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]. Liver damage in these patients is essentially due to HDV only. However, HBV and HDV replicate simultaneously on occasion, each virus contributing to the liver damage, thereby resulting in more severe liver disease [3].
This topic will review the treatment and prevention of HDV infection. The pathogenesis, epidemiology, and clinical manifestations of HDV are discussed in a separate topic review. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
CLINICAL COURSE OF HDV INFECTION — The clinical sequelae of hepatitis D virus (HDV) infection encompass a spectrum of manifestations from fulminant liver failure to the asymptomatic carrier state. The clinical course is influenced by several factors, including the HDV genotype [4]. This issue is discussed in detail elsewhere, but a brief review is warranted to provide the rationale for antiviral therapy. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
The predominant genotype in the Western world is genotype I. Once chronic HDV infection is established, it usually exacerbates the preexisting liver disease due to HBV. Progression towards cirrhosis may be rapid, but does not occur in all patients. HDV-associated chronic liver disease may run an indolent course, and asymptomatic HDV carriers have been found in some geographic areas.
Patients who are referred for management of HDV infection appear to represent cohorts infected many years ago, in whom the HDV-related disease rapidly developed to cirrhosis, but whose subsequent disease progression has been slow. This was illustrated in a report from Italy in which the estimated 5- and 10-year probability of survival (free of liver transplantation) in patients who had already developed clinically overt cirrhosis was 49 and 40 percent, respectively [5]. A more ominous course toward liver decompensation has been documented in patients with active HBV and HDV replication [5]. In the Far East, where the predominant genotype is genotype II, there is a less frequent association of chronic HDV infection with progressive liver disease [4].
TREATMENT OF CHRONIC HEPATITIS D
Approach to treatment — For patients with chronic hepatitis D virus (HDV) infection, we suggest treatment for those with detectable HDV RNA and active liver disease (as evidenced by elevated serum aminotransferase [ALT] levels and/or chronic hepatitis on liver biopsy). Such patients should be treated as soon as possible, particularly if there is advanced fibrosis. Asymptomatic HDV carriers with persistently normal ALT levels do not require therapy but should be monitored for signs of active disease (eg, every six months).
For those who require therapy, pegylated IFN alfa-2a (180 mcg weekly) is the treatment of choice and should be administered for one year [6]. Pegylated IFN alfa-2b, which has been used in the past in several clinical trials, is no longer available. However, the optimal treatment for HDV is uncertain, and patients can be referred to specialized centers that offer experimental therapies. (See 'Novel treatments' below.)
The primary endpoint of treatment is suppression of HDV RNA 24 weeks after completing treatment, accompanied by normalization of the ALT level. Although the rate of virologic suppression with IFN is low, a response is more likely to be attained in patients with a shorter duration of infection [7]. Successful treatment is associated with amelioration of necroinflammatory activity and loss of hepatitis D antigen (HDAg) in the liver. A detailed discussion of the efficacy of IFNa is found below. (See 'Trials of interferon alfa' below.)
There is no benefit of adding a nucleos(t)ide analogue for the treatment of HDV. However, tenofovir or entecavir should be added if treatment for hepatitis B virus (HBV) is warranted to achieve maximal suppression of both viruses. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)
Eradication of HBV infection 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 hepatitis B surface antigen (HBsAg) positive are still at risk of reinfection with HDV. This phenomenon has been observed in the chimpanzee experimental animal models. However, re-exposure to HDV appears to cause only a mild and self-limiting hepatitis [8].
Trials of interferon alfa — The only available drug effective against HDV is interferon alfa (IFNa). Unfortunately, only a minority of patients treated with IFNa clear HDV infection. A meta-analysis of five trials comparing IFNa with observation (including a total of 169 participants) concluded that there was a modest benefit in suppressing viral and liver disease activity in some patients, but such benefits were not sustained in the majority of patients [9]. Another meta-analysis of Peg-IFNa monotherapy reported a 29 percent clearance of HDV RNA from serum 24 weeks after the end of therapy [10].
The mechanism of action of IFNa in hepatitis D is unclear. IFNa does not have any antiviral activity against HDV when tested in vitro [11,12]. Thus, the efficacy of IFNa in patients with chronic hepatitis D may depend upon its antiviral effects on the helper virus (ie, HBV) or its immunomodulatory effects. Interestingly, in vitro studies have found that HDV subverts the effect of IFNa signaling, possibly contributing to viral persistence and treatment resistance [13]. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)
Trials of standard interferon therapy — The absolute number of reported patients with chronic hepatitis D who have been treated with standard IFNa is small, and the available data have shown mixed results [14-21].
Eradication of HDV infection and resolution of liver disease after IFNa treatment have been reported anecdotally in uncontrolled studies [14-16]. In one of these reports, long-term therapy with high doses of IFNa permanently suppressed HDV replication in some patients and dramatically improved liver fibrosis [16]. However, the favorable effects of IFNa have not been confirmed in all controlled trials.
In the largest multicenter trial, 61 Italian patients with chronic hepatitis D were randomly assigned to receive IFNa in doses of 5 MU/m2 three times weekly for four months followed by 3 MU/m2 three times weekly for an additional eight months, or placebo [17]. They were then followed for another 12 months. The following results were noted:
●Eight (25 percent) of the 31 treated patients had a normal serum ALT level versus none of the 30 controls at the end of the 12-month treatment period. However, all but one of the responders had biochemical relapse after discontinuation of therapy. Only one patient had a normal ALT level at the end of the follow-up period.
●Fourteen (45 percent) treated patients were HDV RNA negative at the end of treatment; however, a similar proportion (27 percent) of controls also became HDV RNA negative, suggesting that spontaneous fluctuations in HDV viremia may occur. The frequency of undetectable HDV RNA at the end of the follow-up period was not significantly different (45 versus 33 percent with placebo). The only patient with persistently normal ALT level was also HDV RNA negative at the end of the follow-up period.
●Improvement in liver histology at the end of therapy occurred with similar frequency in the two groups (57 versus 36 percent, p = NS).
The authors concluded that IFNa therapy did not produce any appreciable benefit in patients with chronic hepatitis D.
In another, smaller Italian study, 42 patients with chronic hepatitis D were randomly assigned to receive two different doses (9 versus 3 MU three times weekly) of IFNa for 48 weeks or placebo [18].
●Normal serum ALT levels at the end of treatment occurred more frequently in the patients receiving 9 MU doses of IFNa than in the other two groups (70, 29, and 8 percent, respectively).
●Complete response (normal ALT level and undetectable serum HDV RNA at the end of treatment) was also more frequent with 9 MU dosing (50, 21, and 0 percent, respectively).
●Treatment with 9 MU doses of IFNa was also associated with a marked improvement in liver histology. Five of the 10 responders in the 9 MU dose group had normal ALT levels that lasted for up to four years. However, none of the patients had sustained clearance of HDV RNA.
The authors concluded that high-dose IFNa was effective in suppressing HDV replication, but that the antiviral effect was not sustained. Furthermore, in a follow-up report they found that ALT normalization correlated with improved hepatic function and loss of IgM anti-HDV [19]. Compared with treatment with low-dose IFNa or placebo, those who received high doses of IFNa were more likely to have clearance of HDV RNA and HBV DNA as well as improvement in histologic activity and fibrosis (including reversal of cirrhosis in some patients).
However, these optimistic conclusions have not been confirmed by another randomized, controlled trial performed in Italy that used a similarly aggressive regimen [20]. The reasons for these discrepant findings are unknown.
In view of the poor overall response, it is difficult to identify factors that predict response. The only feature that may be associated with an increased likelihood of response is a short duration of disease [14,15,17].
Pegylated interferon alfa monotherapy — The published experience with pegylated interferon alfa (IFNa) in the treatment of chronic hepatitis D is small compared with that of other viral hepatitis infections [22-24]. The largest published study included 38 patients who were treated with pegylated IFN alfa-2b (1.5 mcg/kg per week) alone or in combination with ribavirin for 48 weeks [22]. Most patients had previously failed treatment with standard IFNa. All patients were maintained on pegylated IFN for an additional 24 weeks, and then followed off therapy for 24 weeks. At the end of follow-up, HDV RNA was undetectable in eight patients (21 percent). Treatment had to be discontinued in 25 percent of patients while 58 percent required dose modification. The response rate was similar in the monotherapy and combination therapy groups, suggesting that ribavirin had no effect on the viral clearance rate. The response rate was somewhat higher in a subset of patients who had not previously received interferon-based therapy (three of eight patients).
A higher virologic response rate (43 percent) was found in another study involving 14 patients treated with 12 months of pegylated IFNa [23]. The higher response rate may have been due to a lower proportion of patients with cirrhosis in the second study (28 versus 74 percent).
Several studies have tried to evaluate the appropriate duration of treatment among patients receiving pegylated IFN.
●In one study, 18 patients with chronic HDV infection were randomly assigned to receive 12 versus 24 months of pegylated IFNa [25]. Extending the treatment duration to 24 months did not increase the likelihood of achieving HDV RNA suppression.
●An observational study followed 104 patients with chronic HDV who received 48 weeks of treatment with pegylated IFNa. Patients with a detectable serum HDV RNA after 24 weeks of therapy were unlikely to have a sustained virologic response after treatment was stopped [26].
However, certain patients may benefit from prolonged therapy if eradication of HBsAg is used as an endpoint. In a case series of four patients receiving pegylated IFNa, treatment was continued until the HBsAg titer was not detected [27]. Most patients required prolonged treatment (ranging from seven months to four years) to achieve a negative HBsAg value. The HBsAg remained negative in all patients 12 months after the end of therapy.
Peginterferon plus nucleoside analogs — A large controlled trial evaluated 90 patients with compensated chronic hepatitis D who were randomly assigned to pegylated IFNa-2a alone or in combination with adefovir dipivoxil or adefovir monotherapy [28]. After 48 weeks, HDV RNA was negative in approximately 25 percent of patients in both pegylated IFNa-2a arms and none in the adefovir monotherapy arm. The response was sustained up to 24 weeks after stopping therapy. Thus, combination therapy appeared to offer no advantage compared to pegylated IFNa monotherapy, while adefovir monotherapy was ineffective. A significant decline in HBsAg levels was observed in patients receiving pegylated IFNa-2a (especially when combined with adefovir) but not in patients treated with adefovir monotherapy.
In another trial, 120 HDV RNA-positive patients received either 180 mcg of pegylated IFN alfa-2a weekly plus either tenofovir disoproxil fumarate (TDF; 300 mg daily) or placebo for 96 weeks [29]. In this trial, the addition of TDF did not result in any significant improvement in HDV RNA response rates at the end of treatment.
HBV nucleotide inhibitors — It is a logical approach to target hepatitis B virus (HBV) in its capacity as an HDV helper virus. A small retrospective series found that all 19 patients coinfected with HIV, HBV, and HDV had undetectable HBV DNA and 10 (53 percent) had undetectable HDV RNA after a median duration of 58 months of tenofovir treatment [30]. In addition, HBsAg seroclearance occurred in three patients. However, in subsequent studies the results have been less encouraging [31,32].
Novel treatments — Several drugs have been evaluated as alternatives to IFNa. Agents that have novel mechanisms of action and show more promise include:
●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 [33]. This link promotes membrane interactions with the prenylated protein since the isoprenoid chain is hydrophobic.
Lonafarnib, a farnesyltransferase inhibitor used to treat other diseases (eg, progeria), was evaluated in a phase 2a study of 14 patients with HDV [34]. Eight patients received 100 mg of lonafarnib twice daily, and six patients received 200 mg of lonafarnib twice daily. Treatment was administered for 28 days, and when compared with placebo, resulted in a greater decline in HDV RNA (average serum HDV RNA decline of 0.73 log and 1.54 log international units/mL for the lower and higher doses, respectively). Although all patients experienced adverse events (nausea, diarrhea, abdominal bloating, and weight loss), no patients had to discontinue treatment due to these effects. Lonafarnib serum concentrations correlated with changes in HDV RNA.
A subsequent study that included 15 patients with chronic hepatitis D infection evaluated several different treatment regimens (lonafarnib at varying doses, lonafarnib plus ritonavir, lonafarnib plus pegylated interferon [IFN]) [35]. In this study, adding the cytochrome P450 3A4 inhibitor ritonavir (100 mg once daily) allowed for a reduction in the lonafarnib dose to 100 mg twice daily and yielded a better antiviral response than higher lonafarnib doses with fewer side effects. A similar improvement was observed when lonafarnib 100 mg twice daily was combined with pegylated IFN 180 mcg once weekly. The mean HDV RNA decrease in the ritonavir and pegylated IFN group at the end of eight weeks of treatment was -2.4 log and -1.8 log, respectively. Six patients were treated with 12 weeks of lonafarnib monotherapy at varying doses, and two underwent a transient post-treatment elevation of serum alanine aminotransferase (ALT), followed by HDV RNA negativity and ALT normalization. The authors speculated that the ALT flares may have reflected restoration of a favorable immune response, although this needs to be confirmed.
Lonafarnib (50 mg twice daily, combined with ritonavir 100 mg twice daily) has also been evaluated in association with IFN lambda 180 mcg once weekly for 24 weeks (LIFT HDV Study). In an interim analysis of data from 26 patients, 24 patients (92 percent) achieved a >2 log decline and 20 patients (77 percent) achieved either undetectable HDV RNA levels or levels below the lower limit of quantification [36]. Five of 22 patients had undetectable HDV RNA, decrease in ALT, and improved liver histology 24 weeks after completion of treatment. However, side effects, especially gastrointestinal, were prominent and led to treatment discontinuation in four patients.
●HDV entry inhibitors − These agents act upon the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor shared by HBV and HDV [37,38]. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection", section on 'HDV life cycle'.)
Bulevirtide (Myrcludex B), which blocks entry of HBV and HDV, was studied in a Phase 2a trial of 24 patients with chronic HDV infection [39]. Bulevirtide was administered to 14 individuals, either as monotherapy (2 mg subcutaneously given daily) or in combination with pegylated IFN for 24 weeks. Bulevirtide was well tolerated both as monotherapy and in combination with pegylated IFN. Of the 14 patients who received bulevirtide, 13 experienced a >1 log10 reduction in HDV RNA after 24 weeks of therapy. In the monotherapy arm, two of the seven patients became HDV RNA negative, compared with five of the seven patients who received combination therapy. However, hepatitis B surface antigen (HBsAg) levels remained unchanged.
An open-label, phase 2b clinical trial assessed the safety and efficacy of bulevirtide in combination with tenofovir in patients with HBV/HDV coinfection [40]. In this trial, 120 patients with chronic hepatitis D who either failed or were unable to take IFN were randomized to receive no bulevirtide or bulevirtide at doses of 2, 5, or 10 mg for 24 weeks. All patients were pretreated with tenofovir disoproxil fumarate (TDF) for 12 weeks, and TDF was continued during treatment with bulevirtide, and for 24 weeks after. Dose-dependent HDV RNA declines without on-treatment breakthrough were seen in parallel with ALT decreases. However, virologic relapse occurred in most patients after bulevirtide was stopped. Modest, asymptomatic dose-dependent increases in bile acid levels were observed in some patients.
On July 31, 2020, the European Medicines Agencies (EMA) provided a conditional marketing authorization to bulevirtide for treatment of compensated chronic HDV infection at the dose of 2 mg subcutaneously once daily [41]. Neither the US Food and Drug Administration nor regulatory authorities in other countries have authorized the use of bulevirtide.
●Inhibitors of virion secretion – REP 2139 is a nucleic acid polymer that has been shown to clear HBsAg by blocking the release of subviral particles. This agent was evaluated for the treatment of HDV infection in an uncontrolled phase 2 study [42,43]. In this study, 12 patients with chronic HDV received 500 mg of REP 2139 intravenously (IV) once per week for 15 weeks, followed by combined therapy with 250 mg IV REP 2139 and 180 mcg SC pegylated IFN once per week for 15 weeks, and finally monotherapy with 180 mcg pegylated IFN once per week for 33 weeks. During treatment, 11 patients became HDV RNA negative; at the end of the one-year post-treatment follow-up period, seven remained HDV RNA negative, eight had suppressed HBV DNA levels, and five seroconverted from HBsAg to anti-HBs. However, marked ALT flares have been reported in studies using REP 2139 and REP 2165. Although the flares have not resulted in liver failure, further studies are needed to establish the safety and efficacy of these compounds.
TREATMENT OF ACUTE HEPATITIS D — There is no specific treatment for acute hepatitis D. In one report, three patients treated with foscarnet for acute liver failure due to HDV recovered, as did two additional patients with acute liver failure due to HBV alone [44]. Foscarnet is an inhibitor of some viral DNA polymerases. However, it was shown to have a paradoxical stimulatory effect on HDV replication in vitro [45]. Thus, the efficacy of foscarnet in acute liver failure due to HBV/HDV coinfection may be secondary to its inhibition of HBV. Due to the extreme paucity of data, foscarnet is currently not recommended for acute hepatitis D.
PREVENTION OF HDV INFECTION — For hepatitis B virus (HBV) carriers, every effort should be made to reduce the risk of hepatitis D virus (HDV) transmission. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
For others, the mainstay of prevention of HDV infection is vaccination against HBV (its helper virus). Chimpanzees who are positive for hepatitis B surface antibody (anti-HBs) are protected against experimental HDV infection [46]. 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".)
However, passive prophylaxis with hepatitis B immunoglobulin has not completely prevented reinfection of transplanted livers by HDV. In some patients, HDV virions were able to infect and replicate within the liver allograft. Nonetheless, HDV infection is abortive and does not result in recurrent liver disease unless the allograft is simultaneously reinfected with HBV. (See "Liver transplantation in adults: Prevention and management of hepatitis D virus recurrence after liver transplantation".)
Animal studies suggest that vaccine strategies for preventing HDV superinfection may be feasible. Chimpanzees rechallenged with HDV many years after recovery from the initial HDV infection were partially protected [8], which suggests that a protective immune response is present.
Woodchucks have served as a useful animal model for evaluating HDV vaccines. Early attempts to vaccinate woodchuck hepatitis virus (WHV) carrier woodchucks with liver-derived hepatitis D antigen (HDAg) [47] or the N-terminal portion of recombinant HDAg that contain a major immunogenic epitope [48] were unsuccessful. However, a later experiment suggested that partial protection against HDV superinfection could be achieved by active immunization [49]. In this study, six WHV carrier woodchucks were repeatedly immunized with the full-size, recombinant, yeast-derived small form of HDAg. Upon challenge with HDV, two woodchucks were not infected, as serum HDV RNA was never detected by polymerase chain reaction; two showed a transient, low-level HDV viremia; and only two had a typical acute HDV infection. All control animals developed acute hepatitis D.
A similar study used the short form of HDAg expressed by recombinant baculovirus or vaccinia virus as immunogen [50]. Again, after challenge of the woodchucks with HDV, partial protection was observed even though anti-HDV was not detected. It is possible that the protection was related to induction of cytotoxic T-cell response.
However, these encouraging results were not confirmed by other investigators who used live recombinant vaccinia virus expressing either the small or the large form of HDAg [51]. The explanations for the different outcomes using vaccines that are manufactured by very similar approaches are unknown.
In another approach, three synthetic HDAg peptides were administered to four woodchucks, resulting in the production of specific antibodies. These woodchucks developed transient, low-level viremia after inoculation with HDV but none developed chronic HDV infection [52].
Vaccination against HBV remains the most cost-effective means to prevent HDV infection, except for individuals who are already infected with HBV.
SUMMARY AND RECOMMENDATIONS
●Hepatitis D virus (HDV) is a defective virus requiring the simultaneous presence of hepatitis B virus (HBV) to fully express its pathogenicity. (See 'Introduction' above.)
●The clinical sequelae of HDV infection encompass a spectrum of manifestations, from fulminant liver failure to the asymptomatic carrier state. The clinical course is influenced by several factors, including the HDV genotype. (See 'Clinical course of HDV infection' above.)
●We suggest that patients with chronic HDV who have elevated HDV RNA levels and active liver disease (as evidenced by elevated serum aminotransferase [ALT] levels and/or chronic hepatitis on liver biopsy) be treated (Grade 2B). Such patients should be treated as soon as possible, particularly if there is advanced fibrosis. Although the rate of success is low, a response is more likely to be attained in patients with a shorter duration of infection. Asymptomatic HDV carriers with persistently normal ALT levels do not require therapy but should be monitored for signs of active disease. (See 'Approach to treatment' above.)
●The optimal treatment of HDV is uncertain. The treatment of choice for chronic HDV is pegylated IFN alfa-2a (180 mcg weekly) for one year. Pegylated IFN alfa-2b, which has been used in several clinical trials, is no longer available. Alternatively, patients can be referred to specialized centers that offer experimental therapies. (See 'Approach to treatment' above and 'Trials of interferon alfa' above and 'Novel treatments' above.)
●Available data have not demonstrated an advantage from the addition of a nucleos/tide analogue. However, tenofovir or entecavir should be added if treatment of HBV is indicated. (See 'Approach to treatment' above and 'Novel treatments' above.)
●The mainstay of prevention of HDV infection is vaccination against its helper virus, HBV. (See 'Prevention of HDV infection' above.)
