Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon-alfa for more than three decades. First studies to treat HDV-infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one-quarter to one-third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long-term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon-alfa will still have an important role in the management of hepatitis D - either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon-based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development.

Infection with the hepatitis D virus induces the most severe form of chronic viral hepatitis, affecting over 12 million people worldwide. Chronic HDV infection leads to rapid development of liver cirrhosis and hepatocellular carcinoma in ~70% of patients within 15 years of infection. Recent evidence suggests that an interplay of different components of the immune system are contributing to viral control and may even be implicated in liver disease pathogenesis. This review will describe general concepts of antiviral immune response and elicit the present evidence concerning the interplay of the hepatitis D virus with the immune system.

Chronic Hepatitis D virus (HDV) infection remains an important global public health problem, with a changing epidemiological landscape over the past decade along with widespread implementation of hepatitis B vaccination and human migration. The landscape of HDV treatments has been changing, with therapies that have been under development for the last decade now in late stage clinical trials. The anticipated availability of these new therapies will hopefully replace the current therapies which are minimally effective.

This narrative review discusses the clinical course, screening and diagnosis, transmission risk factors, epidemiology, current and investigational therapies, and liver transplantation in HDV. Literature review was performed using PubMed and ClinicalTrials.gov and includes relevant articles from 1977 to 2022.

HDV infection is an important global public health issue with a true prevalence that is still unknown. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration. As HDV infection is associated with accelerated disease courses and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy to understand the truth of global prevalence such that new therapies can target appropriate individuals as they become available in the future.

Viral infections affecting the liver have had an important impact on humanity, as they have led to significant morbidity and mortality in patients with acute and chronic infections. Once an unknown etiology, the discovery of the viral agents triggered interest of the scientific community to establish the pathogenesis and diagnostic modalities to identify the affected population. With the rapid scientific and technological advances in the last centuries, controlling and even curing the infections became a possibility, with a large focus on preventive medicine through vaccination. Hence, a comprehensive understanding of hepatitis A, B, C, D and E is required by primary care physicians and gastroenterologists to provide care to these patients. The review article describes the epidemiology, pathogenesis, clinical presentation, diagnostic tools and current medication regimens, with a focus on upcoming treatment options and the role of liver transplantation.

Little data have been published so far on the epidemiological aspects of hepatitis D virus (HDV) infection in immigrant populations and even poorer is the information on the virological, phylogenetic, and clinical aspects of this infection in these populations. This review article, aimed primarily at physicians caring for immigrants, summarizes the information available on HDV infection and analyzes data on this topic concerning the immigrant populations.

The prevalence of HDV infection in HBsAg-positive immigrants varies according to the country of origin. For example, in immigrants from sub-Saharan Africa, this prevalence is higher in those born in Equatorial Guinea (24.4%) than those from other African countries (10.3%). The epidemiological impact of HDV infection linked to migratory flows is a function of the different endemicity between countries of origin and countries in which a new existence has been established. This impact is high when immigrants from areas endemic to HDV infection (eg, Equatorial Guinea) settle in areas of low endemicity (eg, Germany or England, with a prevalence of around 4%), while the impact is lesser or nonexistent if the migratory flows are directed toward countries with intermediate endemicity (eg, Italy and Greece, with a prevalence of around 10%).

This impact of immigration on HDV epidemiology can be strong when HDV endemicity is high in the country of origin and low in the host country and slight when immigrants move to high or medium endemic countries.

The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15-20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.

Chronic hepatitis D is the most severe form of viral hepatitis, affecting ∼20 million HBV-infected people worldwide. The causative agent, hepatitis delta virus (HDV), is a unique human pathogen: it is the smallest known virus; it depends on HBV to disseminate its viroid-like RNA; it encodes only one protein (HDAg), which has both structural and regulatory functions; and it replicates using predominantly host proteins. The failure of HBV-specific nucleoside analogues to suppress the HBV helper function, and the limitations of experimental systems to study the HDV life cycle, have impeded the development of HDV-specific drugs. Thus, the only clinical regimen for HDV is IFNα, which shows some efficacy but long-term virological responses are rare. Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed. Interference with entry, for example through blockade of the HBV-HDV-specific receptor sodium/taurocholate cotransporting polypeptide NTCP by Myrcludex B, and inhibition of assembly by blockade of farnesyltransferase using lonafarnib or nucleic acid polymers such as REP 2139-Ca, have shown promising results in phase II studies. In this Review, we summarize our knowledge of HDV epidemiology, pathogenesis and molecular biology, with a particular emphasis on possible future developments.

Hepatitis-D virus (HDV) is a satellite virus of hepatitis-B virus (HBV) whose intracellular products are required for the completion of the HDV life cycle. HDV can replicate in a cell without the presence of HBV but needs hepatitis B surface antigen (HBsAg) to complete virus assembly and packaging. In order to better understand HDV dynamics, we developed a mathematical model and successfully simulated HBV and HDV data under a range of scenarios. Compared to HBV mono-infection, dual HDV infection resulted in lower chronic HBV DNA levels, with more marked suppression for coinfection (1 logs HBV DNA copies/ml lower) compared to superinfection (0.6 logs HBV DNA copies/ml). Although they have no effect on HBV, prenylation inhibitors may provide the best therapy for reducing HDV viremia irrespective of the stage in which they are commenced. We found that highly effective long term pegylated interferon (IFN) therapy (99.99%) eliminates HBV and HDV viremia while less effective long term IFN therapy (99%) will only produce approximately 2.03 logs and no decrease in HBV and HDV viremia respectively in both coinfection and superinfection settings. Our study also suggests that there is a substantial difference in the outcome of therapies depending upon the time of commencement.

Mathematical modeling of HDV infection can describe the complex interplay between this virus and HBV. Simulations suggest that HDV impacts on the feedback mechanisms that maintain cccDNA levels and that targeting these mechanisms may result in new therapeutic agents for both viruses.

Hepatitis B and D virus coinfection or superinfection lead to chronic liver disease and have poor treatment results and poor prognosis. After transplant, these patients have difficult problems. We aimed to report long-term data of liver transplant recipients who had hepatitis B and D virus-related chronic liver disease.

This retrospective, longitudinal study included 25 consecutive hepatitis B surface antigen-positive patients with antihepatitis D virus antibodies. Patient data (age, sex, antiviral treatment, posttransplant use of hepatitis B hyperimmunoglobulin and/or nucleoside/nucleotide analogues, the presence of hepatocellular carcinoma, age at transplant, follow-up) were extracted from patient records.

Females comprised 32% patients. The median age was 44 years (range, 23-63 y). The serum Hepatitis B envelope antigen level was negative in all patients. At the time of transplant, 4 patients were positive for hepatitis B virus DNA and 11 patients also had hepatocellular carcinoma. Posttransplant follow-up was 59 months (range, 3-120 mo). During follow-up, 4 patients died, 4 patients were lost to follow-up, and 17 patients were alive. Posttransplant survival of patients with hepatocellular carcinoma was 50.45 months (range, 3-84 mo) and without hepatocellular carcinoma was 65.8 months (range, 4-120 mo). There were 3 patients who had acute rejection and were treated successfully with pulse doses of prednisolone. Hyperimmunoglobulin therapy was used in conjunction with oral nucleotide/nucleoside analogues for 12 months (range, 3-24 mo) and then stopped. After transplant, 4 patients had antiviral medicine changed to adefovir or entecavir because of drug resistance, and otherwise all patients remained negative for hepatitis B virus DNA during follow-up.

Patients transplanted for hepatitis B and D virus cirrhosis, even with hepatocellular carcinoma, had favorable prognosis and good longterm results. Close follow-up of patients and effective viral suppression with suitable drugs were key factors for efficient patient care.

Hepatitis delta virus (HDV) infection therapy is unclear. This systematic analysis aimed to clarify the evidence on the efficacy of interferon (IFN)-α-based therapy in HDV.

We performed a systematic search on electronic databases including MEDLINE (1970 to January 2011), Web of Science, The Cochrane Library and ClinicalTrials.gov. Randomized clinical trials (RCTs) comparing IFN-α-based therapy with either another drug, placebo or no intervention were included. We excluded paediatric studies. We calculated relative risks (RRs) for comparison of treatment options on the primary outcome measure, which was defined as undetectable levels of HDV RNA and normal alanine aminotransferase at end of treatment (EOT; 1 year).

Nine RCTs were included. Seven trials evaluated the treatment with IFN-α (n=132). The remaining two trials evaluated treatment with pegylated (PEG)-IFN-α (n=45). We found that 1-year treatment with high-dose IFN-α achieved better primary outcome rates than with PEG-IFN-α (RR=4.14, 95% CI 1.00, 17.14). Data for 1-year treatment with low-dose IFN-α compared with PEG-IFN-α were similar (RR=2.83, 95% CI 0.65, 12.40), as were low-dose IFN-α versus high-dose IFN-α (RR=0.68, 95% CI 0.31, 1.50). High-dose IFN-α and PEG-IFN-α reached similar HDV RNA suppression 24 weeks after EOT (RR=1.00, 95% CI 0.51, 1.97). None of the 55 patients assigned to no intervention obtained undetectable levels of HDV RNA and only one patient achieved normalization of alanine aminotransferase level.

Based on available RCTs, 1-year high-dose IFN-α monotherapy appears to be more effective than PEG-IFN-α for treatment of HDV patients, with efficacy rates of approximately 30%. There is a lack of head-to-head comparisons. Combination therapies and longer treatment duration need to be investigated.

Hepatitis D virus is a small defective RNA virus that requires the presence of hepatitis B virus infection to infect a person. Hepatitis D is a difficult-to-treat infection. Several clinical trials have been published on the efficacy of interferon alpha for hepatitis D virus (HDV) infection. However, there are few randomised trials evaluating the effects of interferon alpha, and it is difficult to judge any benefit of this intervention from the individual trials.

To evaluate the beneficial and harmful effects of interferon alpha for patients with chronic hepatitis D.

We identified relevant for the review randomised clinical trials by electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until May 2011. We also checked the bibliographic references of identified randomised trials, textbooks, and review articles in order to find randomised trials not identified by the electronic searches.

Randomised clinical trials evaluating interferon alpha versus placebo or no intervention for patients with chronic hepatitis D infection.

Two authors assessed the trials and extracted data on mortality, virologic, biochemical, and histological response as well as adverse events at end of treatment and six months or more after completing treatment. The analyses were performed using the intention-to-treat principle including all randomised participants irrespective of follow-up. Drop-outs, withdrawals, and non-compliance were considered as treatment failures. Data were analysed with fixed- and random-effects models. Reported results were based on fixed-effect model except in cases where statistical significance varied between the two models.

Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high. Five trials compared interferon alpha with no treatment in the control group. One of these trials had two treatment arms with a higher dose and lower dose of interferon alpha and a no-treatment control group. We analysed both treatment regimens as a single group in a primary analysis and as separate groups in the subgroup analysis of different interferon dosages. The sixth trial compared only a higher dose of interferon alpha with a lower dose.Meta-analysis of five trials comparing interferon alpha with no-treatment control group included 169 participants. There were seven drop-outs in the treatment group and nine in the control group. One patient out of 92 (1.1%) died in the interferon alpha group compared with zero out of 77 (0.0%) in the no-intervention control group (risk ratio (RR)) 3.00; 95% confidence interval (CI) 0.14 to 66.5). Interferon alpha led to failure of end of treatment virological response in 62/92 (67.4%) of the patients compared with 71/77 (92.2%) in the untreated controls (RR 0.76, 95% CI 0.66 to 0.87, P = 0.0001 by fixed-effect model and RR 0.71, 95% CI 0.43 to 1.16, P = 0.17 by random-effects model). Failure of normalisation of alanine aminotransferase (ALT) at the end of treatment was seen in 60/92 (65.2%) patients treated with interferon alpha versus 76/77 (98.7%) in the control group (RR 0.69, 95% CI 0.59 to 0.80, P < 0.00001). Sustained virological response was not achieved in 76/92 (82.6%) of patients on interferon compared with 73/77 (94.8%) of controls (RR 0.89, 95% CI 0.80 to 0.98, P = 0.02). Serum alanine aminotransferase was abnormal in 81/92 (88.0%) treated with interferon alpha patients at six months post-treatment follow-up compared with 76/77 (98.7%) in controls (RR 0.92, 95% CI 0.84 to 0.99, P = 0.04). There was no significant histological improvement in 67/92 (72.8%) patients treated with interferon alpha compared with 65/77 (84.4%) in controls (RR 0.86, 95% CI 0.74 to 1.00, P = 0.06).Two trials comparing a higher dose of interferon alpha with the lower dose showed no significant difference in sustained virological response (76.7% compared with 90.0%) (RR 0.85, 95% CI 0.68 to 1.07, P = 0.16). Adverse events such as flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all these trials and the adverse events were related to interferon alpha. These were common and sometimes severe. One patient in the treatment group was reported to have died by suicide towards the end of the study period.

Interferon alpha does not seem to cure hepatitis D in most patients. The agent seems effective in suppressing viral and liver disease activity in some patients, but this improvement is not sustained in the majority of patients. We cannot exclude overestimation of benefits and underestimation of harms due to high risk of bias (systematic errors) and high risk play of chance (random errors). Therefore, more randomised trials with large sample sizes and less risk of bias are needed before interferon can be recommended or refuted.

Hepatitis delta virus (HDV) is widely distributed and associated with fulminant hepatitis epidemics in areas with high prevalence of HBV. Several studies performed in the 1980s showed data on HDV infection in South America, but there are no studies on the viral dynamics of this virus. The aim of this study was to conduct an evolutionary analysis of hepatitis delta genotype 3 (HDV/3) prevalent in South America: estimate its nucleotide substitution rate, determine the time of most recent ancestor (TMRCA) and characterize the epidemic history and evolutionary dynamics. Furthermore, we characterized the presence of HBV/HDV infection in seven samples collected from patients who died due to fulminant hepatitis from Amazon region in Colombia and included them in the evolutionary analysis. This is the first study reporting HBV and HDV sequences from the Amazon region of Colombia. Of the seven Colombian patients, five were positive for HBV-DNA and HDV-RNA. Of them, two samples were successfully sequenced for HBV (subgenotypes F3 and F1b) and the five samples HDV positive were classified as HDV/3. By using all HDV/3 available reference sequences with sampling dates (n=36), we estimated the HDV/3 substitution rate in 1.07 × 10(-3) substitutions per site per year (s/s/y), which resulted in a time to the most recent common ancestor (TMRCA) of 85 years. Also, it was determined that HDV/3 spread exponentially from early 1950s to the 1970s in South America. This work discusses for the first time the viral dynamics for the HDV/3 circulating in South America. We suggest that the measures implemented to control HBV transmission resulted in the control of HDV/3 spreading in South America, especially after the important raise in this infection associated with a huge mortality during the 1950s up to the 1970s. The differences found among HDV/3 and the other HDV genotypes concerning its diversity raises the hypothesis of a different origin and/or a different transmission route.

Hepatitis D is caused by infection with the hepatitis D virus (HDV) and is considered to be the most severe form of viral hepatitis in humans. Hepatitis D occurs only in individuals positive for the HBV surface antigen (HBsAg) as HDV is a defective RNA viroid that requires HBsAg for transmission. At least eight different HDV genotypes have been described and each has a characteristic geographic distribution and a distinct clinical course. HDV and HBV coinfection can be associated with complex and dynamic viral dominance patterns. Chronic HDV infection leads to more severe liver disease than HBV monoinfection and is associated with accelerated fibrosis progression, earlier hepatic decompensation and an increased risk for the development of hepatocellular carcinoma. So far, only IFN-alpha treatment has proven antiviral activity against HDV in humans and has been linked to improved long-term outcomes. Studies conducted in the past 2 years on the use of PEG-IFN-alpha show that a sustained virologic response to therapy, measured in terms of undetectable serum HDV RNA levels, can be achieved in about one quarter of patients with hepatitis D. Novel alternative treatment options including prenylation inhibitors are awaiting clinical development for use in hepatitis D.

Hepatitis D virus (HDV) encodes two proteins, the 24-kDa small delta antigen (S-HDAg) and 27-kDa large delta antigen (L-HDAg) in its single open reading frame. Both of them had been identified as nuclear phosphoproteins. Moreover, the phosphorylated form of S-HDAg was shown to be important for HDV replication. However, the kinase responsible for S-HDAg phosphorylation remains unknown. Therefore, we employed an in-gel kinase assay to search candidate kinases and indeed identified a kinase with a molecular mass of about 68 kDa. Much evidence demonstrated this kinase to be the double-stranded RNA-activated kinase, PKR. The immunoprecipitated endogenous PKR was sufficient to catalyze S-HDAg phosphorylation, and the kinase activity disappeared in the PKR-depleted cell lysate. The S-HDAg and PKR could be co-immunoprecipitated together, and both of them co-located in the nucleolus. The LC/MS/MS analysis revealed that the serine 177, serine 180, and threonine 182 of S-HDAg were phosphorylated by PKR in vitro. This result was consistent with previous phosphoamino acid analysis indicating that serine and threonine were phosphorylation targets in S-HDAg. Furthermore, serine 177 was also shown to be the predominant phosphorylation site for S-HDAg purified the from cell line. In dominant negative PKR-transfected cells, the level of phosphorylated S-HDAg was suppressed, but replication of HDV was enhanced. Other than human immunodeficiency virus type 1 trans-activating protein (Tat), S-HDAg is another viral protein phosphorylated by PKR that may regulates HDV replication and viral response to interferon therapy.

Hepatitis due to hepatitis delta virus (HDV) infection is generally associated with severe histological abnormalities and rapid progression of the disease. To assess the efficacy of recombinant interferon-a2b in treatment of chronic delta hepatitis, 22 patients were entered into a randomized controlled trial: 11 received interferon-a2b subcutaneously three times weekly for 12 months (5 MU/m2 for 4 months and then 3 MU/m2 for a further 8 months) and 11 were untreated. All patients were followed up for 6 months after the completion of therapy. Nine treated patients completed the trial: one was withdrawn with hyperthyroidism and one committed suicide. Serum ALT levels were normalized or significantly reduced, always within 3 months of initiating treatment, and remained so in 73% of treated patients at the 4th month and in 54.5% at the 12th month, compared with 18% and 18%, respectively, in the untreated group. Moreover, in seven of nine treated patients, interferon was associated with the clearance of serum HDV-RNA, associated with amelioration of the histological picture, whereas this occurred in only four of 11 untreated patients. On cessation of therapy, all patients but one experienced a biological and/or virological relapse over the 6-month follow up. In conclusion, our data confirm that HDV is sensitive to inhibition by interferon-a2b, although the schedule used did not achieve permanent control of the disease. The adverse effects of interferon require consideration; in particular, care will be needed to avoid serious psychiatric side effects.

Five major hepatotrophic viruses have been identified. The pathogenesis, diagnosis and treatment of chronic viral hepatitis continues to be intensely researched. Experimental evidence suggests that HLA restricted virus-specific T cells play a role in hepatocellular injury in type A hepatitis. The absence of chronic infection indicates the effectiveness of the host immune response to hepatitis A virus (HAV). It is postulated that HAV may rarely trigger an autoimmune chronic hepatitis. Active prophylaxis of hepatitis A is possible. The elimination of hepatitis B is dependent on the recognition of viral determinants in association with HLA proteins on infected hepatocytes by cytotoxic T cells. The specific epitopes recognized by B and T cells are being mapped. Polymerase chain reaction (PCR) amplification and sequencing of genomic DNA in patients with chronic hepatitis B has indicated that nucleotide substitutions in the genome are not uncommon. Their pathogenicity is being explored. Antiviral therapy for hepatitis B remains difficult. Interferon is effective in a proportion of patients. Thymosin may prove to be more effective immunomodulatory therapy. New nucleoside analogues suppress HBV replication, but the safety of these drugs has been questioned after the appearance of severe liver toxicity with fialuridine. The data that hepatitis D virus is pathogenic has recently been challenged with the observation that HDV re-occurs in transplanted liver after engrafting, but without signs of HBV recurrence or evidence of liver damage. Treatment of hepatitis D virus remains difficult. Several isolates of hepatitis C virus have been cloned, and the sequence divergence of these isolates indicates that there are several major genotypes and component subtypes of this polymorphic virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Reinfection of the graft with hepatitis B virus (HBV) and hepatitis delta virus (HDV) is a potential complication in patients undergoing orthotopic liver transplantation (OLT). Therefore, we added recombinant interferon-alpha (rIFNa) to the standard immunosuppressive regimen in 11 patients who received transplants following liver failure attributed to cirrhosis B (n = 10, with HDV co-infection in four cases) or fulminant hepatitis B (n = 1). Patients were treated with rIFNa for periods ranging from 2 to 3 months between the first and the 13th month after OLT. All patients received immunosuppressive treatment with low-dose corticosteroids, azathioprine and cyclosporine. Anti-HBs hyperimmune globulin was also administered. None of the patients showed evidence of severe allograft rejection. Seven patients suffered HBV reinfection of the graft with histological signs of acute hepatitis in five cases and transition to chronic hepatitis in one patient. Treatment with rIFNa did not prevent or reduce HBV replication. Reinfection of the graft with HDV was demonstrated by PCR in four patients co-infected with HDV. During treatment with rIFNa liver biopsy specimens from three reinfected patients were transiently negative for HDV antigen but not for HDV RNA, and the sera from two patients were transiently negative for HDV RNA. The data indicate that rIFNa can reduce HDV replication in reinfected liver allografts.

Chronic delta hepatitis is a severe disease with a rapidly progressive course for which currently no effective treatment exists. Treatment with alpha-interferon (alpha-IFN) can inhibit HDV replication and improve serum chemistries in a number of patients. Meta-analysis of five randomized controlled trials using at least 5 MU/m2 of alpha-IFN t.i.w. for a minimum of 3 months showed that alpha-IFN had a statistically significant effect in normalizing ALT values during therapy at a p level of less than 0.001, with a 10.24 odds ratio and a 28.69% risk difference (Mantel-Haentzel-Peto chi 2 = 24.13) but had no significant effect on ALT activity after its discontinuation. From hitherto available results, it appears that the best treatment schedule is a 5 MU standard dose of alpha-IFN given daily (QD) or 9 MU t.i.w. for at least 1 year, which is associated with a remission of the disease in 50-70% of patients. A trial conducted in Greece showed that the mean duration of disease remission under alpha-IFN therapy was 3.8 months per year compared to 1.7 months per year of non-treatment (relative risk = 2.8). Unlike hepatitis B, no factors predictive of the response to alpha-IFN therapy have been identified except, perhaps, for the duration of the disease. No adjuvants have been found to enhance the efficacy of alpha-IFN treatment and no therapeutic alternatives are available at present. Advances in understanding HDV replication and the pathogenetic mechanisms in chronic delta hepatitis may bring about significant improvement in its therapy in the future.

In this pilot study, 12 patients with chronic delta hepatitis were studied. The diagnosis was based on the presence of antibodies to the hepatitis delta antigen in the serum and hepatitis delta virus RNA and hepatitis delta antigen in the serum and liver. All patients were also positive for hepatitis B surface antigen. The infection was presumed to have been transmitted by intravenous drug abuse in six of the patients, blood transfusion in one and by sexual contact in four (two had antibodies to human immunodeficiency virus in their serum, but did not show signs of acquired immunodeficiency syndrome). In one further patient, the source of infection was unknown. Interferon alfa-2b (INTRON A, Schering-Plough Corporation) was initiated at 5 million units per day subcutaneously for at least 4 months, being reduced by half if side effects occurred. Serum alanine aminotransferase levels, hepatitis delta virus RNA and hepatitis delta antigen were measured at monthly intervals for up to 12 months in some patients. Interferon therapy resulted in decreased serum levels of these three markers. On cessation of therapy, most patients experienced a relapse over 6 months, but alanine amino transferase levels could be normalized once more by restarting interferon therapy. In conclusion, interferon decreased hepatic inflammation by the inhibition of hepatitis delta virus replication, although relapse occurred when interferon was stopped and long-term therapy is required to achieve permanent control of the disease. Care will be required when treating patients with advanced or decompensated liver disease.

Superinfection by hepatitis delta virus (HDV) in hepatitis B virus chronic carriers is normally associated with a progressive liver injury. For this reason, the aim of the present study was to determine the efficacy of recombinant interferon alpha (rIFN-alpha) treatment of chronic delta hepatitis, by giving high doses of rIFN-alpha 2c during a prolonged period. A total of 20 HBsAg, anti-HD carriers with a chronic active hepatitis were randomly allocated in two groups: (I) n = 10, control and (II) n = 10, treated with 10 MU/m2 body surface of rIFN-alpha, twice weekly, intramuscularly (im) during 6 months. Basally, all patients presented HDAg in the liver and serum IgM anti-HD. Serum HDV-RNA was positive in 8 and 7 patients from groups I and II, respectively. The interferon therapy was well tolerated and all patients finished the treatment period. During the first 6 months, a decrease in ALT levels among treated patients (255 +/- 98 vs. 193 +/- 117) was observed. In addition, a transient drop in HDV-RNA levels was also observed. No changes in anti-HD titer, IgM anti-HD and HBsAg concentration were detected. At the end of the follow-up period (15 months) two treated patients had lost IgM anti-HD. In addition, another two patients were HDV-RNA negative. In conclusion, no permanent antiviral effects of rIFN-alpha 2c in chronic delta hepatitis, using this schedule, was achieved.

Chronic viral hepatitis is a common clinical problem; it must be differentiated from other forms of chronic liver disease by history, laboratory data, and liver biopsy. This article reviews the treatment of chronic hepatitis B, delta hepatitis, and nonA and nonB viral hepatitis and emphasizes the controlled trials when available.

The conformational and biologic properties of the hepatitis delta virus (HDV), a defective RNA hepatotropic pathogen dependent on obligatory helper functions provided by the hepatitis B virus (HBV), are different from the properties of conventional RNA animal viruses but resemble in many aspects the characteristics of the satellite RNAs and satellite viruses of higher plants. The HBsAg coat provided to HDV by HBV makes the defective virus transmissible via the vectors and modes of transmission of the ubiquitous helper; alike HBV, HDV is prevalent in tropical and subtropical areas and in the Mediterranean basin. In contrast to HBV, HDV is highly pathogenic and its infection aggravates the underlying HBV infection upon which it thrives. The defective pathogen has been recognized worldwide as a major cause of fulminant hepatitis and of severe chronic hepatitides leading to cirrhosis and liver failure. There is yet no established therapy for this ominous disease.

Current therapies for chronic viral hepatitis, autoimmune "lupoid" chronic active hepatitis, and drug-induced chronic hepatitis are discussed in the context of recent advances in our understanding of the pathophysiology of chronic active liver disease. Accurate diagnosis is the cornerstone of proper treatment; the limitations and pitfalls of conventional techniques are discussed. Current theories of the pathogenesis of chronic hepatitis B are reviewed to provide a framework for the use of antiviral drugs. Data from the early results of therapy with adenine arabinoside, acyclovir, and immunomodulatory agents are reviewed, and the theoretical basis for the use of alpha-interferon as well as preliminary data supporting its efficacy is presented. Strategies for the treatment of chronic delta hepatitis and chronic non-A, non-B viral hepatitis are discussed as well. The immunological changes associated with autoimmune chronic active hepatitis are described to help define those patients with chronic active hepatitis who are likely to respond to immunosuppressive therapy. The recognized hazards of long-term corticosteroid therapy are indicated and guidelines for the management of these patients are suggested. Chronic drug-induced liver disease will usually improve with cessation of the offending agent. An approach to the patient with suspected drug-induced chronic hepatitis is indicated. Finally, the role of liver transplantation is mentioned as the ultimate treatment modality available for endstage liver disease.

The expression of intrahepatic delta antigen (HDAg) was studied in relation to the morphologic features of HDV hepatitis and the outcome of liver disease. The study was performed in 101 patients followed up for an average of 12 years; one or more liver biopsies were available from each patient, giving a total of 167 specimens. The histologic features were assessed using numerical scores. A significant positive relation was observed between the number of HDAg-positive cells and the extent of portal inflammation (Spearman's rank coefficient 0.75). The highest degree of inflammation and intrahepatic expression of HDAg was found before the elimination of the virus, while the outcome of HDV disease was unrelated to the severity of the initial morphologic lesion. These results suggest that the individual immune response may play an important role in the pathogenesis of HDV hepatitis.