Approach
The treatment options for hepatitis D virus (HDV) infection are limited. Currently, no pharmacological therapies are available for acute infection, while patients with chronic infection may be considered for antiviral treatment, including peginterferon alfa and bulevirtide (which is specific for HDV infection). Liver transplant is often required in patients with end-stage liver disease or acute liver failure.[12]
The goal of treatment should be to prevent disease progression and lead to biochemical and virological resolution. In hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, control of virus replication and virus eradication, respectively, leads to improvement in liver function tests (LFTs) and a decrease in clinical endpoints such as cirrhosis, hepatocellular carcinoma, and death.[2][53] In HDV infection, sustained suppression of viral replication and seroconversion of HBV surface antigen (HBsAg) - loss of HBsAg and appearance of antibody to hepatitis B surface antigen (anti-HBs) - would be ideal but is rarely achievable with currently available therapy.
Given the evolving treatment options and issues with standardisation of virological assays, it is advisable to refer all patients with confirmed HDV infection to a specialised centre for management.
This topic does not cover the management of special patient groups (e.g., pregnant women, children) as there are very limited data available on these patients.
Acute HDV infection
Manage patients with acute HDV infection with supportive care, according to their symptoms (e.g., encouraging the patient to remain hydrated and maintaining nutrition).
No antiviral drugs are approved for acute HDV infection.
Note that >95% of immunocompetent adults with simultaneous HDV/HBV co-infection will spontaneously clear the virus. However, evolution to chronic infection may occur in >90% of patients with superinfection (HDV infection in a person with chronic HBV infection).[34]
Monitor patients for any change in clinical status that indicates progression to a disease state that requires treatment.[2]
Evaluate patients with fulminant hepatitis for liver transplantation due to the high risk of mortality in this group of patients without transplant.[12] See Acute liver failure.
Transplantation in eligible patients is associated with an excellent outcome.[54]
Chronic HDV infection
First-line treatment options for patients with chronic HDV infection include peginterferon alfa-2a or bulevirtide. The decision about which drug to use usually depends on clinician preference and experience, and whether or not the patient has any contraindications to either drug. Data on the efficacy of bulevirtide are limited and the optimal treatment duration is unknown, while the safety and efficacy is considered to be better with peginterferon alfa-2a.
Peginterferon alfa
Consider peginterferon alfa-2a in all eligible patients with chronic HDV infection with detectable HDV RNA (with or without associated compensated cirrhosis).[1] The preferred duration of treatment is 48 weeks.[1][55]
Note that the National Institute for Health and Care Excellence (NICE) in the UK recommends giving peginterferon alfa-2a to patients with chronic HDV infection only if there is evidence of significant fibrosis (METAVIR stage ≥F2 or Ishak stage ≥3) (see Criteria).[55]
Consider personalised treatment durations based on HDV RNA and HBsAg kinetics and treatment tolerability.[1]
Consider stopping treatment if there is no decrease in HDV RNA following 6 or more months of treatment.[55]
Stop treatment after HBsAg seroconversion.[55]
Treatment success is defined as undetectable HDV RNA 24 weeks after completing treatment (alongside normalisation of alanine aminotransferase [ALT]).[2] One review of 13 studies including 1078 patients demonstrated that the overall virological response (defined as undetectable HDV RNA after 24 weeks following the end of treatment) was 31%.[56] However, relapses of HDV RNA occur commonly in the post-treatment phase and have been reported even 5-10 years after the end of treatment.[57]
Peginterferon alfa is contraindicated in patients with decompensated cirrhosis.
Bulevirtide
Consider bulevirtide for patients with chronic hepatitis D infection and compensated liver disease.[1]
Bulevirtide is an entry inhibitor that blocks HDV from entering hepatocytes by binding and inactivating the sodium/bile acid cotransporter.
It is approved in Europe and the UK for the treatment of chronic HDV infection in plasma (or serum) HDV RNA-positive adults with compensated liver disease.[58]
NICE recommends bulevirtide as an option for treating chronic HDV infection in adults with compensated liver disease only if:[58]
There is evidence of significant fibrosis (METAVIR stage ≥F2 or Ishak stage ≥3), and
Their hepatitis has not responded to peginterferon alfa‑2a, or for whom peginterferon alfa‑2a is not tolerated or is contraindicated.
Clinical trial evidence shows that bulevirtide is effective compared with standard care despite some uncertainties around how long it works for.[58]
In a multicentre open-label study, 120 patients with chronic HDV infection were randomised to various doses of bulevirtide in combination with tenofovir, or to tenofovir alone, for 24 weeks. The primary endpoint was based on virological response. There was a dose-dependent effect of bulevirtide on decline in HDV RNA. However, the HDV RNA levels rebounded after the drug was stopped. Adverse effects were related to the elevation of serum bile acids, but pruritus was mild.[59]
Treatment duration is usually more than 48 weeks. However, the optimal treatment duration is yet to be determined, and treatment should continue until clinical benefit is seen. An ongoing phase 3 randomised trial of bulevirtide in 150 patients with chronic HDV infection over 144 weeks of treatment found that HDV RNA and ALT levels were reduced after 48 weeks of bulevirtide treatment compared with a control group receiving no treatment, with increasing response rates at 96 weeks relative to 24 and 48 weeks.[60]
Bulevirtide is contraindicated in patients with decompensated cirrhosis.
Combination therapy
Combination therapy may be an option in some patients.
Peginterferon alfa-2a and bulevirtide may be used together in some circumstances. In practice, they may be started simultaneously, or one may be added on to the other. However, evidence for the use of combination therapy is limited and studies are ongoing.
Based on consensus opinion and weak evidence, guidelines from the European Association for the Study of the Liver (EASL) state that bulevirtide may be considered for use in combination with peginterferon alfa‑2a in patients without an intolerance or contraindication to the use of peginterferon alfa‑2a.[1] In the author’s opinion, combination therapy should only be used with caution and in consultation with a specialist.
One phase 2b open-label study of 174 patients with chronic hepatitis D found that bulevirtide used in combination with peginterferon alfa-2a was superior to bulevirtide monotherapy in terms of undetectable HDV RNA at 24 weeks after the end of treatment.[61]
Nucleoside/nucleotide analogue therapy
Give a nucleoside/nucleotide analogue (e.g., entecavir, tenofovir) in all patients with compensated cirrhosis and detectable HBV DNA, regardless of HBV DNA levels.[1] Also consider a nucleoside/nucleotide analogue in patients with persistent HBV infection, especially if HBV DNA levels are close to or higher than 2000 IU/mL.[1][2] See Hepatitis B.
Give a nucleoside/nucleotide analogue to patients with decompensated cirrhosis irrespective of the presence of detectable HBV DNA.[1]
Liver transplantation for decompensated cirrhosis
Evaluate patients with decompensated cirrhosis for liver transplantation.[1][2] This may include patients with end-stage liver disease as well as those with fulminant hepatitis.[12]
Transplantation in eligible patients is associated with an excellent outcome.[54]
If liver transplantation is not possible, a best-supportive-care strategy is recommended.[1] See Cirrhosis.
Give patients who have undergone liver transplantation for chronic HDV infection hepatitis B immunoglobulin combined with a high genetic barrier nucleoside/nucleotide analogue after transplantation.[1]
Patients with hepatocellular carcinoma
Prioritise optimal treatment for hepatocellular carcinoma (including liver transplantation) in patients with chronic HDV infection and hepatocellular carcinoma.[1] Evaluate patients with hepatocellular carcinoma for antiviral treatment on an individual basis.[1] See Hepatocellular carcinoma.
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