Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acute HDV infection

1st line – supportive care

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ACUTE
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acute HDV infection
1st line – 

supportive care

Manage patients with acute hepatitis D virus (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/hepatitis B virus (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]

Consider – liver transplantation

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ACUTE
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acute HDV infection
Consider – 

liver transplantation

Additional treatment recommended for SOME patients in selected patient group

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]

ONGOING

chronic HDV infection

1st line – peginterferon alfa and/or bulevirtide

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ONGOING
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chronic HDV infection
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compensated cirrhosis or no cirrhosis
1st line – 

peginterferon alfa and/or bulevirtide

First-line treatment options for patients with chronic hepatitis D virus (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.

​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 hepatitis B surface antigen (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.[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 is an alternative option to consider 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]

  • Note that 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 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]​

Evaluate patients with hepatocellular carcinoma for antiviral treatment on an individual basis.[1] See Hepatocellular carcinoma.

Primary options

peginterferon alfa 2a: 180 micrograms subcutaneously once weekly for 48 weeks

and/or

bulevirtide: 2 mg subcutaneously once daily

1st line – treatment of hepatitis B co-infection

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ONGOING
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chronic HDV infection
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compensated cirrhosis or no cirrhosis
1st line – 

treatment of hepatitis B co-infection

Add a nucleoside/nucleotide analogue (e.g., entecavir, tenofovir) in all patients with compensated cirrhosis and detectable hepatitis B virus (HBV) DNA, regardless of HBV DNA levels.[1] Also consider nucleoside/nucleotide analogue therapy 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.

1st line – treatment of hepatitis B co-infection

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ONGOING
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chronic HDV infection
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decompensated cirrhosis
1st line – 

treatment of hepatitis B co-infection

Give a nucleoside/nucleotide analog (e.g., entecavir, tenofovir) to patients with decompensated cirrhosis irrespective of the presence of detectable HBV DNA.[1]

Consider – liver transplantation

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ONGOING
|
chronic HDV infection
|
decompensated cirrhosis
Consider – 

liver transplantation

Additional treatment recommended for SOME patients in selected patient group

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] 

Prioritise optimal treatment for hepatocellular carcinoma (including liver transplantation) in patients with chronic HDV infection and hepatocellular carcinoma.[1] See Hepatocellular carcinoma.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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