune-tolerant HBV patients >40 years with persistently high HBV DNA are safe—they have a higher risk of HCC and should be evaluated for treatment 2, 3
- Do not rely solely on traditional laboratory ALT cutoffs to exclude necroinflammation and fibrosis in HBV—normal ALT by conventional criteria does not exclude significant liver disease 2
- Do not delay HCV treatment in patients with advanced fibrosis or cirrhosis—these patients should be prioritized for immediate therapy 1, 5
- Do not forget HCC surveillance after HCV cure—patients with F3-F4 fibrosis require lifelong ultrasound surveillance every 6 months even after achieving SVR 5
- Do not use lamivudine as first-line therapy for HBV—resistance rates are unacceptably high (up to 70% at 5 years) 2, 3
- Do not use pegylated interferon in decompensated cirrhosis or pregnancy—it is absolutely contraindicated 1, 2, 3