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Treatment of Chronic Hepatitis Delta: Mission Impossible?
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Gastroenterology December 2011
RAFFAELLA ROMEO
MASSIMO COLOMBO
First Division of Gastroenterology
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
University of Milan
Milan, Italy
Wedemeyer H, Yurdaydin C, Dalekos GN, et al. Peginterferon plus Adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011;364:322-331.
The hepatitis delta virus (HDV), a small hepatotropic defective RNA virus that requires the presence of the hepatitis B virus (HBV) to replicate, is estimated to chronically infect more than 15 million carriers of HBV worldwide [J Hepatol 2003;39(Suppl 1):S212-219]. Composed of a coat of HBV envelope proteins surrounding the nucleocapsid, the virus consists of a single-stranded, circular RNA genome, which encodes 2 isoforms of a virus protein, the delta antigen. Because of its unique method of replication based on interaction between the surface antigen of HBV (HBsAg) with the protein-RNA complex of the virus, HDV has obtained its own genus (Deltavirus). The virus is unique in size, in possessing a ribozyme, in replicating by a double rolling-circle mechanism and in redirecting to its advantage the cellular replicating mechanism (J Hepatol 2009;50:1043-1050). Being RNA viruses characterized by high genetic heterogeneity, HDV circulates in the form of 8 distinct genotypes which are universally distributed and apparently possess different pathogenic properties (Virology 1997;234:160-167; J Gen Virol 1998;79:1105-1113), whereas genotype 1 predominates in Europe and North America, genotypes 2 and 4 are mainly distributed in Asia, genotype 3 is endemic in South America, and genotypes 5-8 almost exclusively circulate in Africa (Nat Rev Gastroenterol Hepatol 2010;7:31-40). Infection with HDV is confirmed by the presence of detectable serum HDV-RNA, immunohistochemical staining of HDV antigen in the liver, or serum immunoglobulin M anti-HDV. Owing to its contagiousness, HDV rapidly propagates through parenteral exposure (J Hepatol 1999;30:564-569), either after simultaneous transmission with HBV or as superinfection of an HBV carrier, the infection spanning in a clinical spectrum ranging from asymptomatic carriage of the virus to extremely severe disease.
Clinically, HDV is a perfect example of unfair partnership, because the virus concurrently suppresses HBV replication while causing an exacerbation of the accompanying liver disease. Not surprisingly, therefore, HDV/HBV co-infection can be more severe than HBV mono-infection, even though the outcome of HDV infection ultimately depends on the course of acute HBV infection, which in adults maintains high chances (95%) of spontaneous resolution. By contrast, HDV superinfection in chronic HBV carriers often results in chronic hepatitis delta and an increased risk of acute on chronic liver failure, accelerated fibrosis progression, hepatocellular carcinoma and anticipated clinical decompensation (Gastroenterology 2009;136:1629-1638). In the pre-vaccine era, outbreaks of infection with HDV leading to rapidly progressive chronic active liver disease have occurred in several Mediterranean countries, the Middle East, Central Africa, and the Northern part of South America as a consequence of the population exposure to parenteral risks including intravenous drug injections and unsafe sex, causing the prevalence of HDV among selected HBV populations to climb up to 20% [J Hepatol 2003;39(Suppl 1):S212-219]. After implementation of universal vaccination against HBV, improvement of socioeconomic conditions, and widespread use of disposable medical devices, the circulation of HDV in Europe has steadily declined particularly among the younger patients to cluster in <10% of aging patients population (Hepatology 2000;32:824-827). The prevalence of HDV infection in the United States is currently under investigation with a few preliminary reports indicating a low prevalence of HDV mostly clustered in high risk groups such as IV drug users and immigrants from endemic areas (Nat Rev Gastroenterol Hepatol 2010;7:31-40). In the Asia-Pacific area, HDV infection remains a major health problem, as it is in Pakistan where the prevalence of the infection has increased over time. Conversely, in countries like China, Turkey, Australia, Japan, India, and Taiwan, there is circumstantial evidence that HDV infection is declining, although still maintaining high prevalence rates (World J Gastroenterol 2010;16:554-562). Along with the decline of HDV circulation, the clinical scenario of hepatitis delta has changed in parallel. Although many HDV-infected patients in the past had floridly active liver disease, many current HDV-infected patients demonstrate almost clinically inactive cirrhosis (J Hepatol 2009;50:1043-1050). Thus, the European scenario of HDV is represented by a residual pool of domestic aging survivors of the HDV epidemic of the 1970s, mixed with fresh cases of HDV imported by infected immigrants from hyperendemic areas and a domestic pool of young IV drug users.
Despite attempts with interferon (IFN) alone or in combination with the nucleoside analog lamivudine, hepatitis delta has substantially resisted any therapeutic trial in the past. Recently, the finding that both PegIFN and the nucleotide analog adefovir dipivoxil (ADV) inhibits covalently closed circular DNA in the liver of HBV carriers opened the way to a new era of research in HDV. This is based on the assumption that suppression of the template for HBsAg production, necessary to HDV for its replication and propagation within the liver, might help "cool down" HDV replication (Gastroenterology 2004;126:1750-1758; Hepatology 2006;44:675-684).
The proof of concept of this was the Hep-Net International Delta Hepatitis Interventional Trial I (HIDIT-I) by Wedemeyer et al, which depicted the safety and efficacy of a 48-week treatment with either Peg-IFN alpha-2a plus ADV or either drug alone in patients with chronic infection with the genotype 1 HDV, randomly assigned to different treatment arms. Between March 2004 and September 2006, 90 adults with chronic hepatitis delta were recruited in 5 centers in Germany, 4 in Turkey (an hyperendemic region for HDV), and 1 in Greece, and included in the study. After patient stratification according to country and previous history of treatment with IFN, patients were randomized to receive either 180 μg/wk of Peg-IFN alpha-2a plus 10 mg/d ADV (group 1), 180 μg/week of Peg-IFN alpha-2a (group 2), or 10 mg/d ADV alone (group 3), all for 48 weeks. Although 10 patients withdrew for disease progression (n = 6), side effects (n = 1), and non-liver-related causes (n = 3), the primary endpoint of undetectable HDV-RNA and normal transaminases by intention-to-treat analysis was reached by 4 of these patients (2 from group 1 and 2 from group 2). At week 48, the overall proportion of patients who cleared HDV RNA was 23% in the groups treated with Peg-IFN either with or without ADV, as compared with 0% in the group treated with ADV alone (P = .006 group 1 versus group 3; P = .004 group 2 versus group 3). By the same token, at week 72, 28% of patients treated with Peg-IFN in either group had reached the secondary end points of cleared HDV RNA compared with 0% of patients treated with ADV alone (P = .006 group 1 versus group 3; P = .004 group 2 versus group 3). Similarly, a reduction in median HDV RNA levels of >2 log10 copies per milliliter from baseline to week 72 was observed in 8 (26%) patients from group 1, 9 (31%) from group 2, but none from group 3 (P = .003 for group 1 versus group 3; P = .001 for group 2 versus group 3). Whereas 2 patients treated with Peg-IFN (1 in each group) broke through after treatment completion, 9 other patients (4 in group 1 and 5 in group 2) became HDV RNA negative during follow-up. Interestingly, a consistent decline of serum HBsAg levels was observed in patients receiving Peg-IFN plus ADV, with a median decline of 0.89 log10 IU/mL from baseline to week 48 (P = .002) followed by further decline by 1.12 log10 IU/mL from baseline to week 72 (P < .001), but not in patients treated with either regimen alone. Despite these encouraging serologic outcomes, liver biopsies obtained at the end of treatment in 59 patients (65%) showed no substantial benefits in any treatment arm compared with pretreatment liver biopsies and paradoxically worsened in the PegIFN monotherapy groups compared with pretreatment liver biopsies. In summary, although treatment with Peg-IFN alpha-2a for 48 weeks resulted in a sustained HDV RNA clearance in a similar proportion of patients as in previous studies with IFN monotherapy, the real gain from addition of ADV to PegIFN was the significant decline of serum HBsAg levels, which is instrumental to HDV for its replication and pathogenicity.
Comment
Since its discovery in 1977 (Gut 1977;18:997-1003), chronic HDV infection has presented as a difficult to treat and more severe liver disease than chronic infection with HBV alone. The demonstration that chronic hepatitis delta is an immune-mediated disease involving hepatocytes as major histocompatibility complex class II presenting cells and cytotoxic CD4 T cells, provided the rationale for attempting IFN therapy in patients with chronic HDV infection (Hepatology 2003;37:1079-1085). However, this therapeutic paradigm was not fully validated in clinical practice, as demonstrated by the disappointingly low rates of successful suppression or eradication of the virus infection in pivotal trials with standard IFN (J Hepatol 1991;13(Suppl 1):S21-S26). The success of anti HDV therapy with IFN was only marginally improved by extended duration regimens or administration of pegylated IFN for 48 weeks (N Engl J Med 1994;330:88-94; Gastroenterology 2004;126:1740-1749). Indeed, the promising 43% rates of sustained virologic response of a pilot study in France with Peg IFN alpha 2a administered for 48 weeks were subsequently negated by 2 small studies in similar patients conducted in Germany and Italy, which reported a less encouraging rate of response of 17% and 21%, respectively (Hepatology 2006;44:728-735; Liver Int 2006;26:805-810; Hepatology 2006;44:713-720). Less encouraging were the outcomes of treatment with first-generation HBV polymerase inhibitors, even in patients achieving suppression of residual replication of HBV, which is necessary to sustain HDV replication and pathogenicity. Indeed, pilot studies with lamivudine alone or in combination with IFN and with famciclovir (Hepatology 1999;30:546-549; J Viral Hepatitis 2000;7:428-434; J Hepatol 2002;37:266-271) reported no improvement of such an hard endpoint of therapy as liver histology. Not surprisingly, the experts of the European Association for the Study of the Liver (J Hepatol 2009;50:227-242) consensually recognized that conventional or pegylated IFN alfa is of unproven clinical efficacy, even though it is the only drug effective on HDV replication.
Although therapeutic failures in HDV can be partly explained by the ability of HDV to impair the IFN stimulated JAK-STAT signaling pathway of innate immunity (Hepatology 2009;49:397-400), the mechanisms of IFN resistance in HDV are likely to be multiple and favored by the biological and clinical heterogeneity of HDV/HBV co-infection. Indeed, although the patient population in the multinational Hep-Net study was homogeneously constituted by HDV genotype 1-infected individuals, the cohort was only partially analyzed for the infecting HBV genotype, which in the few patients (n = 30) tested was invariably (100%) the IFN resistant strain D. Because the clinical pattern of hepatitis delta may influence the rates of response to IFN in HDV patients, it should be mentioned that the prevalence of young age (≤42 years) and HBV viremic patients (50%) in the Hep-Net study suggests the predominating existence of florid hepatitis cases with respect to burn out forms of HDV infection, mixed with many patients (40%) who had received previous treatments with IFN. Finally, another reason for clinical heterogeneity of the Hep-Net cohort is the lack of patient stratification for predictors of a response to IFN, particularly the interleukin-28B polymorphisms, which are known to predict a sustained response to IFN not only in hepatitis C but also in HBV-infected patients (Nature 2009;481:399-401; Hepatology 2010;52:A237; J Hepatol 2011;54:A71).
Given the link between HBV and HDV, it may be worth investigating whether the response of HDV patients to IFN really associates to interleukin-28B polymorphisms, especially with virologic endpoints like serum HDV-RNA suppression and HBsAg decline. Thus, patient analysis for interleukin-28B polymorphisms might help not only understanding the real effectiveness of IFN -based therapy in HDV patients and optimize patient care through pretreatment patient stratification by predictors of response.
In the Hep-Net study, the decline in serum HBsAg levels and suppression of HDV replication coupled with an improvement of serum alanine aminotransferase values might herald the off-therapy clinical benefit of HBsAg clearance and strengthens the rationale for prolonging therapy with IFN in these patient populations. Concurrently, the lack of histologic benefits at the end of therapy should not discourage extended therapy with IFN, because it might just reflect a limitation of the study design, namely, a too-short follow-up to capture an off-therapy histologic response once suppression of HDV is achieved. This seems to be the message of a 12-year follow-up study in Italian patients with florid chronic hepatitis delta including active cirrhosis in two thirds of the cases (Gastroenterology 2004;126:1750-1758). This study demonstrated that the efficacy of IFN in chronic hepatitis delta is related to IFN dosing (9 versus 3 million of conventional IFN given thrice weekly for 48 weeks) and that remarkable improvement in hepatic fibrosis could only be appreciated in liver biopsies taken in survivors 5-10 years after completion of therapy rather than in liver biopsies taken in the immediate posttreatment period. In that study, the histologic improvement seen in patients treated with high doses of IFN correlated with a better survival (9 MU versus control: 86% vs 31%; P = .003). This outcome could not be assessed in the short term follow-up of the Hep-Net study and long-term follow-up of the patients in the study by Wedemeyer et al may be helpful.
Overall, the Hep-Net study tells us that current treatment of HDV remains largely unsatisfactory. Ultimately, molecularly targeted drugs that interfere with HDV replication and prenylation inhibitors that interfere with the interaction between the large HDV antigen and HBsAg may be the best options to improve therapy of HDV, and on-going studies may identify new treatments (J Viral Meth 1997;65:183-198; J Clin Invest 2003;112:407-414).
Because practice in Italy is governed by strict guidelines for reimbursement of drug therapies, we are currently bound to IFN-based regimens as the sole treatment modality for HDV patients. ADV in fact cannot be prescribed as a first-line treatment modality for HBV-infected patients, whereas it is uncertain whether a treatment related decline in serum HBsAg after potent antivirals like tenofovir or Entecavir, benefits HDV patients, too, thus confining the use of these drugs to clinical trials only. Because the cure of HDV infection outside the scenario of liver transplantation seems to be an impossible mission, we eagerly look forward to any new medical treatment that can suppress HDV more efficiently than Peg-IFN, ultimately resulting in the prevention of the long-term sequelae of the infection.
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