Management of chronic viral hepatitis B and D

BACKGROUND Chronic viral hepatitis is a significant global health concern that contributes to a substantial disease burden. In 2019, it was estimated that 316 million people worldwide were infected with HBV, accounting for 550,000 deaths.1 Chronic hepatitis D (CHD) occurs as co-infection or superinfection in patients already infected with HBV, as the HDV is dependent on structural proteins provided by HBV.2 The prevalence of hepatitis D is estimated at 4.5%, with strong regional variations.3 Regions with higher prevalence include, for example, Mongolia and some African countries.3 Chronic hepatitis B (CHB) is a major risk factor for liver cirrhosis and HCC.1 The risk is even further accelerated by the co-infection or superinfection with HDV.4 Given the significant disease burden associated with CHB, prevention measures such as widespread vaccination, early diagnosis, antiviral treatment, and public health initiatives aimed at reducing transmission are crucial in controlling the disease and its long-term consequences. The World Health Organization formulated viral hepatitis elimination goals with the aim of reducing the global disease burden attributable to chronic viral hepatitis to near zero by 2030.5 On this path, preventive strategies are of great importance. Already in the 1980s, it could impressively be shown that vaccination programs in children can not only reduce HBV seroprevalence6 but also HBV-related complications such as the development of HCC.7 For those already infected, optimal disease management, including antiviral treatment, early detection of secondary complications, and the treatment of such, are important. Aiming for viral hepatitis elimination treatment strategies need to be adopted in regional circumstances, again emphasizing the importance of effective and, at the same time, inexpensive vaccination. In this context, the prevention of vertical spread from an infected mother to a newborn also needs to be considered. However, we believe that setting out the challenges of viral hepatitis elimination is beyond the scope of this review. Instead, we would like to summarize advances in the drug treatment of viral hepatitis based on current guidelines and recent publications. CURRENT TREATMENT STRATEGIES OF CHB This review will focus on the use of nucleos(t)idanaloga (NUC) in CHB as current treatment strategies are mainly based on the use of NUC. NUC inhibits the viral replication leading to a decline in viral load. However, the ultimate goal of functional cure, ie, HBsAg-loss, is rarely achieved. The rationale behind the treatment with NUC is the proven improvement in clinical endpoints such as progression to liver cirrhosis, hepatic decompensation, or HCC.8 Accordingly, treatment should be initiated in patients with some degree of liver damage or those at high risk of hepatic decompensation. The recently updated German guideline on the treatment of CHB9 suggests that NUC therapy should be given to patients with repeatedly elevated transaminases and HBV-DNA>2000 IU/mL, patients with compensated liver cirrhosis and detectable HBV-DNA and patients with decompensated liver cirrhosis regardless of HBV-DNA levels (Figure 1). Besides the right time point for NUC treatment initiation, there has been a scientific discussion on the possibility of treatment termination. The above-cited guideline describes circumstances under which pausing a NUC treatment can be considered (Table 1). Guaranteeing regular controls of viral kinetics and potential hepatitis flares, which can be life-threatening if not responded to adequately, is paramount.FIGURE 1: Indications for treatment with NUC in chronic HBV infection. Abbreviation: NUC, nucleos(t)idanaloga. TABLE 1 - Circumstances under which a controlled nucleos(t)idanaloga treatment interruption can be considered Clinical characteristics Viral and biochemical characteristics No advanced fibrosis HBeAg negative No signs of hepatic decompensation HBV-DNA negative/below lower limit of quantification for 3 y No immunosuppression Feasibility of frequent HBV-DNA and ALT controls after NUC cessation No hepatic comorbidities Abbreviations: ALT, alanine transaminase; NUC, nucleos(t)idanaloga. CURRENT TREATMENT STRATEGIES OF CHD The conditional approval of bulevirtide (BLV) by the European Medicines Agency in 2020 followed by the full approval in 2023, had a significant impact on the therapeutic field in countries where BLV became available. BLV is an HDV-entry-inhibitor that blocks the main bile acid receptor natrium-taurocholate cotransporting polypeptide, which is needed for the uptake of HBV and HDV into hepatocytes. Clinical trials and real-world analysis showed that BLV leads to a decline in HDV viral load and improvement of alanine transaminase levels.10,11 Following this recent development, the European Association for the Study of the Liver published a clinical practice guideline on the management of HDV.12 Generally, all patients chronically infected with HDV should be considered for antiviral treatment. Screening for liver fibrosis and cirrhosis is important, and transient elastography as noninvasive measurement of liver stiffness allows for accurate fibrosis grading.13 In the case of hepatic decompensation, patients should be transferred to a liver transplantation center. Optimal treatment of liver cirrhosis complications, including the listing for liver transplantation, is paramount as there is no approved medical treatment for chronic HDV in decompensated liver disease. However, recent real-world data on the off-label use of BLV in decompensated HDV-related liver cirrhosis suggest that BLV might be efficacious and safe in selected patients while emphasizing the importance of controlled trials in the vulnerable group of patients with decompensated HDV.14 Patients without decompensation can be considered for treatment with pegylated interferon alfa (pegIFNα) for the preferable treatment duration of 48 weeks. Response rates to pegIFNα lie around 25%. The use of pegIFNα has been linked to improved clinical outcomes with less liver-related events when HDV-RNA remained undetectable 6 months after treatment cessation. Viral response was shown to be more likely in patients with low HDV-RNA and low HBsAg. In the context of interferon treatment, special attention needs to be given to potential adverse events. Especially in patients with clinically significant portal hypertension, a careful evaluation of the risk-benefit ratio is recommended. The introduction of BLV extended the therapeutic range to patients with signs of portal hypertension but still compensated liver disease. BLV therapy administered as a daily subcutaneous injection of 2 mg BLV can be considered in all patients with CHD without decompensation. According to the approval statement, the treatment should be continued as long as the patient shows a clinical benefit. Findings from clinical trials with viral response and improvements in hepatic inflammation as well as favorable safety profile have been reproduced in real-world cohorts.11,15 However, data on the optimal treatment duration and long-term clinical endpoints, such as the prevention of hepatic decompensation or HCC are still lacking. Pausing or terminating BLV might be possible in selected patients16 while reliable biomarkers for safe treatment termination remain elusive. In summary, the treatment decision needs to be based on patient-specific characteristics. The use of BLV can be considered in all compensated disease stages, while pegIFNα should be considered in earlier disease stages aiming for a cure of the disease (Table 2). While being a promising option in selected cases, clear recommendations on the combination of BLV and pegIFNα cannot be made at the moment. Given the high risk of developing liver cirrhosis and associated complications antiviral treatment for patients with CHD with decompensated liver disease represent an unmet medical need. In view of the dangerous nature of the disease, screening to detect possible undetected infections, in particular, must be stepped up. The recently published practice guideline states that all patients who are HBsAg-positive should at least be tested once. Retesting should be carried out depending on the course of the disease. For example, an increase in transaminases or the occurrence of hepatic decompensation should be seen as a reason for retesting in patients who are HBsAg-positive.12 For future directions, the development of treatment strategies for low-income and middle-income countries remains an important challenge. In the future, other substances for the treatment of CHD but also CHB currently under clinical investigation (Table 3) will potentially complement the clinical toolbox for treating this severe viral infection. TABLE 2 - Circumstances in favor of interferon or bulevirtide treatment PegIFNα treatment Bulevirtide treatment Potential advantages Possibility of functional cure especially in cases with low viremia and low HBsAg Only approved treatment for chronic hepatitis D Simultaneous treatment of both viral infections (HBV and HDV) Safety and antiviral efficacy for compensated liver disease due to chronic hepatitis D proven in clinical trials Limited treatment duration Very limited side effects, good tolerability Case reports on the off-label use also in decompensated liver disease Potential disadvantages Wide range of contraindications, eg, in autoimmune disease, psychiatric disorders Long-term treatment without (yet) defined treatment endpoints Risk of hepatic decompensation when used in the presence of portal hypertension Limited approval for compensated liver disease Limited treatment efficacy Patient selection with regard to compliance with daily injections Patient selection with regard to compliance with expected IFN-specific side effects Abbreviation: IFN, interferon alfa. TABLE 3 - Drug candidates under advanced clinical investigation for the treatment of chronic hepatitis B and/or D Substance name Investigated for the use in Mode of action Potential advantages Clinical development phase Lonafarnib Hepatitis D Disturbs viral life cycle through inhibition of the prenylation of the large hepatitis delta antigen All oral treatment Phase III Interferon lambda Hepatitis D Improved immune control, potential effect on viral cell-to-cell spread Less systemic side effects expected when compared to pegIFN-α Phase III; currently on hold siRNAs Hepatitis B and D Interfere with viral RNA and can inhibit translation of viral proteins Possible dual treatment for HBV and HDV Phase 2 Monoclonal antibodies against HBsAg Hepatitis B and D Binding of HBsAg Possible dual treatment for HBV and HDV Phase 2 Nucleic acid polymers Hepatitis B and D Interference with viral entry and secretion of HBsAg; potential additional modes of action Potentially high rates of seroconversion implicating a dual treatment for HBV and HDV Phase 2a, case reports Abbreviations: pegIFN-α, pegylated interferon; siRNAs, small-interfering ribonucleic acid. CONCLUSIONS Viral hepatitis B and D infections represent a global health threat. While vaccination against HBV is a highly effective preventive measure, antiviral treatment is an important pillar for reducing the disease burden. In HBV, NUC therapy suppresses viral replication and thereby reduces morbidity, while functional cure is rarely achieved and sought in innovative trails. In CHD, BLV is the only approved treatment and can be used in patients with compensated liver disease. In early disease stages, interferon-based therapies can be considered. Antiviral treatment in patients with decompensated hepatitis delta and treatment strategies for low-and-middle-income countries are important unmet needs. While widespread vaccination against HBV also protects against HDV infection, there is no specific HDV vaccine for the protection of HBV-infected individuals.