Treatment and prevention of hepatitis D virus infection

INTRODUCTION — Hepatitis D virus (HDV) is a defective virus requiring the simultaneous presence of hepatitis B virus (HBV) to fully express its pathogenicity; thus, hepatitis D always occurs in the presence of HBV. In most cases of HDV infection, HBV replication is suppressed to low levels by HDV [1,2]. In most patients with hepatitis D, liver damage is predominantly due to HDV. However, HBV and HDV may replicate simultaneously on occasion, each virus contributing to the liver damage, thereby resulting in more severe liver disease [3]. The clinical course is influenced by several factors, including the HDV genotype [4]. The predominant genotype in the Western world is genotype 1.

Once chronic HDV infection is established, it usually exacerbates the pre-existing liver disease due to HBV. Thus, progression towards cirrhosis and its sequelae is often faster than among patients with HBV monoinfection [5].

This topic will review the treatment and prevention of HDV infection. The pathogenesis, epidemiology, clinical manifestations, and diagnosis of HDV are discussed in separate topic reviews. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

TREATMENT OF ACUTE HEPATITIS D — Treatment of acute hepatitis D is mostly supportive. There are no specific antiviral treatments for acute hepatitis D. However, patients with severe acute hepatitis D should be referred for liver transplant evaluation, and hepatitis B virus (HBV) antiviral should be administered, particularly in those with detectable HBV deoxyribonucleic acid (DNA), as prevention of recurrent HBV is key to preventing recurrent HDV posttransplant. (See "Liver transplantation in adults: Hepatitis D virus reinfection in liver transplant recipients" and "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients" and "Hepatitis B virus: Overview of management", section on 'Acute infection'.)

TREATMENT OF CHRONIC HEPATITIS D

Pretreatment evaluation — To help determine the approach to treatment in patients with chronic HDV infection, patients should have laboratory testing for HDV ribonucleic acid (RNA) and transaminase levels. In patients with chronic hepatitis B virus (HBV)/HDV infection, we consider patients with elevated serum alanine aminotransferase (ALT) levels to have evidence of active liver disease.

In addition, a noninvasive test for fibrosis or a liver biopsy should be performed to assess for the presence of fibrosis and cirrhosis. Liver biopsy is generally preferred since specific cutoffs for advanced fibrosis or cirrhosis have not been validated for most noninvasive tests, in part because concomitant inflammation is generally more intense in chronic HDV than chronic HBV or chronic hepatitis C virus (HCV) infection. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)

More detailed information on the pretreatment evaluation for HBV infection is presented separately. (See "Hepatitis B virus: Overview of management", section on 'Initial evaluation'.)

Patients without advanced fibrosis or cirrhosis

Whom to treat — For patients with chronic HDV infection without advanced fibrosis or cirrhosis, we suggest treatment for those with:

●Elevated ALT levels and/or chronic hepatitis on liver biopsy

AND

●Detectable HDV RNA.

Once the indication has been established, patients should be treated as soon as possible, particularly if there is liver fibrosis. Available agents include pegylated interferon alfa-2a (Peg-IFNa-2a) and, in some European countries, bulevirtide. (See 'Pegylated Interferon alfa-2a' below and 'Bulevirtide' below.)

Treatment is generally not warranted for persons with HDV who have no or very mild fibrosis (ie, F0/F1) (table 1) and persistently normal ALT levels. However, clinical and laboratory monitoring (eg, ALT levels and HDV RNA) should be performed every 6 to 12 months to assess for signs of disease progression, which would indicate the need for treatment.

Considerations for patients with advanced fibrosis or cirrhosis are discussed below. (See 'Patients with advanced fibrosis or cirrhosis' below.)

Antiviral therapy for treatment of HDV

Regimen selection — If antiviral therapy is indicated for treatment of HDV, Peg-IFNa-2a is the only available option in most countries, even though it is not officially approved for this indication. (See 'Pegylated Interferon alfa-2a' below.)

Bulevirtide, an entry inhibitor, has been conditionally approved in parts of Europe for treatment of persons with compensated chronic liver disease due to HDV but is not available in many countries, including the United States. (See 'Bulevirtide' below.)

In some institutions, patients can be referred to a clinical trial of investigational therapies. (See 'Other agents under investigation' below.)

Pegylated Interferon alfa-2a — The mechanism of action of IFNa for treatment of hepatitis D is unclear since IFNa does not have any antiviral activity against HDV when tested in vitro [6,7]. The efficacy of IFNa in patients with chronic hepatitis D may depend upon its immunomodulatory effects or the antiviral effects on the helper virus, HBV. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

●Dosage and administration — Peg-IFNa-2α (180 mcg subcutaneously once weekly) should be administered for 48 weeks [8]. Peg-IFNa-2b, which had been used in the past, is no longer available.

Several studies have tried to evaluate the appropriate duration of treatment with Peg-IFNa using HDV RNA suppression as the end point. In one study of 18 patients with chronic HDV infection who were randomly assigned to receive 12 versus 24 months of Peg-IFNa-2b, extending the treatment duration to 24 months did not increase the likelihood of achieving HDV RNA suppression [9]. In another larger trial, response rates of Peg-IFNa-2a given for 96 weeks yielded similar response rates as a similar trial where Peg-IFNa-2a was given for 48 weeks [10,11].

●Adverse reactions – Adverse events associated with Peg-IFNa-2a can be severe and may require dose reduction or discontinuation of treatment.

•The major side effects of Peg-IFNa-2a include flu-like symptoms, which occur in approximately 90 percent of patients [12].

•Other side effects include fatigue, anorexia and nausea, diarrhea, weight loss, hair loss, emotional lability and depression, and bone marrow suppression.

•Induction of autoantibodies can also occur, and this may result in thyroid abnormalities in up to 30 percent of patients or enhancement of autoimmune diseases [13,14].

●Patient monitoring – Patients receiving Peg-IFNa-2a should be assessed for virologic and biochemical responses both during treatment and after therapy has been completed. Patients should also be monitored for evidence of toxicity. We monitor patients at weeks 4, 12, 24, and 48 during treatment and weeks 12 and 24 post treatment (table 2).

We also monitor the efficacy of interferon on HBV (table 3). Hepatitis B surface antigen (HBsAg) loss with development of hepatitis B surface antibody (anti-HBs) will protect the individual from reinfection with HBV as well as HDV. Patients who have cleared HDV but who remain positive for HBsAg are at risk of reinfection with HDV. This phenomenon has been observed in the chimpanzee experimental animal model. However, re-exposure to HDV appears to cause only a mild and self-limiting hepatitis [15].

●Treatment endpoints and efficacy – The commonly accepted primary endpoint for treatment of chronic HDV with Peg-IFNa-2a is an undetectable serum HDV RNA 24 weeks after completing therapy, accompanied by normalization of the ALT level. The correlation between these surrogate endpoints and the long-term clinical benefits of treatment is based on the results of a small trial of Peg-IFNa [16]. Although the ideal endpoint of treatment would be the clearance of HBsAg, which is associated with improved survival [16], this is rarely achieved [17].

After a standard 48-week course of Peg-IFNa, HDV RNA becomes undetectable 24 weeks after the end of therapy in about 30 percent of cases [17]. This endpoint is associated with improvement in clinical outcomes. In one observational report, complications such as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death occurred less frequently in those who were treated with IFNa-based therapies compared with those who received no therapy (hazard ratio 2.2; 95% CI, 1.0-5.0) [16].

In another observational study of 99 patients with chronic HDV who were treated with IFNa, those who had an undetectable HDV RNA two years after treatment was discontinued were significantly less likely to die from liver disease or develop complications compared to patients without this response [18]. However, persons with cirrhosis at baseline did worse than those without cirrhosis.

Transient low-level recurrence of HDV RNA after this endpoint may be observed. However, in the absence of cirrhosis, clinical outcomes appear to be improved despite transient relapses [19]. These relapses may be due to low-level residual HDV RNA at the end of the treatment that was not detected by insensitive assays [20].

More recently, a 2 log reduction of serum HDV RNA level (either alone [21] or combined with ALT normalization [22]) has been proposed for patients on treatment. However, this endpoint is not routinely used in clinical practice as data are based on the findings of a single study that followed 36 patients with chronic HDV and rely on the availability of reliable quantitative HDV RNA assays [23]. In this report, patients who reached an average 2 log reduction of serum HDV RNA at the end of a standard 48-week course of high-dose (9 million units three times per week), standard IFNa had further reductions in HDV RNA after the end of therapy and improved survival over the course of 12 years. This endpoint has been used to evaluate the efficacy of bulevirtide [24]. (See 'Bulevirtide' below.)

Bulevirtide — The HDV entry inhibitor, bulevirtide, acts upon the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor shared by HBV and HDV [25,26]. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Virology'.)

On July 31, 2020, the European Medicines Agencies (EMA) provided a conditional marketing authorization to bulevirtide for chronic hepatitis D alone or in combination with a nucleoside or nucleotide analog for the treatment of underlying hepatitis B. Based on data from the phase 3 trial discussed below [27], the EMA granted standard approval of bulevirtide on July 18, 2023. This approval is only for patients with compensated liver disease. There are very limited data on the use of bulevirtide in persons with decompensated cirrhosis and none after liver transplant. Neither the US Food and Drug Administration (FDA) nor regulatory authorities in other countries have authorized the use of bulevirtide.

●Dose and administration – In countries where bulevirtide is available, the standard dose is 2 mg administered subcutaneously once daily. Per the EMA, therapy may be continued for as long as there appears to be a benefit [28]. However, the optimal dose and duration of therapy, as well as the role of additional Peg-IFNa-2a, are still being evaluated [27].

●Adverse reactions – Limited data suggest that bulevirtide appears to be safe, even in patients with cirrhosis and clinically significant portal hypertension [29]. Although increases in bile acid levels have been observed, they have not been associated with pruritus or other symptoms.

●Monitoring – In patients receiving bulevirtide monotherapy, the HDV DNA and ALT should be checked 24 weeks (or six months) after initiating treatment, and every 24 weeks while on treatment. If treatment is stopped, more frequent monitoring should be performed during the first 24 weeks (eg, every month for the first three to six months).

●Treatment endpoints and efficacy – The goal of therapy with bulevirtide is a persistent decline of serum HDV RNA by two or more log10 IU/mL (100-fold). This endpoint has been linked to improved survival in a small study using a 48-week course of high-dose IFNa [23] and has been used in the trials discussed below.

In a randomized, open-label phase 2 trial (MYR 202) of 120 patients with chronic HDV (59 with cirrhosis), patients received bulevirtide at various doses (2 mg, 5 mg, or 10 mg subcutaneous once per day) with tenofovir disoproxil fumarate (TDF) or TDF alone for 24 weeks [30]. Although many patients receiving bulevirtide achieved undetectable or a >2 log₁₀ international units/mL decline in HDV RNA by 24 weeks, levels rebounded when therapy was stopped. Bulevirtide was well tolerated overall, but modest, asymptomatic dose-dependent increases in bile acid levels were observed in some patients.

An ongoing phase 3 trial (MYR 301) is comparing two doses of bulevirtide (2 versus 10 mg daily for 144 weeks) to each other, as well as to a third arm, in which bulevirtide administration is delayed by 48 weeks. After the initial 48 weeks of therapy, a virological response (HDV RNA decline by at least 2 logs or undetectable) was reached in 71, 76, and 4 percent in the three arms, respectively [27]. ALT normalized in 51, 56, and 12 percent, and the combined response (virologic and biochemical endpoints) was observed in 45, 48, and 2 percent of patients, respectively. A small percentage of patients failed to achieve a >1 log10 reduction in HDV RNA level after 48 weeks of treatment. The reason for this is unclear as preliminary data did not find evidence of selection of bulevirtide-resistant HDV variants [31]. After 96 weeks, the groups receiving 2 or 10 mg of bulevirtide from the start showed a slight, further increase of the virologic response and ALT response [32]. HBsAg levels underwent minimal changes.

Bulevirtide has also been evaluated in combination with Peg-IFNa-2a in the phase 2 MYR 203 study [24,33,34]. In this phase 2 trial, 60 patients with chronic HDV were randomized to receive 48 weeks of monotherapy with Peg-IFNa-2a (180 mcg subcutaneously once weekly) or bulevirtide (2 mg subcutaneously once daily) or combination therapy with Peg-IFNa-2a plus bulevirtide (2 mg or 5 mg daily) [34]. An undetectable HDV RNA was achieved in eight and four of the patients who received combination therapy with the 2 and 5 mg doses of bulevirtide, respectively. In addition, HBsAg also became undetectable in 4 of 15 patients receiving the combination regimen using 2 mg of bulevirtide. Response rates were lower in the monotherapy groups.

In another phase 2 trial (MYR204), 175 patients were randomized to receive bulevirtide monotherapy (10 mg daily), combination therapy with bulevirtide (2 or 10 mg daily) plus Peg-IFNa, or Peg-IFNa monotherapy. Interim results at week 24 demonstrated virologic response rates of 72, 88, 92, and 38 percent; biochemical (ALT) response rates of 64, 30, 24, and 13 percent; and combined response rates of 50, 30, 24, and 13 percent, respectively [35]. Although combination therapy appears to result in greater rates of on treatment virologic response, biochemical response rates and combination response rates are lower than with monotherapies. The reason for the dissociation between virologic and biochemical response during bulevirtide therapy in some patients is unclear.

These clinical trial results are consistent with those reported in several real-world observational studies carried out in European countries where bulevirtide is available [24].

Other agents under investigation — Several drugs have been evaluated as alternatives to Peg-IFNa. Agents that have novel mechanisms of action and show promise include:

●Interferon lambda – Interferon (IFN) lambda has activity against hepatitis B and D viruses with fewer side effects than IFNa due to the preferential expression of its receptor in hepatocytes. In a phase 2, randomized, open-label study (LIMT HDV Study), 33 patients received pegylated IFN lambda dosed at 120 mcg or 180 mcg subcutaneously once weekly for 48 weeks [36]. An undetectable HDV RNA was achieved 24 weeks after treatment in 16 and 36 percent, respectively. Patients previously treated with IFNa reported significantly fewer side effects while receiving IFN lambda. In particular, no significant changes in blood counts were observed, and only one patient had mild depression. However, eight patients (24 percent) had to interrupt therapy due to hyperbilirubinemia that resolved after stopping treatment. Pegylated IFN lambda has also been evaluated in combination with the farnesyltransferase inhibitor, lonafarnib, as discussed below.

●Specific inhibitors of HDV prenylation − Prenylation involves the covalent addition of a farnesyl or geranylgeranyl isoprenoid molecule to a conserved cysteine residue at or near the C-terminus of a protein [37]. This link promotes membrane interactions with the prenylated protein since the isoprenoid chain is hydrophobic.

Lonafarnib is a farnesyltransferase inhibitor approved for the treatment of progeria. HDV replication requires the addition of a farnesyl group to the C-terminus of L-HDAg using a host farnesyltransferase. Lonafarnib interferes with the proper assembly of HDV. It has been evaluated for treating HDV in several phase 2 studies, which established its dose dependent activity on HDV replication [38,39]. However, significant gastrointestinal side effects (nausea, diarrhea, abdominal bloating, leading to weight loss) were reported. Boosting with the cytochrome P450 3A4 inhibitor ritonavir has allowed lonafarnib to be administered in lower doses with fewer side effects while preserving its antiviral effects [39].

A phase 3 trial compared lonafarnib (50 mg)/ritonavir (100 mg) twice daily with or without PegIFNa to PegIFNa monotherapy and to placebo for 48 weeks in 407 patients. An interim analysis of 338 patients found a combined virologic and ALT response of 19, 10, 10, and 2 percent at the end of treatment and 26, 16, 15, and 0 percent 24 weeks after the end of treatment in the four treatment arms, respectively [40]. Final data are awaited.

Lonafarnib (50 mg)/ritonavir (100 mg) twice daily has also been evaluated in combination with pegylated IFN lambda, 180 mcg once weekly for 24 weeks. After 24 weeks of treatment, 11 of 22 (50 percent) patients achieved either undetectable or unquantifiable HDV RNA levels. Five (23 percent) maintained a virological response 24 weeks after the end of therapy with improved liver histology [41]. However, side effects, especially gastrointestinal, were prominent and led to treatment discontinuation in four patients.

●Inhibitors of virion secretion – REP 2139 is a nucleic acid polymer that has been shown to block the release of subviral HBsAg particles from hepatocytes. This agent was evaluated for the treatment of HDV infection in an uncontrolled phase 2 study in 12 patients with chronic HDV who received 500 mg of REP 2139 intravenously (IV) once per week for 15 weeks, followed by combination therapy with 250 mg of IV REP 2139 and 180 mcg of subcutaneous Peg-IFNa-2a once per week for 15 weeks, and finally, monotherapy with 180 mcg Peg-IFNa-2a once per week for 33 weeks [42,43]. At the end of treatment, HDV RNA was undetectable in nine patients and five lost HBsAg. Most responders had a sustained response after treatment discontinuation. According to an analysis performed 7.4 years after the end of therapy, HDV RNA remained undetectable in seven patients, all of whom had normal ALT, and four were HBsAg negative [44].

Role of nucleos(t)ide analogs for treatment of HBV — Nucleos(t)ide analogs (eg, tenofovir and entecavir) should be used in patients fulfilling the criteria for HBV treatment as per international guidelines. (See "Hepatitis B virus: Overview of management".)

However, available data do not support their use as monotherapy or in combination with IFN therapy for treatment of HDV [10,45-51]. A study from the Swiss HIV Cohort found nucleos(t)ide analog monotherapy had only a minimal effect on HDV replication in patients with human immunodeficiency virus (HIV)/HBV/HDV infection [46]. In this study, only 14 percent of patients achieved an undetectable HDV RNA after five years of treatment with tenofovir-containing antiretroviral therapy, and this may have been due to host immune reconstitution rather than to an antiviral effect on HBV.

A large, controlled trial evaluated 90 patients with compensated chronic hepatitis D who were randomly assigned to Peg-IFNa-2a alone or in combination with the nucleoside analog adefovir dipivoxil or adefovir monotherapy [10]. After 48 weeks, HDV RNA was undetectable in approximately 25 percent of patients in both Peg-IFNa-2a arms and none in the adefovir monotherapy arm. The response was sustained up to 24 weeks after stopping therapy. A significant decline in HBsAg levels was observed in patients receiving Peg-IFNa-2a (especially when combined with adefovir) but not in patients treated with adefovir monotherapy.

In the HIDIT-II trial, 120 patients were randomly assigned to receive Peg-IFNa-2a combined with TDF or placebo for 96 weeks. At the end of treatment, 48 and 33 percent of patients had undetectable HDV RNA in serum in the TDF and placebo arms, respectively, which was a numerical but not statistical difference (odds ratio 1.84; 95% CI 0.86-3.91) [11].

Patients with advanced fibrosis or cirrhosis — Patients with HBV/HDV and advanced fibrosis (bridging fibrosis) or cirrhosis (≥F3) (table 1) should receive nucleos(t)ide analogs for HBV regardless of HBV DNA, HDV RNA, or ALT level. In addition, this group needs management of their cirrhosis and surveillance for hepatocellular carcinoma. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis" and 'Monitoring for hepatocellular carcinoma' below.)

The use of antiviral agents specific for HDV depends on whether the patient has complications related to cirrhosis (ie, decompensated cirrhosis) (see "Cirrhosis in adults: Overview of complications, general management, and prognosis"):

●Patients without decompensated cirrhosis should be considered for Peg-IFNa-2a. Bulevirtide can also be considered in countries where it is available. (See 'Antiviral therapy for treatment of HDV' above.)

For those who initiate Peg-IFNa, nucleos(t)ide analogs can be held temporarily since Peg-IFNa also has activity against HBV. However, they should be restarted after completing Peg-IFNa. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogs'.)

●Patients with HDV-related decompensated liver disease are not candidates for Peg-IFNa or bulevirtide. They should receive nucleos(t)ide analogs for HBV and be referred for liver transplant evaluation. (See "Liver transplantation in adults: Hepatitis D virus reinfection in liver transplant recipients" and "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

Additional considerations

Patient counseling — For all patients with chronic HDV, management should include counseling regarding the safe consumption of alcohol, a healthy lifestyle to prevent concomitant fatty liver, and control of other comorbidities that could potentially affect the liver (eg, diabetes). (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)

Patients with chronic HDV should also be vaccinated against hepatitis A virus (HVA) if they are not already immune. (See "Hepatitis A virus infection: Treatment and prevention".)

Monitoring for hepatocellular carcinoma — Patients with chronic HDV and advanced fibrosis or cirrhosis should be screened for hepatocellular carcinoma every six months with ultrasound. Such patients have a higher risk of hepatocellular carcinoma compared to those with advanced fibrosis or cirrhosis due to chronic HBV monoinfection [52]. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Chronic HDV infection'.)

PREVENTION OF HDV INFECTION — The mainstay of prevention of HDV infection is vaccination against hepatitis B virus (HBV; its helper virus). Chimpanzees, who are positive for hepatitis B surface antibody (anti-HBs), are protected against experimental HDV infection [53]. A detailed discussion of HBV immunization is presented elsewhere. (See "Hepatitis B virus immunization in adults" and "Hepatitis B virus immunization in infants, children, and adolescents".)

For patients with chronic HBV, it is important to discuss ways to reduce the risk of HDV transmission (eg, reducing high-risk drug use and sexual behaviors. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Epidemiology'.)

There are no available vaccines to prevent HDV infection in patients with chronic HBV. However, a recent study showed that a prime-boost immunization strategy exploiting the preS1 domain of HBsAg and the large form hepatitis delta antigens (L-HDAg) elicited antibodies that were used to provide passive prophylaxis against HDV/HBV coinfection in HBV-naïve mice and against HDV superinfection in HBV-infected mice [54]. This promising work may pave the way toward the development of a vaccine to protect HBV carriers from HDV superinfection.

SUMMARY AND RECOMMENDATIONS

●Virology – Hepatitis D virus (HDV) is a defective virus requiring the simultaneous presence of hepatitis B virus (HBV) to fully express its pathogenicity; thus, hepatitis D always occurs in the presence of HBV. In most cases of HDV infection, HBV replication is suppressed to low levels by HDV. (See 'Introduction' above.)

●Treatment of acute HDV – Treatment of acute hepatitis D is mostly supportive. There are no specific antiviral treatments for acute hepatitis D. (See 'Treatment of acute hepatitis D' above.)

●Treatment of chronic HDV – The approach to treatment of chronic HDV depends largely on the presence of active liver disease, which includes an HDV RNA level, elevated serum alanine aminotransferase (ALT) levels, fibrosis, and/or chronic hepatitis on liver biopsy. (See 'Pretreatment evaluation' above and 'Treatment of chronic hepatitis D' above.)

•Patients without advanced fibrosis or cirrhosis

-Whom to treat – For patients with chronic HDV who have active liver disease and a detectable HDV RNA, we suggest antiviral therapy (Grade 2C). By contrast, treatment is generally not needed for persons with chronic HDV who have persistently normal ALT levels and no or very mild fibrosis (ie, F0/F1). However, close monitoring (eg, ALT levels) should be performed to assess for signs of disease progression. (See 'Whom to treat' above.)

-Regimen selection – In most countries, pegylated interferon alfa-2a (Peg-IFNa-2a) is the only available treatment. Peg-IFNa-2a (180 mcg subcutaneously once weekly) should be administered for 48 weeks. Patients should be treated as soon as possible, since virologic suppression with Peg-IFNa-2α is more likely to be attained in patients with a shorter duration of infection. (See 'Pegylated Interferon alfa-2a' above.)

Bulevirtide, an entry inhibitor, may also be an option for certain patients. This agent has been approved in Europe for treatment of patients with compensated liver disease due to HDV but is not available in most countries in the world, including the United States. (See 'Bulevirtide' above.)

-Role of nucleos(t)ide analogs – We suggest against the routine use of nucleos(t)ide analogs for management of HDV (Grade 2C). These agents are ineffective in inhibiting HDV replication when used alone or in combination with Peg-IFNa. (See 'Role of nucleos(t)ide analogs for treatment of HBV' above.)

However, nucleos(t)ide analogues should be used in patients with an indication for management of HBV. (See "Hepatitis B virus: Overview of management".)

•Patients with cirrhosis – For patients with chronic HDV/HBV cirrhosis, HBV nucleos(t)ide therapy should be administered. In addition, surveillance for hepatocellular carcinoma should be performed.

Patients with compensated cirrhosis should also be considered for HDV-specific antiviral therapy (eg, Peg-IFNa) if they have a detectable HDV RNA.

However, for patients with decompensated cirrhosis, Peg-IFNa should not be used and the safety of bulevirtide has not been well established in these patients. These patients should be referred for liver transplant evaluation. (See 'Patients with advanced fibrosis or cirrhosis' above.)

●Prevention – The best way to prevent HDV infection is vaccination against HBV (its helper virus). For persons who already have chronic hepatitis B infection, it is important to educate patients about ways to reduce the risk of HDV transmission (eg, reducing high-risk drug use and sexual behaviors). (See 'Prevention of HDV infection' above.)