48: Chronic hepatitis B and D

Chronic hepatitis B and D

Grace L.H. Wong1 and Anna S. Lok2

1 Institute of Digestive Disease, Department of Medicine and Therapeutics, and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China

2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

Chronic hepatitis B

Chronic hepatitis B virus (HBV) infection, defined as the presence of hepatitis B surface antigen (HBsAg) for 6 months or more (Table 48.1), remains a major global health problem, affecting an estimated 292 million persons worldwide and causing 91 000 deaths annually. Up to 30–40% of chronically infected persons will die of complications of chronic liver disease, including cirrhosis and HCC (Figures 48.1 and 48.2).

The most common modes of transmission in low‐prevalence areas are heterosexual contact (42%), men having sex with men (15%), and injection drug use (21%). By contrast, in high‐prevalence areas, most infections occur as a result of mother‐to‐child transmission, and to a lesser extent horizontal transmission during childhood.

Hepatitis B virus is a DNA‐containing virus but it relies on reverse transcription of an RNA intermediate – the pregenomic RNA – for replication. The HBV transcriptional template exists in the nucleus of the infected hepatocyte as a population of covalently closed circular (ccc) DNA molecules organized into a viral minichromosome. These molecules of HBV cccDNA have a long intracellular half‐life (Figure 48.3) and can be replenished not only via entry of HBV virions but also via recycling of nucleocapsids from the hepatocyte cytoplasm, accounting for the difficulty in eradicating HBV once infected. The clinical significance of key HBV genotypes A to G is evolving (Table 48.2).

Several new markers have emerged and may provide prognostic value or help in monitoring response to treatment. Quantitative HBsAg level reflects the amount and the transcriptional activity of cccDNA though recent studies suggest integrated HBV DNA may also contribute to circulating HBsAg. Hepatitis B core‐related antigen (HBcrAg) quantification is the sum of HBcAg, HBeAg (both free and in antibody complex) and the 22 kDa precore protein. Full‐length HBV RNA is a more direct measure of cccDNA transcription and may be important in assessing response to “curative” therapy. Anti‐HBc titer may reflect HBV‐specific adaptive immunity to HBcAg and has been shown in some studies to predict HBeAg seroconversion in both peginterferon and NA‐ treated patients.

Accurate assessment of liver inflammation and fibrosis is important in guiding decisions on when to initiate treatment. Noninvasive methods using serum markers and transient elastography have largely replaced liver biopsies to assess liver fibrosis nowadays. Liver stiffness measurement with transient elastography has been validated as a noninvasive tool to assess liver fibrosis in patients with chronic HBV infection and to predict future risk of HCC but this test is less reliable in patients with hepatitis flares or severe inflammation.

The outcome of chronic HBV infection is variable and affected by patient, virus, and environmental factors (Figure 48.4). Recent studies showed that persistently high HBV DNA (>104 IU/mL) levels have a major impact on progression of liver disease and risk of HCC. HBV vaccination is the best primary prevention for HBV‐related HCC (Figure 48.5). Antiviral treatment has been demonstrated to be effective in the secondary prevention of HCC. Antiviral treatment can also be used for tertiary prophylaxis to prevent HCC recurrence after surgical resection or locoregional therapy (Figure 48.6).

Current treatments for hepatitis B are safe and effective in suppressing HBV replication and have been shown to decrease the risk of cirrhosis, HCC, and death but they rarely result in HBsAg clearance. The goal of treatment is to improve quality of life and survival of the infected person by preventing progression to cirrhosis, decompensation and HCC. Sustained viral suppression has been shown to prevent fibrosis progression and to reverse fibrosis, including in patients with established cirrhosis, and to reduce the risk of clinical outcomes, namely cirrhosis, HCC, and HCC‐related death. HBsAg seroclearance further reduced risk of HCC and other cirrhosis complications compared to those with viral suppression but no HBsAg clearance (see Figure 48.6). However, antiviral treatment does not abolish the risk of HCC even in patients with maintained virus suppression during long‐term NA therapy.

Currently available treatments include peginterferon α and nucleos/tide analogs (NAs) (Table 48.3). The six approved NAs are lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF). Lamivudine, adefovir dipivoxil, and telbivudine are not recommended because of low genetic barrier to resistance; therefore, the following sections focus on entecavir, TDF, and TAF.

Table 48.1 Interpretation of serological/virological hepatitis B and D virus tests.

Serological/virological marker Clinical meaning
HBsAg Infected (acute or chronic) and potentially infectious
Anti‐HBs Immune
Anti‐HBc Exposed
IgM anti‐HBc Recent or acute infection
IgG anti‐HBc Past or current infection
HBeAg High replication
Anti‐HBe Generally low replication, may be high replication in presence of precore/BCP variant
HBV DNA Indicator of HBV replication
Anti‐HDV Recent or current infection with HDV
HDAg/HDV RNA Indicator of HDV replication

BCP, basal core promoter; HBc, hepatitis B core (antigen); HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDAg, hepatitis D (δ) antigen; HDV, hepatitis D (δ) virus; IgG, immunoglobulin G; IgM, immunoglobulin M.

Antiviral treatment is indicated in patients with cirrhosis, acute liver failure or severe exacerbations of chronic hepatitis B. Among patients with no cirrhosis, treatment is recommended for both HBeAg‐positive and HBeAg‐negative patients with high HBV DNA, elevated ALT (>2 × ULN), and/or moderate‐to‐severe necroinflammatory activity and/or fibrosis on biopsy. The HBV DNA threshold and the definition of normal ALT for initiating treatment differ slightly across the liver associations’ guidelines (Table 48.4). The recommended first‐line therapies for both HBeAg‐positive and HBeAg‐negative disease are entecavir, TDF, TAF, or peginterferon‐α. In NA‐experienced patients (in particular those with previous exposure to lamivudine or telbivudine), TDF or TAF is preferred while in patients with risk factors for renal impairment or osteoporosis, TAF or ETV is the treatment of choice (Table 48.5). All NAs need dose adjustment according to renal function (see Table 48.5).

The recent advances in understanding of the HBV lifecycle and availability of improved cell culture systems and animal models have facilitated the development of new therapies targeting all steps in HBV lifecycle and/or restoring immune response against HBV. While sterilizing cure is not feasible in the foreseeable future, functional cure, defined as HBsAg clearance with or without anti‐HBs seroconversion and undetectable serum HBV DNA, after a finite course of therapy, is the goal of new HBV therapies (see Figure 48.3). Entry inhibitors target HBV entry and establishment of HBV infection in uninfected hepatocytes and may reduce intrahepatic spread of HBV. Myrcludex B, an entry inhibitor, is currently in clinical trials for both HBV monoinfection as well as HBV and HDV coinfection (see section on Chronic hepatitis D). Capsid protein allosteric modulators (CpAMs) can act at multiple steps in the HBV lifecycle, including formation of aberrant or empty capsids, interference with capsid disassembly and intracellular recycling and hence cccDNA formation. RNA interference therapy with small interfering RNAs (siRNAs) or antisense oligonucleotides directly targets HBV transcripts, reducing HBsAg production. The goal is to reverse immune exhaustion. Nucleic acid polymers (NAPs) target virus assembly and secretion and have been shown to decrease HBsAg secretion.

Schematic illustration of natural history of chronic hepatitis B.

Figure 48.1 Natural history of chronic hepatitis B. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

Schematic illustration of disease progression of chronic HBV infection.

Figure 48.2 Disease progression of chronic HBV infection. The percentage indicates the lifetime risk of corresponding complications.

Source: Adapted from Likhitsup A, Lok AS. Understanding the natural history of hepatitis B virus infection and the new definitions of cure and the endpoints of clinical trials. Clin Liver Dis 2019;23:401.

Schematic illustration of HBV lifecycle and novel treatment targets.

Figure 48.3 HBV lifecycle and novel treatment targets. HBV entry: Lipopeptides mimicking pre‐S1 domain competing with Dane particle for binding to NTCP (e.g., Myrcludex B). Other small molecule inhibitors are in development. Targeting cccDNA: Prevention of cccDNA formation. Damage and destruction through cytokines or cccDNA sequence‐specific nucleases. Functional silencing through modulation of host cellular epigenetic‐modifying enzymes by cytokines or inhibition of viral protein function. HBV mRNAs: siRNA approaches or antisense oligonucleotides to block viral replication and viral protein expression. HBV polymerase: Reverse transcriptase inhibitors include approved NAs. Ribonuclease H inhibitors are in preclinical evaluation. Nucleocapsid assembly and pgRNA packaging: Capsid assembly modulators can affect nucleocapsid assembly and pgRNA encapsidation and may affect the nuclear functions of hepatitis B core protein (cccDNA regulation and IFN‐stimulated gene expression). Targeting HBsAg: Phosphorothioate oligonucleotides inhibiting HBsAg release and monoclonal antibodies to decrease circulating HBsAg load are under evaluation. dslDNA, double‐stranded linear DNA; MVB, multivesicular body; rcDNA, relaxed circular DNA.

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Nov 27, 2022 | Posted by in GASTROENTEROLOGY | Comments Off on 48: Chronic hepatitis B and D

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