Viral Hepatitis, Chronic

Chronic hepatitis B and C are defined by persistence of the virus beyond 6 months — hepatitis B surface antigen (HBsAg) positivity for hepatitis B, and both anti-HCV and detectable HCV RNA for hepatitis C. Both infections are usually silent for years, and their real danger is slow, often asymptomatic progression to cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Management of the two diseases now differs fundamentally. Chronic hepatitis C is a curable disease — pangenotypic direct-acting antivirals (DAAs), taken orally for as little as 8 weeks, achieve cure in the great majority of appropriately treated patients across genotypes and disease stages, and many treatment-naive patients can now be managed safely in primary care using a simplified, minimal-testing pathway.^[1] Chronic hepatitis B, by contrast, is not curable with current therapy — oral antivirals suppress viral replication and halt disease progression, but functional cure (HBsAg loss) remains rare, so most patients who meet treatment criteria require lifelong therapy.^[2] Distinguishing who needs HBV treatment now versus monitoring only, and who is at risk of a preventable HBV reactivation flare, is the core clinical task of this chapter — acute presentation, diagnosis, and post-exposure prophylaxis are covered separately in Viral Hepatitis, Acute.

Chronic hepatitis B

Most chronic HBV infection is entirely asymptomatic for years to decades — it is usually identified through screening or incidentally abnormal liver enzymes, not through symptoms. When present, symptoms are nonspecific: fatigue or mild right-upper-quadrant discomfort. A minority of patients develop rare immune-complex-mediated extrahepatic manifestations, including glomerulonephritis and polyarteritis nodosa. Untreated, chronic HBV can progress silently to cirrhosis, decompensated liver disease, and HCC — notably, HCC can occur even without cirrhosis in chronic HBV, unlike most other causes of chronic liver disease.

Chronic hepatitis C

Chronic HCV is also usually asymptomatic until advanced fibrosis or cirrhosis develops; fatigue is the most common nonspecific symptom when present. Extrahepatic manifestations include mixed cryoglobulinemia (which can cause vasculitis, arthralgia, and glomerulonephritis), porphyria cutanea tarda, and lichen planus. As with HBV, most morbidity and mortality comes from silent progression to cirrhosis and its complications, including HCC, rather than from the infection itself.

Hepatitis D co-infection

Chronic hepatitis D (delta hepatitis) can only occur in someone already infected with HBV, since HDV cannot infect a cell without HBsAg. Co-infection generally produces more severe liver disease and worse outcomes than HBV alone, and current treatment options for HDV remain limited and largely unsatisfactory — refer any confirmed HDV co-infection to hepatology.

The presentation that changes management

Ascites, variceal bleeding, and hepatic encephalopathy mark the transition from compensated to decompensated cirrhosis and always warrant hepatology referral rather than routine primary-care management, regardless of which virus is responsible (see Red Flags & Refer).

• Perinatal or early-childhood HBV acquisition — carries a substantially higher lifetime risk of chronic infection than infection acquired as an immunocompetent adult.
• Immunocompromising conditions, including HIV co-infection — increase the risk that both HBV and HCV infection become chronic rather than clearing spontaneously.
• Male sex, age over 40 years at the time of HCV acquisition, and longer duration of infection — associated with faster fibrosis progression.^[3]
• Alcohol use — a major accelerant of fibrosis progression in both chronic HBV and HCV.
• HIV co-infection — independently accelerates fibrosis progression and complicates antiviral selection in both chronic HBV and HCV.
• Diabetes mellitus and higher body mass index — independently associated with faster fibrosis progression, particularly in HCV.
• Ongoing injection drug use without access to harm-reduction services — increases both progression risk through repeated exposure and the risk of missed follow-up.
• Family history of hepatocellular carcinoma or cirrhosis, and older age at HBV acquisition — both raise HCC risk independent of current viral suppression status.
• High, persistently elevated HBV DNA level and HBeAg-positive status — the strongest viral predictors of progression to cirrhosis and HCC in chronic HBV.

Confirming chronic infection

Persistence of HBsAg beyond 6 months confirms chronic hepatitis B. Presence of both anti-HCV and detectable HCV RNA confirms chronic hepatitis C — anti-HCV alone only indicates exposure, since it remains positive for life even after spontaneous or treatment-induced clearance.

Staging investigations — chronic hepatitis B

• HBeAg and anti-HBe status — determines the replicative phase and which treat-versus-monitor track applies.
• Quantitative HBV DNA, repeated every 6 months during monitoring or treatment — the single strongest viral predictor of progression to cirrhosis and HCC.
• ALT and AST, ideally interpreted against an HBV-specific upper limit of normal (35 U/L in males, 25 U/L in females) rather than a standard laboratory reference range, since standard ranges can under-detect clinically relevant elevation in this population.
• Total bilirubin, albumin, and INR to assess synthetic liver function.
• Test every household member and sexual contact for HBsAg and anti-HBs; offer hepatitis B vaccine and confirm response with post-vaccination anti-HBs testing in anyone negative for both.
• Test every patient with chronic HBV for HCV and HIV co-infection, especially before starting nucleos(t)ide analogue therapy.
• Test for HDV co-infection (anti-HDV) when ALT remains elevated despite antiviral therapy, and in patients with an injection drug use history or origin from a higher-prevalence region.
• One-time universal HBsAg, anti-HBs, and anti-HBc screening is now recommended for every adult regardless of risk factors, which changes how many chronic infections are first identified.^[4]

Baseline investigations — chronic hepatitis C

• Quantitative HCV RNA confirms active infection and establishes the baseline viral load.
• Genotype testing is no longer required before starting a pangenotypic regimen in the simplified treatment pathway, though it remains needed for a cirrhotic patient being considered for sofosbuvir-velpatasvir, to exclude genotype 3 with resistance.^[1]
• Minimal pretreatment testing for the simplified pathway: complete blood count, hepatic function panel, estimated glomerular filtration rate, quantitative HCV RNA, HIV serology, HBsAg, and a pregnancy test where relevant — a fibrosis assessment is still required to confirm simplified-pathway eligibility (see below).^[1]

Noninvasive fibrosis assessment

Liver biopsy is rarely needed now that noninvasive tools reliably stage fibrosis for treatment decisions in both chronic HBV and HCV; reserve biopsy for a genuinely uncertain picture, such as discordant noninvasive results or suspected coexisting liver disease.

FIB-4 is calculated as age in years multiplied by AST in IU/L, divided by the product of the platelet count (×10⁹/L) and the square root of ALT in IU/L.^[5] Because this is a continuous formula involving division and a square root rather than a simple point-sum, it is not implemented as a live interactive calculator on this page — calculate the patient-specific value using a validated external FIB-4 calculator or laboratory-integrated tool, then apply the cutoffs above.

Vibration-controlled transient elastography (FibroScan) directly measures liver stiffness and is the preferred second-tier test when FIB-4 is indeterminate, or a reasonable first-line tool where available; a result at or above 7 kPa indicates clinically significant fibrosis (stage F2 or higher), which prioritizes treatment and, in the cirrhosis range, changes HCV treatment-pathway eligibility.^[2]

Consider liver biopsy specifically when noninvasive results are discordant with the clinical or laboratory picture, or when a coexisting liver disease — metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, or autoimmune hepatitis — is suspected.

• Sustained suppression of HBV DNA to below the assay's lower limit of quantification, with normalization of ALT and improvement in liver histology or noninvasive fibrosis markers, in patients on HBV treatment.
• Functional cure of HBV — HBsAg loss, with or without appearance of anti-HBs — when achievable; the most desirable outcome, though it remains uncommon with current therapy.
• Sustained virologic response (SVR) — undetectable HCV RNA 12 weeks or more after completing therapy — which constitutes a cure of chronic HCV.
• Prevention of HBV reactivation in patients undergoing immunosuppressive or chemotherapy.
• Prevention of transmission to sexual partners, household contacts, and, for HBV, future children.
• Prevention or reversal of progression to cirrhosis, decompensated liver disease, and hepatocellular carcinoma.
• Coordinated management of HDV co-infection where present, recognizing that current treatment options for HDV remain limited.

• Advise against alcohol use exceeding 20 g/day (about 1.5 standard drinks) in women and 30 g/day (about 2 standard drinks) in men — alcohol accelerates fibrosis progression in both chronic HBV and HCV independent of viral suppression status.
• Encourage smoking cessation.
• Recommend weight reduction for patients with a body mass index over 30 kg/m² and glycemic optimization for those with diabetes — both independently accelerate fibrosis progression.
• Advise against nonprescription "liver protective" herbal or natural health products — some carry genuine hepatotoxicity risk and none has demonstrated benefit in chronic viral hepatitis.
• Confirm hepatitis A and hepatitis B vaccination status in every patient with chronic HCV who is not already immune, and hepatitis A vaccination in every patient with chronic HBV who is not already immune — a superimposed acute infection is more severe on top of underlying chronic liver disease.
• Counsel on transmission prevention: safer sex practices, not sharing injection or personal-care equipment such as razors and toothbrushes, and covering open wounds.
• Reinforce medication adherence and follow-up attendance at every visit — one of the highest-yield modifiable factors in achieving viral suppression or cure and avoiding resistance or relapse.
• Screen for and address substance use disorders before starting therapy — untreated addiction is a major barrier to completing follow-up and achieving cure or sustained suppression.

Pregnancy — chronic hepatitis B

Tenofovir disoproxil fumarate is the preferred antiviral in pregnancy given the most extensive pregnancy safety experience; avoid entecavir given teratogenicity signals in animal studies, and switch a pregnant patient already on entecavir to tenofovir.^[2] Antiviral therapy specifically to reduce vertical transmission targets pregnant patients with a high HBV DNA level in the third trimester, distinct from standard treatment-eligibility criteria; continue nucleos(t)ide analogue therapy postpartum in anyone who otherwise meets ongoing treatment criteria, since stopping abruptly carries flare risk.

Pregnancy — chronic hepatitis C

Direct-acting antiviral treatment is generally deferred to the postpartum period given more limited pregnancy safety data; patients of childbearing age with known HCV who are planning a pregnancy should be treated beforehand when feasible.^[3]

Breastfeeding

Chronic HBV: tenofovir and entecavir are considered compatible with breastfeeding based on current evidence; breastfeeding is not contraindicated except for cracked or bleeding nipples until healed. Chronic HCV: not shown to transmit through breastfeeding, with the same cracked/bleeding-nipple caveat; direct-acting antiviral safety in lactation is less established, so treatment is usually deferred to a non-lactating period, or specialist guidance sought if treatment during lactation is being considered.

Pediatrics

Entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide each have defined pediatric age gates and weight-band dosing per their product monographs — direct pediatric HBV antiviral therapy to a pediatric hepatologist rather than extrapolating adult dosing. Glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are approved from age 3 years with weight-band dosing under current guidance.^[1]

Renal impairment

Tenofovir disoproxil fumarate and entecavir both need dose or interval adjustment as renal function declines (see Drug Tables for the full schedule); tenofovir alafenamide needs no adjustment until eGFR falls below 15 mL/min/1.73m². For HCV, glecaprevir-pibrentasvir needs no dose adjustment at any level of renal function, including dialysis, and is generally the preferred pangenotypic option in this setting; sofosbuvir-containing regimens historically required caution below an eGFR of 30 mL/min/1.73m², though current evidence and labelling now support use without dose adjustment in most patients, including on dialysis.

HIV co-infection

Never use a nucleos(t)ide analogue as HBV monotherapy in a patient with undiagnosed or untreated HIV co-infection — this can select for resistant HIV strains. Confirm HIV status before starting HBV antiviral therapy; if HIV-positive, use a fully suppressive antiretroviral regimen that includes an HBV-active tenofovir-based backbone rather than treating HBV in isolation. Coordinate HCV treatment in HIV co-infected patients with the patient's HIV care team, given drug-interaction potential between DAAs and antiretrovirals.

HBV/HCV co-infection

Check HBV status (HBsAg, anti-HBc) before starting any HCV direct-acting antiviral regimen — DAA therapy for HCV can trigger HBV reactivation in a patient with current or resolved HBV infection. Apply the same reactivation-prophylaxis or monitoring framework used for immunosuppressive therapy (see Choose Initial Treatment) for the duration of HCV treatment.

Decompensated cirrhosis and post-transplant

Manage in conjunction with, or refer to, a transplant hepatologist — antiviral regimen selection, ribavirin use, and monitoring differ substantially from compensated disease.

• Chronic HBV not yet on treatment: ALT and HBV DNA every 6-12 months, more frequently (every 3 months) in the HBeAg-negative pattern with fluctuating ALT and HBV DNA, since this pattern is most likely to flare; reassess fibrosis periodically.
• Chronic HBV on treatment: HBV DNA every 3-6 months until undetectable, then every 6-12 months; ALT alongside; renal function, and bone density where relevant, periodically on tenofovir-based therapy.
• Hepatocellular carcinoma surveillance with ultrasound every 6 months, with or without alpha-fetoprotein, continues indefinitely in every patient with cirrhosis and in eligible higher-risk noncirrhotic patients, regardless of viral suppression or SVR status — antiviral suppression or cure reduces but does not eliminate HCC risk once cirrhosis has developed.^[2]
• Chronic HCV during treatment: minimal on-treatment monitoring is needed for most patients using the simplified pathway — routine on-treatment labs are not required.^[1]
• Chronic HCV after treatment: quantitative HCV RNA at 12 weeks or more after completing therapy confirms SVR (cure); no further HCV-specific monitoring is needed in a noncirrhotic patient who achieves SVR beyond routine reinfection-risk counselling and periodic re-testing in patients with ongoing exposure risk.
• Confirm medication adherence and screen for drug interactions at every follow-up, particularly with any new medication started during DAA therapy.
• Reassess HBV reactivation prophylaxis need and duration whenever a patient's immunosuppressive regimen changes.

1. HCV: confirmed virologic failure (detectable HCV RNA at or after 12 weeks post-treatment) — before assuming the regimen failed, confirm the full course was actually taken and reassess drug interactions, then refer to hepatology or infectious diseases for resistance-associated variant testing and a specialist-directed retreatment regimen rather than repeating or empirically extending the same one.^[1]
2. HBV: rising HBV DNA on treatment (virologic breakthrough) — confirm adherence first, since nonadherence is the most common cause; if adherence is confirmed, test for resistance and switch to, or add, an agent with a different resistance profile and a high barrier to resistance, under specialist guidance if the picture is unclear.
3. Persistently elevated ALT despite HBV DNA suppression — reassess for a coexisting cause (metabolic dysfunction-associated steatotic liver disease, alcohol use, another hepatotoxic exposure, or HDV co-infection) rather than assuming ongoing HBV activity.
4. New or progressive fibrosis or cirrhosis despite HBV DNA suppression or HCV cure — refer to hepatology to intensify HCC surveillance and evaluate for other contributing causes.
5. HBV flare after stopping antiviral therapy — resume treatment promptly; this is the expected relapse risk of stopping before HBsAg loss, not a sign that a different regimen is needed.
6. Reinfection after HCV cure, identified on routine re-testing in a patient with ongoing exposure risk — treat as a new infection using the same simplified pathway rather than as a treatment failure.

• Treating chronic hepatitis B as if it were curable with a finite antiviral course — oral antivirals suppress HBV DNA but achieve functional cure only rarely; treatment is lifelong for most patients and should not be stopped short of HBsAg loss without specialist guidance.^[2]
• Starting nucleos(t)ide analogue therapy for HBV as monotherapy in a patient with undiagnosed HIV co-infection — confirm HIV status first.
• Missing HBV reactivation prophylaxis before starting immunosuppressive or chemotherapy in an HBsAg-positive or anti-HBc-positive patient — check HBV serology before every new immunosuppressive regimen, not only at the original diagnosis.^[6]
• Starting an HCV direct-acting antiviral regimen without first checking HBsAg status — can trigger HBV reactivation in a co-infected or previously infected patient.
• Using an abbreviated or shortened DAA course to reduce pill burden — this produces inferior response rates; use the full guideline-directed duration.
• Assuming SVR (HCV cure) removes the need for ongoing HCC surveillance in a patient with pretreatment cirrhosis — surveillance continues indefinitely regardless of cure status.
• Relying on a standard laboratory reference range for ALT in chronic HBV rather than the HBV-specific upper limit of normal, which is lower — this can miss clinically relevant elevation.
• Using lamivudine as first-line therapy for ongoing HBV treatment — reserve it for short-duration, low-risk prophylaxis only, given its high resistance rate with prolonged use.
• Skipping fibrosis staging before starting HCV treatment — cirrhosis status changes both the regimen/duration decision and whether the simplified primary-care pathway applies.
• Treating a single lab result as definitive — repeat HBV DNA or HCV RNA testing per the monitoring schedule rather than making a one-time call.

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Chronic hepatitis B — nucleos(t)ide/nucleotide analogues (high barrier to resistance, 1st-line)

Chronic hepatitis B — low-barrier-to-resistance agent (prophylaxis-only)

Adefovir dipivoxil, an older nucleotide analogue, is rarely used today given lower potency and the availability of more effective, better-tolerated first-line agents; it is not detailed further here.

Chronic hepatitis B — immunomodulator

Chronic hepatitis C — pangenotypic direct-acting antivirals (preferred, simplified-pathway regimens)

Chronic hepatitis C — genotype-specific and retreatment direct-acting antivirals

Chronic hepatitis C — adjunct antiviral