Treatment of Chronic Hepatitis B Infection — Older and Newer Modalities

HBV is a partially double-stranded DNA hepadnavirus. It persists as covalently closed circular DNA (cccDNA) in the hepatocyte nucleus and integrates into host DNA — this is why complete cure is not achievable with current drugs.

The infection passes through phases: HBeAg-positive chronic infection (immune tolerant), HBeAg-positive chronic hepatitis, HBeAg-negative chronic infection (inactive carrier), HBeAg-negative chronic hepatitis, and the HBsAg-negative (occult) phase. Phase determines whether to treat or to monitor.

Elderly patients are usually in the HBeAg-negative phase, with fluctuating ALT and HBV DNA, longer duration of infection, and therefore a higher cumulative risk of cirrhosis and hepatocellular carcinoma.

The realistic goal is durable suppression of HBV DNA, which prevents progression, reverses fibrosis, reduces decompensation and lowers HCC risk. Cirrhosis regression on long-term therapy is well documented.

End points are virological (undetectable HBV DNA), biochemical (normal ALT), serological (HBeAg seroconversion; and the ideal, HBsAg loss with or without anti-HBs), and histological.

'Functional cure' means sustained HBsAg loss with undetectable HBV DNA off treatment. It is achieved in only about 1% per year with current nucleos(t)ide analogues, and is the target of all new drug development.

Conventional interferon-alfa and then pegylated interferon alfa-2a 180 µg subcutaneously once weekly for 48 weeks — the advantages are a finite duration, no resistance, and the highest rate of HBsAg loss.

Interferon is largely unsuitable for older patients — flu-like illness, cytopenias, depression, thyroid dysfunction and autoimmune flares. It is absolutely contraindicated in decompensated cirrhosis and autoimmune disease.

Lamivudine 100 mg daily — the first oral nucleoside analogue; low genetic barrier, with resistance in about 70% by five years (YMDD mutation). No longer first-line.

Adefovir dipivoxil — weak antiviral effect and dose-dependent nephrotoxicity; telbivudine — potent but high resistance and myopathy/neuropathy. Both are obsolete.

Three high-barrier agents are first-line: tenofovir disoproxil fumarate (TDF) 300 mg daily, tenofovir alafenamide (TAF) 25 mg daily, and entecavir 0.5 mg daily (1 mg if lamivudine-experienced). All are once-daily, oral, and produce virtually no resistance over a decade.

Choice in the elderly is decided by renal and bone safety. TDF causes proximal tubular dysfunction, hypophosphataemia and loss of bone mineral density — a real hazard in patients already at risk of falls and fracture. Prefer TAF or entecavir if eGFR is below 60, if there is osteoporosis, or if other nephrotoxic drugs are being used. Entecavir itself needs dose reduction in renal impairment.

Duration is usually indefinite. In HBeAg-positive patients, treatment may be stopped after seroconversion plus at least 12 months of consolidation; in HBeAg-negative patients and in all cirrhotics, treatment is lifelong unless HBsAg is lost.

Decompensated cirrhosis: treat with entecavir or tenofovir immediately and lifelong; never use interferon. Refer simultaneously for transplant assessment.

Classical indications: any cirrhosis with detectable HBV DNA; HBV DNA above 2000 IU/mL with ALT above the upper limit of normal; significant fibrosis or inflammation; extrahepatic manifestations; and a family history of cirrhosis or HCC.

Antiviral prophylaxis is mandatory before immunosuppression. All HBsAg-positive patients receiving chemotherapy, rituximab, high-dose steroids, TNF inhibitors or transplantation need prophylactic tenofovir or entecavir; anti-HBc-positive, HBsAg-negative patients need monitoring or prophylaxis depending on the regimen. This is a common and lethal omission in older oncology patients.

Hepatocellular carcinoma surveillance every six months with ultrasound (with or without alpha-fetoprotein) is required in HBsAg-positive patients even without cirrhosis — HBV causes HCC more often than other liver diseases in the absence of cirrhosis. Continue surveillance even after HBV DNA becomes undetectable.

Monitoring on therapy: HBV DNA and ALT every 3–6 months, creatinine and serum phosphate on TDF, and quantitative HBsAg where available; assess adherence at every visit.

Hepatitis D is the most severe form of viral hepatitis; test every HBsAg-positive patient for anti-HDV. Bulevirtide, an entry inhibitor blocking the NTCP receptor, is the first specific approved therapy for chronic hepatitis D.

HIV coinfection: use an antiretroviral regimen containing tenofovir plus lamivudine or emtricitabine, so that both viruses are treated. Never treat HBV alone with lamivudine in a coinfected patient.

Prevention: hepatitis B vaccine with a timely birth dose (part of India's Universal Immunisation Programme), plus antiviral prophylaxis in highly viraemic pregnant women, is the foundation of elimination. Older adults who are non-immune and at risk should be vaccinated; response rates are lower with age, so post-vaccination anti-HBs testing and double-dose or adjuvanted schedules may be needed.

Antisense oligonucleotide — bepirovirsen. The phase 2b B-Clear study showed sustained HBsAg and HBV DNA loss in roughly 9–10% of patients; phase 3 programmes are ongoing.

Small interfering RNA (siRNA) — xalnesiran, imdusiran, elebsiran. Xalnesiran with or without an immunomodulator produced HBsAg loss in a subset of patients (NEJM 2024). These silence viral transcripts and reduce HBsAg.

Capsid assembly modulators (core protein allosteric modulators) block nucleocapsid formation and cccDNA replenishment; entry inhibitors (bulevirtide) block NTCP; nucleic acid polymers (REP 2139) block subviral particle release.

Immunotherapeutic approaches — therapeutic vaccines, TLR7/TLR8 agonists, PD-1 checkpoint inhibitors and engineered T cells — aim to restore the exhausted HBV-specific T-cell response. Most current strategies use combination therapy on a nucleos(t)ide analogue backbone.

WHO Guidelines on the prevention, diagnosis, care and treatment of chronic hepatitis B (released March 2024 at APASL, Kyoto) — the single most important recent change. They substantially simplify and expand eligibility for treatment.

Expanded eligibility (WHO 2024): treat all adults and adolescents with cirrhosis or significant fibrosis (APRI >0.5 or transient elastography >7 kPa); treat where HBV DNA >2000 IU/mL with ALT above the upper limit of normal; and treat those with coinfection (HIV, HCV, HDV), a family history of cirrhosis or HCC, extrahepatic manifestations, or immunosuppression.

Simplified criteria for resource-limited settings: where HBV DNA testing is unavailable, treatment may be started on APRI alone, or on persistently abnormal ALT alone — designed to overcome the fact that only about 3% of people with chronic hepatitis B globally were on treatment in 2022.

Comparative analyses (JAMA Network Open 2024) confirm the WHO 2024 criteria make a markedly higher proportion of treatment-naive patients eligible than AASLD 2018, EASL 2017 or APASL 2015 — the practical consequence is that many patients previously 'monitored' now qualify for antivirals.

Expanded PMTCT: antiviral prophylaxis for pregnant women is broadened, with simpler criteria to determine eligibility, alongside universal timely birth-dose vaccination.

Point-of-care HBV DNA (viral load) testing and reflex testing are recommended to decentralise care; routine HDV testing of all HBsAg-positive people is now advised.

Journal of Hepatology 2024 commentary on the WHO update sets out the implications for the next AASLD/EASL/APASL revisions — the direction of travel internationally is towards 'treat more, treat earlier, treat simply'.

Treat-all debate: multiple expert panels (including the broad Chinese Society of Hepatology 2022 criteria, which use any detectable HBV DNA) argue for further expansion, on the basis that even 'immune-tolerant' patients accumulate HBV integration and HCC risk.

TAF is increasingly preferred over TDF in older adults because of superior renal and bone safety, though with a small unfavourable lipid effect; entecavir remains an excellent, inexpensive alternative in nucleos(t)ide-naive patients with normal renal function.

Functional cure pipeline (2023–2025): siRNA and antisense agents (bepirovirsen, xalnesiran, imdusiran) combined with immunomodulators are in phase 2b/3; none is yet approved, and nucleos(t)ide analogues remain the standard of care.

Bulevirtide has full European approval for chronic hepatitis D, with improving long-term combined virological and biochemical response data.

Indian context: HBsAg prevalence is approximately 1–3%, classing India as intermediate endemicity with an estimated 3–4 crore people infected. The National Viral Hepatitis Control Programme provides free tenofovir and free testing, and the hepatitis B birth dose is part of the Universal Immunisation Programme. Cost and access make generic tenofovir the practical first-line agent in most Indian settings.