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Lamivudine for Chronic Delta Hepatitis
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Summary: Chronic delta hepatitis is a severe form of chronic liver disease caused by hepatitis delta virus (HDV) infection superimposed on chronic hepatitis B or the hepatitis B surface antigen (HBsAg) carrier state. Therapy of delta hepatitis is currently unsatisfactory. We have evaluated lamivudine (3-thiacytidine), an oral nucleoside analogue with marked effects against hepatitis B, as therapy in 5 patients with chronic hepatitis D. Five men, ages 38 to 65 years, were treated. All had HBsAg, antibody to HDV, and HDV RNA in serum, as well as persistent elevations in alanine aminotransferase (ALT) levels and liver histology showing severe chronic hepatitis with fibrosis or cirrhosis. Lamivudine was given in a dose of 100 mg orally daily for 12 months. Patients were monitored carefully and tested for HBsAg, HBV-DNA and HDV-RNA levels serially during the year of treatment and for 6 months thereafter. Liver biopsies were performed before therapy and repeated after 1 year. Serum levels of HBV DNA fell rapidly in all 5 patients, becoming undetectable even by polymerase chain reaction (PCR) in 4. However, all 5 patients remained HBsAg- and HDV-RNA-positive, and serum ALT levels and liver histology did not improve. All patients tolerated therapy well. When lamivudine was stopped, HBV-DNA levels returned to pretreatment values without a change in disease activity. Lamivudine is a potent inhibitor of HBV-DNA replication, but does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis.
Editorial note: the results of this study suggest concerns regarding treatment for HBV-infected patients coinfected with HDV. I am not expert in this field but based on limited research Iıve done it is uncertain how to treat patients coinfected with HBV and HDV. Itıs my understanding that HDV-infection is uncommon in the generalm population infected with HBV-infection. Several new therapies are unavailable and in development for HBV and an answer may lie in them. Adefovir has since been approved by the FDA. Entecavir is in phase III and several other drugs for HBV are in earlier development. Pegasys is a pegylated form of interfeon being studied in HBV-infected individuals and limited research suggests that perhaps combining Pegasys with antivirals for HBV might provide effective ptreatment for HBV/HDV but this is a very preliminary notion. But I do not know of any studies looking at responses for HDV-infected individuals. It appears that HDV is not getting much attention. It is my understanding that an individual can acquire HDV at the same time as HBV or can acquire HDV after acquiring HDV and this is called superinfection. Based on details reported below HDV appears spread by IV drug use and by sex. But HDV appears rarely discussed.
Hepatology August 1999, Volume 30, Number 2
Daryl Lau, Jay Hoofnagle, et al. Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases.
The hepatitis delta virus (HDV) is a small defective RNA virus that replicates only in the presence of hepatitis B surface antigen (HBsAg). Chronic HDV infection often results in severe liver disease that progresses to cirrhosis in as many as 70% of patients. All patients with delta hepatitis have HBsAg in serum, but most lack markers of active hepatitis B virus (HBV) replication such as hepatitis B e antigen (HBeAg) and HBV DNA. Diagnosis is suggested by the finding of anti-HDV in an HBsAg-positive patient and is confirmed by the finding of HDV RNA in serum or HDV antigen in liver.
Therapy of chronic delta hepatitis is problematic. Pilot studies suggested that interferon alfa was effective in reducing serum aminotransferase elevations and improving hepatic histology. Subsequent randomized, controlled trials showed that interferon was effective in only a proportion of patients and had to be administered in high doses for prolonged periods. Relapses were common after therapy unless HBsAg was cleared, which occurred uncommonly. Interferon alfa therapy is also expensive, difficult to administer, and often poorly tolerated. Thus, current options for therapy of chronic delta hepatitis are limited.
Other antiviral agents have been used in chronic delta hepatitis, but results have been limited. Both ribavirin and levamisole appear ineffective. Recently, lamivudine (3-thiacytidine), an oral nucleoside analogue, has been shown to have inhibitory effects against HBV in vitro and in vivo. Studies in humans indicated that lamivudine was well tolerated and led to rapid decreases in serum HBV-DNA levels, followed by decreases in serum aminotransferases levels. Prolonged treatment was associated with improved histology in more than half of patients and clearance of HBeAg in 20% to 30%. Its safety and effects against HBV led us to evaluate lamivudine for its biochemical, virological, and histological effects in a small group of patients with moderate to severe chronic delta hepatitis.
Patients with chronic delta hepatitis without evidence of other chronic liver disease were enrolled. Inclusion criteria were presence of persistent elevations in serum aminotransferases accompanied by HBsAg and anti-HDV in serum for at least 6 months, and the presence of either HDV RNA in serum or HDV antigen in liver. Exclusion criteria included seropositivity for antibody to human immunodeficiency virus or hepatitis C virus (HCV) RNA by commercial reverse-transcriptase polymerase chain reaction (PCR) (Amplicor: Roche Diagnostics, Nutley, NJ). Other exclusion criteria were the presence of signs of decompensated liver disease such as muscle wasting, jaundice, ascites, hepatic encephalopathy, or history of variceal bleeding. Liver biopsies were performed before therapy on all patients who had no contraindications. Liver histology was graded using a modification of the histology activity index (HAI), which comprised the sum of 4 scores, including periportal necrosis and inflammation (0-10), lobular necrosis and inflammation (0-4), portal inflammation (0-4), and fibrosis (0-4).
After initial evaluation, patients were started on lamivudine (kindly provided by GlaxoWellcome, Research Triangle Park, NC) orally at a dose of 100 mg once daily for 12 months. Compliance was monitored by medication diaries and counting of the residual tablets returned at the monthly outpatient visits. Patients were seen in the outpatient clinic, questioned about symptoms and possible side-effects, and had blood drawn at regular intervals, including day 1 and weeks 1, 2, and 4 during the first month, and then every 4 weeks for the remainder of the treatment and 6-month follow-up period. Patients underwent liver biopsy shortly before starting therapy and again after 12 months of treatment. Thereafter, patients were followed on no treatment for 6 months.
RESULTS
Clinical, Demographic, and Histological Features Before Treatment
Five patients were treated. All 5 were male; 4 were white, and 1 was African-American; their ages ranged from 38 to 65 years (mean, 47 years). The source of hepatitis was unknown in 2, likely from sexual exposure in 2, and from previous injection drug use in 1. The average known duration of chronic hepatitis was 15 years (range, 4-27 years). Three patients had been treated with interferon alfa without lasting effect. Before treatment, all 5 patients had persistent elevations in serum alanine aminotransferase (ALT) levels (range, 43-156; mean, 94 U/L) and HBsAg (range, 102.7-105.6; geometric mean, 104.9 IU/mL); 1 patient was reactive for HBeAg, and the remaining 4 for anti-HBe without HBeAg. Levels of HBV DNA in serum ranged widely. The 4 patients without HBeAg had low levels of HBV DNA (103.0 to 105.3 copies per milliliter) that were detectable only by PCR. In contrast, the patient with HBeAg in serum had high levels of HBV DNA (109.9 copies per milliliter) detectable easily by branched DNA assay. HDV RNA was also detected in all 5 patients, at levels ranging from 105.4 to 108.4 copies per milliliter. Two
patients were reactive for anti-HCV by both enzyme immunoassay and immunoblot assay, but both tested negative on repeated occasions for HCV RNA by PCR. All patients were nonreactive for antibody to the human immunodeficiency virus.
Liver biopsies were performed shortly before starting therapy on 4 patients. One patient (patient 3) had severe thrombocytopenia (less than 50,000/mm3) secondary to advanced liver disease and did not undergo biopsy for this study, but had undergone liver biopsy 4 years previously shortly before being treated with interferon alfa. The pretreatment liver biopsies showed active inflammation and fibrosis in all 5 patients; total HAI scores ranged from 11 to 17 (of a maximal score of 22). Three patients had cirrhosis. HDV antigen was detectable by immunoperoxidase staining in all liver biopsies, whereas HBsAg was detectable in only 3 and hepatitis B core antigen in 2.
On lamivudine, serum levels of HBV DNA decreased in all 5 patients, becoming undetectable (by PCR) (<100 copies per milliliter) in the 4 anti-HBe-positive
patients between weeks 4 and 32 of therapy. The patient with HBeAg had a 5-log reduction of HBV-DNA levels (from 109.9 to 104.9 per milliliter) and a slight reduction in HBeAg (103.8 to 103.2 IU per milliliter), but he remained positive for both.
Serum aminotransferase levels remained abnormal in all 5 patients, and mean levels did not change (initial mean ALT = 94 U/L; final = 105 U/L). All 5 patients also remained positive for both HBsAg and HDV RNA. Titers of HBsAg and HDV RNA fell in the patient with HBeAg (HBsAg from 105.6
to 104.8 IU/mL and HDV RNA from 107.7 to 105.1 copies per milliliter), but not in the 4 patients with anti-HBe (initial and final levels of HBsAg being 103.9 vs.
103.8 IU per milliliter, and of HDV RNA being 107.4 vs. 107.4 copies per milliliter). Liver biopsy histology also showed no consistent improvement in inflammatory or fibrotic scores nor in patterns of immunohistochemical staining for HBsAg or HDV antigen.
Therapy was tolerated without evident side-effects, and compliance was excellent. All patients finished the year of therapy without dose reduction or discontinuation. There were no serious or unexpected side-effects, and no patient reported a change in symptoms.
In follow-up, serum levels of HBV DNA returned to baseline values within 2 to 4 months of stopping therapy, and there were no increases in serum aminotransferases that accompanied this rise in viral levels. Patient 3 was referred for liver transplantation, whereupon the decision was made to maintain him on lamivudine (Epivir: 150 mg/d) in preparation for transplantation as prophylaxis against recurrence of hepatitis B.27 Subsequently, this patient had further deterioration of hepatic
synthetic function despite improved ALT level, and developed ascites and variceal hemorrhage. He underwent liver transplantation, but died 10 days
later from hepatic failure caused by primary graft nonfunction. The explant liver showed well-established cirrhosis with active inflammation (HAI = 14) and both HDV antigen and HBsAg by immunoperoxidase staining.
DISCUSSION
Chronic delta hepatitis is caused by a unique hepatitis virus, HDV, a small single-stranded circular RNA virus that replicates by the double-rolling circle model in the cytoplasm of hepatocytes.2 HDV is a defective virus in that it requires a helper virus, HBV, for complete replication and transmission. Actually, HDV can replicate at low levels independently of hepatitis B. The helper function provided by HBV appears to be HBsAg, which is necessary for viral packaging, export, and spread of HDV infection to other cells. Replication of HDV independent of hepatitis B has been shown to occur in vitro in cell culture as well as in vivo in patients after liver transplantation. However, without HBV, delta replicates at low levels only, virions are not exported, and infection does not result in widespread infection or cell
damage. These findings indicate that it is not HBV replication so much as production of HBsAg that is important in the disease expression and transmission of delta hepatitis.
This pilot study of lamivudine therapy of chronic delta hepatitis further supports the hypotheses surrounding the replicative cycle of HDV and HBV and their interactions. Lamivudine led to a rapid and marked decrease in serum levels of HBV DNA, but had little or no effect on HBsAg titers or on HDV-RNA levels. Even with inhibition of HBV DNA by greater than 5 logs and lack of detectability of viral DNA by sensitive PCR assays, HDV replication was largely unaffected, and the activity of the liver disease and cell injury did not change. Because lamivudine blocks the viral polymerase, it affects the replicative cycle of the HBV after production of RNA, and has little effect on the covalently closed circular HBV DNA from which RNAs are produced that synthesize viral proteins such as HBsAg.28 If HBsAg is the helper function provided by HBV, then packaging, export, and spread of HDV in the liver would be unaffected by any antiviral agent that inhibits HBV polymerase only.
In this study, 1 patient had HBeAg and high levels of HBV DNA in serum, and treatment with lamivudine led to a marked fall in HBV DNA and a slight decrease in HBsAg. This was also the only patient in whom HDV-RNA titers fell, suggesting again that the production of HDV virions is linked to production of HBsAg. However, in this patient, despite a year of antiviral therapy, both HBsAg and HDV RNA remained at moderate to high levels, and there was no improvement in serum ALT levels or liver histology. Thus, delta hepatitis remains an important therapeutic challenge that deserves further investigation and a search for safe and efficacious therapies. Several promising agents have recently become available for therapy of hepatitis B, but unless they can substantially reduce HBsAg levels and
adequately eradicate the covalently closed HBV-DNA molecules more effectively, these agents are unlikely to be of benefit in chronic delta hepatitis.
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