# Viral Hepatitis - B and C Management

## Hepatitis B Virus (HBV)

### Virology and Natural History

Hepatitis B virus is a member of the Hepadnaviridae family and possesses a partially double-stranded DNA genome that replicates through a reverse transcriptase intermediate. A central virologic concept with direct therapeutic implications is the formation of covalently closed circular DNA (cccDNA) within the hepatocyte nucleus. This cccDNA serves as the persistent transcriptional template for all viral RNA species and is extraordinarily stable, persisting in hepatocytes for the life of the cell. The durability of cccDNA is the fundamental barrier to achieving true virologic cure of HBV infection, as currently available antiviral agents suppress viral replication but do not eliminate cccDNA.

Transmission of HBV occurs through perinatal exposure, which is the most common route globally, sexual contact, percutaneous inoculation, and close household contact. The risk of developing chronic infection is strongly influenced by the age at acquisition: perinatal infection carries a 90 percent chronicity rate, early childhood infection carries a 30 to 50 percent rate, and immunocompetent adults develop chronic infection in fewer than 5 percent of cases. The natural history of chronic HBV infection is characterized by dynamic phases that may cycle over the patient's lifetime: the immune tolerant phase with high viral replication but minimal liver damage, the immune active phase with immune-mediated hepatocyte destruction and fluctuating transaminases, the inactive carrier state with low-level replication and quiescent liver disease, and the reactivation phase. Chronic HBV infection carries a 15 to 40 percent lifetime risk of cirrhosis, hepatocellular carcinoma, or liver failure.

### Serologic Interpretation

Interpretation of HBV serologic markers is fundamental to the management of hepatitis B and requires familiarity with the multiple clinical scenarios defined by specific serologic patterns.

| Clinical Scenario | HBsAg | Anti-HBs | HBeAg | Anti-HBe | Anti-HBc | HBV DNA | ALT |
|---|---|---|---|---|---|---|---|
| Chronic HBV, immune active (HBeAg+) | + | − | + | − | + | >20,000 IU/mL | Elevated |
| Inactive chronic carrier | + | − | − | + | + | <2,000 IU/mL | Normal |
| HBeAg-negative chronic hepatitis | + | − | − | + | + | >2,000 IU/mL | Elevated |
| Resolved infection | − | + | − | + | + | Undetectable | Normal |
| Vaccine-induced immunity | − | + | − | − | − | Undetectable | Normal |
| Isolated anti-HBc | − | − | − | ± | + | Check DNA | Normal |

A patient who is HBsAg-positive, anti-HBc-positive, HBeAg-positive, and has high HBV DNA exceeding 20,000 IU/mL has chronic HBV in the immune active, HBeAg-positive phase, reflecting high viral replication and high infectivity. An HBsAg-positive, anti-HBc-positive patient who is HBeAg-negative, anti-HBe-positive, with low HBV DNA below 2,000 IU/mL and normal ALT represents the inactive chronic HBV carrier state. An HBsAg-positive patient who is HBeAg-negative with HBV DNA above 2,000 IU/mL and elevated ALT has HBeAg-negative chronic hepatitis B, typically driven by precore or basal core promoter mutants that abolish HBeAg production while maintaining viral replication. This variant may follow a fluctuating clinical course.

An HBsAg-negative patient with positive anti-HBc and positive anti-HBs has resolved HBV infection with immunity from prior natural infection. A patient with only anti-HBs positivity has vaccine-induced immunity. Isolated anti-HBc positivity, in the absence of HBsAg and anti-HBs, may represent resolved infection with waned anti-HBs, a false-positive result, or occult HBV infection, and warrants HBV DNA testing. This serologic pattern is important for reactivation risk assessment in the setting of immunosuppressive therapy.

### HBV Treatment Indications (AASLD 2018)

Treatment of chronic HBV is indicated for patients with immune active disease, defined as HBV DNA above 2,000 IU/mL combined with elevated ALT above twice the upper limit of normal or significant histologic disease with fibrosis stage F2 or greater. All patients with cirrhosis and detectable HBV DNA should receive antiviral therapy regardless of ALT level. Additional indications include a family history of hepatocellular carcinoma and extrahepatic manifestations of HBV infection. In pregnant women with high viral loads exceeding 200,000 IU/mL, antiviral therapy in the third trimester is recommended to prevent perinatal transmission. The AASLD 2023 update has moved toward simplified treatment criteria, with a trend toward treating all HBeAg-positive patients with HBV DNA above 2,000 IU/mL and ALT above the upper limit of normal, reflecting lower treatment thresholds.

### First-Line Antiviral Therapy

Current first-line antiviral therapy for chronic HBV consists of nucleos(t)ide analogues with a high barrier to resistance. Tenofovir disoproxil fumarate at 300 milligrams daily provides potent viral suppression, a high barrier to resistance, and efficacy across all HBV genotypes. Tenofovir alafenamide at 25 milligrams daily offers a pharmacokinetic advantage with less renal and bone toxicity compared to TDF and is preferred in patients with renal impairment, osteoporosis, or age greater than 60 years. Entecavir at 0.5 milligrams daily (or 1 milligram in lamivudine-experienced patients) is an equally potent alternative with a high barrier to resistance, though it should not be used in patients with prior lamivudine resistance due to cross-resistance concerns.

Treatment duration with nucleos(t)ide analogues is indefinite for most patients. HBsAg loss, considered a functional cure, occurs in fewer than 5 percent of patients on nucleos(t)ide analogue therapy. Discontinuation may be considered after confirmed HBsAg seroconversion with development of anti-HBs, but close monitoring is essential. Pegylated interferon alfa-2a offers a finite 48-week course with a somewhat higher HBsAg loss rate of approximately 5 to 10 percent but carries significant side effects and is used less commonly in current practice.

### HBV Reactivation

HBV reactivation in the setting of immunosuppressive therapy represents a preventable but potentially fatal complication. The highest risk is associated with B-cell-depleting agents, particularly rituximab, which carries a reactivation risk of 20 to 50 percent in HBsAg-positive patients. Other immunosuppressive agents associated with reactivation risk include anti-TNF agents, cytotoxic chemotherapy, corticosteroids at doses of 20 milligrams of prednisone or more for four weeks or longer, and JAK inhibitors.

Screening with HBsAg and anti-HBc is mandatory before initiating immunosuppressive therapy. HBsAg-positive patients who are starting high-risk immunosuppression should begin entecavir or tenofovir before or concurrently with the immunosuppressive agent, continuing antiviral prophylaxis for 6 to 12 months after cessation of immunosuppression. For patients with resolved infection (anti-HBc-positive, HBsAg-negative), management depends on the immunosuppressive agent. With rituximab or other high-risk B-cell-depleting therapies, antiviral prophylaxis is recommended. For moderate-risk therapies, quarterly monitoring of HBV DNA may suffice, with initiation of antiviral therapy at the first sign of reactivation.

### HBV and HCC Screening

Hepatocellular carcinoma surveillance is essential in patients with chronic HBV infection. Abdominal ultrasound with or without alpha-fetoprotein should be performed every six months in patients with cirrhosis and in at-risk populations without cirrhosis, including Asian males over 40 years, Asian females over 50 years, African or Black patients over 20 years, patients with a family history of HCC, and patients with HBV-HIV co-infection.

<image>A comprehensive serologic interpretation chart for hepatitis B. Create a grid with columns for: HBsAg, Anti-HBs, HBeAg, Anti-HBe, Anti-HBc IgM, Anti-HBc total, HBV DNA level, ALT. Rows should show different clinical scenarios: "Acute infection," "Chronic HBV (immune active, HBeAg+)," "Chronic HBV (HBeAg-negative hepatitis)," "Inactive carrier," "Resolved infection," "Vaccinated," "Isolated anti-HBc." Each cell should show positive (+), negative (-), or variable (+/-) with numerical ranges where applicable. Use green highlighting for "no treatment needed" scenarios and red for "treatment indicated." Include a footnote about reactivation risk with immunosuppression for resolved infection. Professional medical laboratory reference table format.</image>

## Hepatitis C Virus (HCV)

### Virology and Epidemiology

Hepatitis C virus is a member of the Flaviviridae family with a single-stranded RNA genome. Six major genotypes are recognized, with genotype 1 being the most common in the United States and globally, accounting for approximately 46 percent of infections, and genotype 3 being the second most common. Unlike HBV, HCV is an RNA virus that does not integrate into the host genome and does not form a cccDNA-equivalent latent reservoir, making virologic cure achievable.

Transmission occurs primarily through percutaneous exposure, with injection drug use being the most common route in the United States. Blood transfusion was a major route prior to universal screening implemented in 1992. Other transmission routes include sexual contact, which is more efficient among men who have sex with men and in the setting of HIV co-infection, perinatal transmission at a rate of 5 to 6 percent, and percutaneous exposures through tattooing and needlestick injuries. Approximately 2.4 million people are living with HCV in the United States, with a substantial proportion remaining undiagnosed. The United States Preventive Services Task Force recommends one-time HCV screening for all adults aged 18 years and older.

Spontaneous viral clearance occurs in 15 to 45 percent of acutely infected individuals, with higher clearance rates in women, those with the favorable IL28B CC genotype, and those who develop symptomatic acute infection. Among those who develop chronic infection, 20 to 30 percent progress to cirrhosis over 20 to 30 years. Hepatitis C has historically been the leading indication for liver transplantation in the United States.

### Diagnosis

The diagnostic approach to HCV begins with the HCV antibody test, an enzyme immunoassay used for screening. A positive antibody result indicates past or current infection but does not distinguish between active and resolved infection. Confirmation of active infection requires quantitative HCV RNA by PCR, which becomes detectable one to two weeks after exposure, preceding the antibody response. Genotyping, while less critical in the era of pan-genotypic regimens, remains relevant as genotype 3 may require modified treatment approaches.

Fibrosis assessment is a critical component of the pre-treatment evaluation. FibroScan, or transient elastography, is the preferred non-invasive method. The FIB-4 score, calculated from AST, ALT, platelet count, and age, provides an additional non-invasive assessment. Liver biopsy is rarely needed in current practice. Resistance-associated substitution testing for NS5A is indicated when using certain regimens, specifically elbasvir-grazoprevir for genotype 1a, but is not required for most current preferred regimens.

### HCV Treatment -- The DAA Revolution

The introduction of direct-acting antivirals has transformed hepatitis C from a chronic, progressive disease into a curable condition. DAA regimens achieve cure rates exceeding 95 percent, defined as sustained virologic response at 12 weeks after treatment completion (SVR12), meaning undetectable HCV RNA at that time point. Treatment is recommended for all patients with chronic HCV infection, with rare exceptions. The field has been further simplified by the development of pan-genotypic regimens that are effective across all HCV genotypes.

### Preferred Regimens (AASLD/IDSA 2023)

| Regimen | Dosing | Duration (no cirrhosis) | Duration (compensated cirrhosis) | Decompensated Cirrhosis | Key Notes |
|---|---|---|---|---|---|
| Sofosbuvir/velpatasvir (Epclusa) | 1 tablet daily | 12 weeks | 12 weeks | 12 weeks + ribavirin | Pan-genotypic; first-line |
| Glecaprevir/pibrentasvir (Mavyret) | 3 tablets daily | 8 weeks | 12 weeks | CONTRAINDICATED | Shortest course; no renal adjustment |
| SOF/VEL/VOX (Vosevi) | 1 tablet daily | 12 weeks | 12 weeks | CONTRAINDICATED | Salvage for prior NS5A failure |

Two pan-genotypic regimens form the foundation of current HCV treatment. Sofosbuvir/velpatasvir (Epclusa) is administered as one tablet daily for 12 weeks and is effective for treatment-naive patients without cirrhosis, for patients with compensated cirrhosis, and for genotype 3 with compensated cirrhosis, with ribavirin added in certain situations for the latter group. Glecaprevir/pibrentasvir (Mavyret) is administered as three tablets daily and offers the advantage of the shortest available treatment course: 8 weeks for treatment-naive, non-cirrhotic patients, or 12 weeks for patients with compensated cirrhosis.

For DAA-experienced patients who have failed a prior NS5A-containing regimen, the triple combination of sofosbuvir/velpatasvir/voxilaprevir (Vosevi) for 12 weeks is the recommended salvage therapy.

### Special Populations

Several special populations require modified treatment approaches. Patients with decompensated cirrhosis (Child-Pugh class B or C) should receive a regimen containing an NS5A inhibitor plus an NS5B nucleotide polymerase inhibitor, specifically sofosbuvir/velpatasvir with ribavirin for 12 weeks. Protease inhibitor-containing regimens, including glecaprevir/pibrentasvir and voxilaprevir-containing combinations, are contraindicated in decompensated cirrhosis due to hepatotoxicity risk, as protease inhibitors undergo extensive hepatic metabolism and may accumulate to toxic levels in patients with impaired hepatic function.

For patients with chronic kidney disease or on hemodialysis, glecaprevir/pibrentasvir is the preferred regimen as it requires no renal dose adjustment and does not contain sofosbuvir. Updated data, however, have demonstrated the safety of sofosbuvir-based regimens in patients with eGFR below 30, expanding the available options.

Patients with HBV co-infection are at risk for HBV reactivation during and after HCV DAA therapy, particularly those who are HBsAg-positive. HBV DNA should be monitored, and HBV antiviral prophylaxis should be considered, especially in HBsAg-positive patients. For HIV co-infection, most DAA regimens are effective, but drug interactions with antiretroviral therapy must be carefully evaluated, particularly with ritonavir or cobicistat-boosted protease inhibitors, which alter DAA levels, and efavirenz, which reduces velpatasvir levels.

DAAs are not yet FDA-approved for use during pregnancy, though studies are ongoing. Treatment should be administered before or after pregnancy when possible. For acute HCV infection, shortened treatment courses with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for 8 weeks are under study.

### Post-Treatment Monitoring

SVR12, defined as undetectable HCV RNA 12 weeks after completion of therapy, constitutes a virologic cure. Reinfection remains possible, as cure does not confer protective immunity, and ongoing risk assessment is essential for patients with continued risk behaviors, including injection drug use and high-risk sexual contact.

HCC surveillance must continue indefinitely in patients with advanced fibrosis (stage F3) or cirrhosis even after achieving SVR, as the risk of hepatocellular carcinoma is reduced but not eliminated by viral cure. Patients with cirrhosis should also continue variceal screening and HCC surveillance with abdominal ultrasound every six months.

<image>A simplified HCV treatment algorithm. Start with "Confirmed HCV infection (HCV RNA positive)." Step 1: "Assess fibrosis: FibroScan or FIB-4 score." Branch: "No cirrhosis" and "Compensated cirrhosis" (both receive treatment) and "Decompensated cirrhosis" (different regimen required). For No Cirrhosis: "Glecaprevir/pibrentasvir x 8 weeks (shortest) OR Sofosbuvir/velpatasvir x 12 weeks." For Compensated Cirrhosis: "Sofosbuvir/velpatasvir x 12 weeks OR Glecaprevir/pibrentasvir x 12 weeks." For Decompensated Cirrhosis (in a yellow warning box): "Sofosbuvir/velpatasvir + ribavirin x 12 weeks (NO protease inhibitors)." Post-treatment: "Check HCV RNA at 12 weeks post-treatment (SVR12). If undetectable = CURED. Continue HCC screening if F3/F4." Include a "DAA-experienced/treatment failure" pathway leading to "Sofosbuvir/velpatasvir/voxilaprevir x 12 weeks." Use a clean clinical pathway format with treatment boxes.</image>

## Hepatitis B and C Co-infection

### HBV Reactivation During HCV DAA Therapy

The phenomenon of HBV reactivation during HCV DAA therapy is an important clinical consideration that arises from the complex interplay between these two viruses. HCV exerts a suppressive effect on HBV replication, and when HCV is rapidly cleared by DAA therapy, this suppressive effect is removed, allowing HBV to reactivate. The risk is highest in HBsAg-positive patients and lower, but real, in patients with resolved HBV infection who are anti-HBc-positive and HBsAg-negative.

Screening for both HBsAg and anti-HBc should be performed before initiating DAA therapy for HCV. HBsAg-positive patients should start concurrent HBV antiviral therapy with entecavir or tenofovir at the time of DAA initiation, and HBV DNA should be monitored during and after treatment.

## Hepatitis Delta (HDV)

Hepatitis delta virus is a defective RNA virus that requires HBV co-infection, specifically the presence of HBsAg, for its own replication and assembly. All HBsAg-positive patients should be screened for HDV with anti-HDV antibody, with particular attention to patients with a history of injection drug use, men who have sex with men, and immigrants from endemic areas.

HDV co-infection produces the most severe form of viral hepatitis, with accelerated progression to cirrhosis compared to HBV monoinfection. Treatment has historically been limited to pegylated interferon alfa-2a for 48 weeks, which achieves low response rates of approximately 25 percent. Bulevirtide, a novel entry inhibitor that blocks the sodium taurocholate co-transporting polypeptide receptor used by both HBV and HDV for hepatocyte entry, was approved in Europe in 2020 and represents the first targeted HDV therapy. FDA approval in the United States is pending.

## Key Clinical Pearls

- HCV is now curable in >95% of patients with 8-12 weeks of oral DAA therapy -- the focus has shifted from treatment to screening and linkage to care
- Universal HCV screening is recommended for all adults ≥18 years (one-time) and all pregnant women (each pregnancy)
- Protease inhibitor-containing DAA regimens (glecaprevir/pibrentasvir, voxilaprevir) are CONTRAINDICATED in decompensated cirrhosis (Child-Pugh B/C)
- HBV reactivation can occur during HCV DAA therapy -- always check HBsAg and anti-HBc before starting DAAs
- HBV antiviral therapy is indefinite for most patients -- HBsAg loss (functional cure) occurs in <5% on nucleos(t)ide analogs
- Screen all HBsAg-positive patients for hepatitis delta (HDV) -- co-infection dramatically accelerates liver disease progression
- HBV reactivation with rituximab is a life-threatening and preventable complication -- screen HBsAg and anti-HBc before all B-cell depleting therapies
- HCC surveillance must continue even after HCV cure in patients with advanced fibrosis or cirrhosis

## References
1. 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;67(4):1560-1599.
2. Ghany MG, Morgan TR; AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C guidance 2019 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. *Hepatology*. 2020;71(2):686-721.
3. Pawlotsky JM, Negro F, Aghemo A, et al. EASL recommendations on treatment of hepatitis C: final update of the series. *J Hepatol*. 2020;73(5):1170-1218.
4. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies. *Ann Intern Med*. 2017;167(3):ITC17-ITC32.
5. Wedemeyer H, Schoneweis K, Bogomolov PO, et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection. *J Hepatol*. 2023;78(1):35-44.