Viral Hepatitis — Treatment and Surveillance

The answer first

Chronic viral hepatitis is a topic of three disciplines at once: serology (what do the markers mean), antiviral therapy (who do I treat, with what, for how long), and surveillance (whose liver cancer risk outlives their virus). For the broad virological survey of all five hepatotropic viruses — HAV through HEV — see the hepatic companion topic; this page owns the infectious-diseases depth: interpreting serology, deciding and monitoring treatment, preventing reactivation, and curing HCV [1] [18]. Four rules carry most of the exam:

1. Read the serology as a pattern, never as single markers. HBsAg tells you the virus is present; anti-HBc tells you there has been real infection; anti-HBs tells you immunity. The combination is the diagnosis — and vaccine immunity is isolated anti-HBs, never anti-HBc [1].
2. Treat immune-active HBV; monitor immune-tolerant HBV; treat all cirrhosis with detectable DNA. The decision hinges on ALT, HBV DNA and fibrosis stage — not on how the patient feels. First-line therapy is tenofovir or entecavir, chosen for their high resistance barrier, and for most patients it is indefinite suppression, not cure [1] [2].
3. Every immunosuppressed patient gets screened before, not rescued after. HBsAg and anti-HBc before chemotherapy, anti-CD20 antibodies, HSCT or high-dose steroids — reactivation is common, occasionally fulminant, and almost entirely preventable with prophylactic antivirals [9] [10].
4. HCV is now a cure. Test with RNA, treat essentially everyone with a pangenotypic DAA for 8–12 weeks, and confirm SVR12. But cure is not the end of the story: cirrhosis keeps its HCC surveillance for life [16] [18].

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Reading HBV serology — the grid examiners demand

Serology questions are free marks if you think in patterns. The logic: HBsAg is the viral surface coat in the blood — its presence means current infection. Anti-HBc (total, including IgG) appears only after real, whole-virus infection — it is the scar of having met the virus, and it persists for life. Anti-HBs is the neutralising antibody — immunity, from recovery or from vaccine. HBeAg and anti-HBe track replicative activity within chronic infection [1] [3].

HCV serology is simpler but has its own trap: anti-HCV is an exposure marker, not an infection marker. About a quarter of acutely infected people clear HCV spontaneously, so an anti-HCV-positive patient may have current infection, past resolved infection, or a false positive — only HCV RNA distinguishes them, and RNA is therefore the mandatory second step of every positive antibody [18]. The same RNA-first logic applies before treatment, and SVR is judged on RNA, never on antibody, which remains positive for life after cure [19].

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The four phases of chronic HBV — natural history as a clinical tool

Chronic HBV is not a steady state but a decades-long negotiation between virus and host immunity, and the phase defines the management [3] [2]. Two framing facts first: age at acquisition determines chronicity — perinatal infection becomes chronic in about 90% of cases, adult-acquired in about 5% — which is why the chronic HBV clinic is dominated by people born in endemic regions; and liver injury in HBV is immune-mediated, not cytopathic — the virus does not kill hepatocytes, the immune response to it does, which explains why the highest viral loads coexist with the healthiest livers [3].

The trap is that phases are not a one-way escalator: patients move between immune-active and inactive states, sometimes repeatedly, and a single normal ALT means nothing. "Fluctuating ALT" in an HBeAg-positive patient is the sound of the immune system intermittently attacking infected hepatocytes — it is the signature of immune-active disease and the classic long-case presentation [3].

A precision point for the viva: the inactive carrier label requires serial confirmation — HBeAg negative, anti-HBe positive, DNA persistently below 2,000 IU/mL and ALT normal on repeated testing over at least a year — because HBeAg-negative chronic hepatitis can masquerade as inactivity between flares. One normal ALT does not make a carrier [2].

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Who to treat — the HBV treatment thresholds

The treatment decision in chronic HBV is made on three axes — ALT, HBV DNA, and fibrosis stage — and the goal is to suppress viral replication before the immune war scars the liver into cirrhosis [1]. The AASLD 2018 guidance anchors the numbers every examiner expects [1]:

[1]

The cirrhosis rule overrides everything: any patient with cirrhosis and detectable viraemia should be on antivirals, because suppression reduces decompensation and HCC risk, and long-term tenofovir therapy has been shown to regress fibrosis and even reverse cirrhosis on serial biopsy in the majority of treated patients [1] [8]. EASL is more aggressive still, treating cirrhosis at any detectable DNA and lowering the ALT bar for older patients and those with family histories of HCC [2].

The grey zone is where vivas are won: HBeAg-negative disease with DNA hovering at 2,000–20,000 IU/mL and ALT borderline elevated. Here the fibrosis assessment decides — transient elastography (or APRI/FIB-4 where elastography is unavailable), with biopsy reserved for genuine discordance. Significant fibrosis tips the decision to treatment; the alternative is structured 3-monthly monitoring, not discharge [2].

Household and sexual contacts of every chronic carrier should be tested and vaccinated if susceptible — the consult is not complete until the family is protected, and in the exam this single sentence signals a physician rather than a prescriber [12].

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First-line therapy — tenofovir and entecavir

The modern first-line agents share one property that defines them: a high barrier to resistance. Tenofovir disoproxil fumarate (TDF 300 mg daily), tenofovir alafenamide (TAF 25 mg daily) and entecavir (0.5 mg daily in nucleoside-naive patients) all suppress HBV DNA profoundly, and on-treatment resistance in naive patients is negligible — the exact opposite of lamivudine, whose resistance rate made it obsolete as monotherapy [1] [4].

The evidence behind the choices, in the order examiners quote it [4] [5]:

• Marcellin 2008 (TDF vs adefovir): tenofovir DF produced far higher rates of complete viral suppression than adefovir across HBeAg-positive and -negative disease — the trial that made tenofovir first line [4].
• Chang 2006 (entecavir vs lamivudine): entecavir beat lamivudine on histological, virological and biochemical endpoints in HBeAg-positive chronic hepatitis — the trial that retired lamivudine [5].
• Sherman 2006 (lamivudine-refractory): entecavir still works after lamivudine failure but with reduced potency and a resistance price — the origin of the 1 mg dose in this group and the modern preference for tenofovir when there is any lamivudine history [6].
• Buti 2016 (TAF vs TDF): tenofovir alafenamide was non-inferior for viral suppression with significantly smaller declines in renal function and bone mineral density — the rationale for TAF in kidneys and bones that matter [7].

Pegylated interferon survives as a finite option — 48 weeks, once weekly — for a narrow band of patients: young, HBeAg-positive, high ALT, low-ish DNA, genotype A or B, who want a defined course and can tolerate the toxicity. The Lau 2005 trial established the peginterferon alfa-2a response benchmark, and the candidacy checklist matters more in the exam than the drug itself [26].

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HBV reactivation in immunosuppression — the preventable disaster

The AGA technical review stratifies by agent and serology [9]:

Two physician-level nuances [10]: first, prophylaxis beats pre-emptive rescue in high-risk settings — waiting for the DNA to rise before treating leaves a window in which hepatitis declares; entecavir or tenofovir are the prophylactic agents (never lamivudine, given resistance). Second, the HBsAg-negative, anti-HBc-positive patient is not safe: rituximab in particular can deplete the B-cell compartment that keeps occult virus suppressed, and reactivation of resolved HBV — reverse seroconversion — is well documented, which is why anti-CD20 therapy in this group still earns prophylaxis [10] [13].

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HCC surveillance — whose liver cancer risk outlives the virus

Hepatitis B is directly oncogenic — HBV DNA integrates into hepatocyte genomes — so HCC risk exists even without cirrhosis, and it persists, attenuated but real, despite effective antiviral suppression [14]. The evidence that surveillance works is the Zhang randomised trial: six-monthly ultrasound plus AFP in a high-risk Chinese population reduced HCC mortality by 37% through earlier detection [15].

Who enters 6-monthly ultrasound (with or without AFP, per local practice) — the AASLD list, which the DWE expects verbatim [14]:

• All patients with cirrhosis — HBV, HCV (including after SVR), or any cause.
• Non-cirrhotic chronic HBV in defined risk groups: Asian men from about age 40, Asian women from about age 50, people of African ancestry from about age 20, and anyone with a first-degree family history of HCC.
• Patients with advanced (bridging) fibrosis are commonly enrolled by extension, and post-SVR HCV patients with F3 fibrosis are individualised [14] [18].

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HCV — test, treat, cure

Hepatitis C has been transformed from an interferon ordeal into one of medicine's cleanest cures, and the physician's job is now logistics and vigilance, not heroics: find the viraemic patient, stage the liver, pick a pangenotypic regimen, and confirm SVR [18].

The two pangenotypic workhorses, with their pivotal trials [16] [17]:

The remaining subtleties, at guideline depth [18]: decompensated cirrhosis excludes protease-inhibitor regimens (glecaprevir/pibrentasvir is contraindicated) — sofosbuvir/velpatasvir for 24 weeks, or with ribavirin for 12 weeks, under specialist care; prior DAA failure earns retreatment with sofosbuvir/velpatasvir/voxilaprevir; people who inject drugs should be treated without a sobriety precondition — treatment-as-prevention is the backbone of elimination; and HBV coinfection screening precedes DAAs because HCV treatment can unmask HBV replication [18].

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HDV — the parasite of hepatitis B

Hepatitis delta virus is a defective RNA virus that requires HBsAg to assemble and spread — it exists only in HBsAg-positive hosts, which makes every HBsAg-positive patient a candidate and every HDV diagnosis an HBV diagnosis first [20]. Two clinical patterns: coinfection (HBV and HDV acquired together, usually self-limited but with a higher fulminant rate than HBV alone) and superinfection (HDV landing on established chronic HBV — the dangerous one, with rapid progression to cirrhosis) [20].

The physician-level facts [20]:

• Screen every HBsAg-positive patient with anti-HDV at least once — and repeat when hepatitis is disproportionate to HBV DNA, when ALT flares in a suppressed patient, or with endemic exposure (Mediterranean, Middle East, Central Asia, parts of Africa and South America). Confirm with HDV RNA.
• Chronic HDV is the most aggressive chronic viral hepatitis — faster to cirrhosis and HCC than HBV alone — and suppressing HBV with nucleos(t)ides does nothing to HDV itself [20].
• Bulevirtide, an entry inhibitor blocking the NTCP receptor the viruses share, is the first specific therapy: the phase 3 trial showed combined virological and biochemical response at 48 weeks in about half of patients on 2 mg daily versus almost none untreated [21]. Availability varies by jurisdiction — in Australia and many regions it remains specialist-access or trial-based.
• Pegylated interferon for 48 weeks was the previous backbone; the HIDIT-1 trial showed sustained HDV RNA suppression in roughly a quarter of treated patients, with late relapses — it remains an option where bulevirtide is unavailable [22].
• Management belongs with a viral-hepatitis service; transplant-free survival, not eradication, is the realistic near-term goal [20].

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HEV — two diseases in one virus

Hepatitis E is usually a self-limited acute hepatitis from contaminated water or undercooked pork and game, but it wears two faces the exam loves [23]:

• In pregnancy, genotype 1 HEV can produce fulminant hepatic failure with maternal mortality reported around a fifth of cases in endemic series — the reason jaundice in a pregnant traveller is an emergency, and a classic DWE discriminator against the benign "acute hepatitis, supportive care" answer [23].
• In the immunosuppressed — classically solid-organ transplant recipients — genotype 3 HEV becomes chronic: persistent RNA, quietly rising transaminases, and progressive fibrosis. The treatment sequence is evidence-based: first reduce immunosuppression where possible, then ribavirin; in the Kamar series of transplant recipients, about three-quarters achieved sustained clearance with a ribavirin course [24].

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Prevention — vaccination, exposure management, elimination

Hepatitis B is vaccine-preventable, and the physician-level content is in the details [12]:

• Standard schedule is three doses (0, 1, 6 months) of recombinant vaccine; healthcare workers, dialysis patients, immunosuppressed patients and household contacts of carriers need post-vaccination anti-HBs testing — a level of 10 IU/L or more is protective [12].
• Non-responders (anti-HBs below 10 IU/L after a complete series): give a second complete series — about half respond — and consider higher-dose or adjuvanted formulations in dialysis and immunocompromised patients; document the status explicitly for occupational health [12].
• Post-exposure prophylaxis: a susceptible person with a needlestick or sexual exposure from an HBsAg-positive source gets HBIG plus the first vaccine dose, ideally within 24 hours; a non-responder with a completed second series gets HBIG. Know that the exposed healthcare worker question is answered with serology of BOTH parties, not guesswork [12].
• There is no HCV vaccine — prevention is harm reduction (needle-syringe programs, opioid agonist therapy), screening of risk groups, and treatment-as-prevention, the pillars of the WHO 2030 elimination targets that Australia has committed to [18].

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Pregnancy — protecting the next generation

Chronic HBV in pregnancy is a two-part problem: the mother's liver, and the baby's lifetime risk. Without intervention, mothers with high-level viraemia transmit perinatally at high rates — and perinatal infection is precisely the kind that becomes chronic in about 90% of cases [11] [3].

[11] [12]

HCV in pregnancy is different again: DAAs are not yet routine in pregnancy, so the plan is screen, quantify, defer treatment to post-partum, and test the infant (antibody testing is unhelpful before 18 months because of transplacental antibody — use RNA if early diagnosis is needed) [18].

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Acute liver failure — when hepatitis becomes an emergency

Any of the hepatotropic viruses can tip into acute liver failure — coagulopathy (INR 1.5 or more) with hepatic encephalopathy in a patient without pre-existing cirrhosis — and the physician's contribution is recognition and transfer, not disease-specific therapy [25]. The viral patterns worth naming: acute HBV (including reactivation), HEV in pregnancy, HDV superinfection, and HAV in the elderly or those with chronic liver disease. Management is a transplant-centre conversation early: supportive care, N-acetylcysteine as in other aetiologies, cerebral-oedema vigilance, and listing before the window closes — antivirals (entecavir or tenofovir) are given for severe acute HBV, but they do not substitute for transfer [25] [1].

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DCE angles — how this topic is examined live

The long case archetype: a 45-year-old, born overseas, with chronic HBV and "fluctuating ALT" referred from a screening program. The examiner's arc runs phase assignment (is this immune-active disease?), the treat-versus-watch defence (quote the ALT/DNA/fibrosis thresholds and own the grey zone), the surveillance frame (is he in the HCC program and is he actually attending?), and the human layer — stigma, family screening, vaccination of the household, adherence to an indefinite therapy for an asymptomatic disease [1] [14]. A second archetype: the cured-HCV patient with cirrhosis, testing whether you understand that SVR ended the virus but not the surveillance [18].

The short case is the abdominal examination for chronic liver disease stigmata — spider naevi, palmar erythema, gynaecomastia, parotid fullness, a firm liver edge, splenomegaly of portal hypertension, ascites — presented toward a synthesis: "chronic liver disease with portal hypertension, in a patient with treated chronic viral hepatitis, currently compensated" [14].

References

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