Original Article
Treatment of Chronic Hepatitis D with Interferon Alfa-2a
N Engl J Med 1994; 330:88-94January 13, 1994
- Abstract
Background and Methods
Chronic hepatitis D is a severe and rapidly progressive liver disease for which no therapy has been proved effective. To evaluate the efficacy of treatment with interferon, we studied 42 patients with chronic hepatitis D who were randomly assigned to receive either 9 million or 3 million units of recombinant interferon alfa-2a (three times a week for 48 weeks) or no treatment.
Results
By the end of the treatment period, serum alanine aminotransferase values had become normal in 10 of 14 patients receiving 9 million units (71 percent), as compared with 4 of 14 treated with 3 million units (29 percent, P = 0.029) and 1 of 13 untreated controls (8 percent, P = 0.001). Seven patients treated with the higher dose of interferon (50 percent) had a complete response (normal levels of alanine aminotransferase and no detectable serum hepatitis delta virus [HDV] RNA), as compared with three of those who received the lower dose (21 percent, P = 0.118), and none of the controls (P = 0.004). Treatment with 9 million units of interferon was associated with a marked improvement in the histologic findings (reduced periportal necrosis and portal and lobular inflammation), whereas in the untreated controls there was considerable histologic deterioration. In 5 of the 10 patients treated with 9 million units of interferon whose alanine aminotransferase values became normal, the biochemical responses persisted for up to 4 years (mean, 39 months), but the effects of treatment on viral replication were not sustained. In contrast, none of those who received 3 million units and none of the untreated controls had a sustained biochemical or virologic response.
Conclusions
In about half the patients with chronic hepatitis D treated with high doses of interferon alfa-2a (9 million units three times a week for 48 weeks), the serum alanine aminotransferase level becomes normal, HDV RNA becomes undetectable in serum, and there is histologic improvement. However, a relapse is common after treatment has been stopped.
Media in This Article
Figure 1
Biochemical and Virologic Course of Chronic Hepatitis D in Two Patients Treated with 9 Million Units of Interferon Alfa-2a.Table 1
Characteristics of Patients Treated with Interferon (9 Million Units or 3 Million Units) and Untreated Controls at the Time of Enrollment.Article Activity
- Article
Hepatitis delta virus (HDV) is a unique RNA virus that requires a helper function provided by hepatitis B virus (HBV) for replication1-3. Thus, HDV can replicate only in people who are also infected with HBV4. Infection with HDV may result in either acute or chronic hepatitis4,5. The clinical course of hepatitis D is variable but usually more severe than that of other forms of viral hepatitis6. Patients with acute hepatitis D may present with fulminant hepatitis7 -- a rare sequela of the acute hepatitis caused by other hepatitis viruses. Chronic hepatitis D is a serious and rapidly progressive liver disease8.
Currently, there is no effective therapy for chronic hepatitis D. Because of its wide spectrum of antiviral actions,9 interferon is being investigated as a possible treatment for the disease. Preliminary reports suggest that a three- to four-month course of interferon alfa is associated with suppression of HDV replication and improvement of liver disease in some patients, but in almost all cases, discontinuation of therapy is followed by a relapse10-12. Subsequent, more promising results with longer courses of interferon alfa13-18 have been difficult to interpret because of inadequate control groups and large variations in the doses of interferon, the duration of treatment, and the characteristics of the patients19.
We conducted a randomized controlled trial designed to compare a 48-week course of high doses (9 million units) or low doses (3 million units) of interferon alfa with no treatment in patients with chronic hepatitis D. The trial was conducted in Sardinia, Italy, where infection with HDV is endemic20.
Methods
Patients
All adult patients attending the hepatitis clinic at the University of Cagliari (Cagliari, Italy) were considered for inclusion in the trial if they met the following criteria: an age between 18 and 60 years; the presence of serum hepatitis B surface antigen (HBsAg), serum antibody to hepatitis delta antigen of the IgG and IgM classes, and serum HDV RNA documented on three occasions within six months before enrollment; elevated serum levels of alanine aminotransferase (at least twice the upper limit of normal) for at least six months before enrollment; histologic evidence of chronic hepatitis; and a positive test for intrahepatic hepatitis delta antigen. The exclusion criteria included a course of antiviral or immunosuppressive therapy within six months before consideration for enrollment, pregnancy or lactation, advanced or decompensated cirrhosis, clotting abnormalities precluding a liver biopsy, hepatocellular carcinoma, a white-cell count under 3000 per cubic millimeter, a platelet count under 100,000 per cubic millimeter, hemophilia, drug abuse, the presence of antibodies to human immunodeficiency virus type 1 (HIV-1), and other serious medical illnesses that might preclude completion of the study. The protocol used in this trial was approved by the university's research committee, and all patients provided informed consent. A total of 42 patients who met the criteria for entry were enrolled in the study. Five of the 42 were treated at the department of internal medicine at the University of Catania (Catania, Italy).
Treatment Regimen and Clinical and Laboratory Evaluation
Using computer-generated sealed envelopes, we randomly assigned patients to three groups: the first received recombinant interferon alfa-2a at doses of 9 million units (14 patients), the second received interferon at doses of 3 million units (14 patients), and the third received no treatment (14 patients). In both the high- and low-dose groups, interferon was given intramuscularly three times a week for 48 weeks. During the treatment period, the patients were seen each week for the first two weeks, then biweekly through week 16, and then at four-week intervals. Subsequently, 41 of the 42 patients (98 percent) were followed for 6 months, and 39 (93 percent) were followed for a mean of 32 months (range, 24 to 48). During the follow-up period, the patients were seen during the first month, during the third month, and then every three months. During each visit, the patients underwent a complete physical examination and were asked about possible side effects of therapy. Blood samples were obtained to determine complete blood counts; alanine and aspartate aminotransferase, bilirubin, albumin and total protein, and creatinine levels; and prothrombin time. On each occasion, blood samples were also tested for serologic markers of hepatitis D (IgG antibody to hepatitis delta antigen, IgM antibody to hepatitis delta antigen, and HDV RNA). Serologic markers of hepatitis B (HBsAg, antibody to HBsAg, antibody to hepatitis B core antigen [HBcAg], IgM antibody to HBcAg, hepatitis B e antigen [HBeAg], antibody to HBeAg, and HBV DNA) were assessed within six months before enrollment; at the time of enrollment; during weeks 4, 12, 24, 36, and 48 of therapy; during months 1, 3, and 6 after the completion of treatment; and every six months thereafter. Aliquots of serum were stored at -70 °C for HDV RNA and HBV DNA testing. Stored serum samples obtained at the time of enrollment, during weeks 16, 32, and 48 of treatment, and six months after treatment were tested for antibodies to interferon.
Drug Toxicity
Clinical and laboratory criteria for drug toxicity were established before the trial to specify the conditions under which the dose of interferon would be reduced, or the drug discontinued. If intolerable dose-related side effects occurred in patients treated with 9 million units, the dose was to be reduced to 3 million units.
Liver-Biopsy Studies
The interferon-treated patients underwent three liver biopsies: the first within six months before enrollment, the second at the end of treatment, and the third six months after the completion of treatment. The untreated patients underwent two liver biopsies: the first within six months before enrollment and the second in the sixth month of follow-up. All biopsy specimens, which were coded, were evaluated by three independent pathologists, and the histopathological changes were graded according to the scoring system of Knodell et al.21. Improvement or deterioration was defined as a difference of at least two points between the total scores for two biopsy specimens from the same patient. The coded specimens were stained for intrahepatic hepatitis delta antigen, HBsAg, and HBcAg with the use of standard procedures22. Immunohistochemical staining was used to determine the percentage of cells that were positive for hepatitis delta antigen.
Definitions of Treatment Response and Relapse
The criteria for a response to treatment and for a relapse were established in advance. A biochemical response to treatment was defined as normal serum alanine aminotransferase levels at the end of treatment, a virologic response as the absence of serum HDV RNA at the end of treatment, and a complete response as normal serum alanine aminotransferase levels and the absence of serum HDV RNA at the end of treatment. A relapse after a biochemical response to treatment was defined as an increase in the serum alanine aminotransferase level to more than 1.5 times the upper limit of normal, a relapse after a virologic response was defined as the reappearance of serum HDV RNA, and a relapse after a complete response was defined as either a biochemical or a virologic reactivation of disease.
Assays
HBsAg, antibody to HBsAg, antibody to HBcAg, HBeAg, antibody to HBeAg, and IgM antibody to HBcAg were measured with commercial radioimmunoassays (Abbott Laboratories, North Chicago), as were IgG and IgM antibodies to hepatitis delta antigen (Sorin Biomedica, Saluggia, Italy). Titers of serum IgG and IgM antibodies to hepatitis delta antigen were determined by testing 10-fold serial dilutions of the serum samples, as previously described23. Antibodies to hepatitis C virus (anti-C-100) and to HIV-1 were tested with commercial enzyme immunoassays (Ortho Diagnostic Systems, Raritan, N.J., and Elavia Diagnostics Pasteur, Paris, respectively). Serum HBV DNA was measured by a dot blot-hybridization technique24. Serum HDV RNA was determined by a dot blot-hybridization technique25 with a 32P-labeled cDNA probe (2 × 108 to 5 × 108 cpm per microgram; kindly provided by J. Taylor, Fox Chase Cancer Center, Philadelphia). The detection limit was less than 0.1 pg of cloned DNA. Total anti-interferon antibodies were determined by enzyme immunoassay; in samples that were positive, neutralizing activity was evaluated by a neutralizing bioassay26.
Statistical Analysis
The results are expressed as means ±SD. An analysis of variance was used to test for significant differences (P<0.05, by the F test) between mean values of continuous variables whenever data from all three groups of patients were analyzed; we then used the Newman-Keuls test for comparisons of groups. Student's t-test was used to compare continuous variables between two groups. The differences between dichotomous variables were evaluated with Fisher's exact test or a chi-square analysis when samples were of sufficient size.
Results
At the time of enrollment in the study, the three groups of patients were similar with respect to sex, age, and various clinical, biochemical, serologic, and histologic characteristics (Table 1Table 1
Characteristics of Patients Treated with Interferon (9 Million Units or 3 Million Units) and Untreated Controls at the Time of Enrollment.). Most of the patients were men, and all were heterosexual. All the patients had positive tests for serum HDV RNA and intrahepatic hepatitis delta antigen. The mean base-line titers of IgG and IgM antibodies to hepatitis delta antigen did not differ among the three groups (range, 102 to 105). All the patients had positive tests for HBsAg but negative tests for IgM antibody to HBcAg. Most of the 42 patients (88 percent) had antibody to HBeAg with no signs of active HBV infection. A retrospective analysis revealed that three patients (7 percent) had antibody to HCV.The biochemical and virologic responses in the three groups of patients at the end of treatment are summarized in Table 2Table 2
Biochemical and Virologic Responses to Interferon Alfa.. Serum alanine aminotransferase values became normal in 10 of the 14 patients (71 percent) treated with 9 million units of interferon, as compared with normal values in 1 of 13 untreated controls (8 percent, P = 0.001) and in 4 of the 14 patients treated with 3 million units of interferon (29 percent, P = 0.029). The difference between the biochemical response in the low-dose group and that in the control group was not significant (P = 0.186). Serum HDV RNA was no longer detectable in 10 of the 14 patients treated with 9 million units of interferon (71 percent), as compared with 0 of 13 controls (P = 0.001) and 5 of the 14 patients treated with 3 million units (36 percent, P = 0.064). The difference between the low-dose group and the controls was not significant (P = 0.098). Seven of the 14 patients (50 percent) treated with 9 million units had a complete response (normal alanine aminotransferase levels and no detectable serum HDV RNA) (Figure 1Figure 1Biochemical and Virologic Course of Chronic Hepatitis D in Two Patients Treated with 9 Million Units of Interferon Alfa-2a.), as compared with 0 of 13 controls (P = 0.004) and 3 of 14 patients treated with 3 million units (21 percent, P = 0.118). In patients without a complete response, there was no correlation between the pattern of viremia and the alanine aminotransferase levels. A single biochemical or virologic response was observed in six patients receiving 9 million units of interferon (Figure 1) and in three receiving 3 million units.Short-Term Follow-up
All patients, with the exception of one in the control group, were evaluated at the end of the six months of follow-up (Table 2). Among the 14 patients treated with 9 million units of interferon, 7 (50 percent) still had normal alanine aminotransferase values, as compared with 1 of the 13 controls (8 percent, P = 0.022) and 1 of the 14 patients treated with 3 million units (7 percent, P = 0.017). Serum HDV RNA was still undetectable in six patients in the high-dose group (43 percent), as compared with one in the control group (8 percent, P = 0.048) and two in the low-dose group (14 percent, P = 0.104). Three patients in the high-dose group (21 percent) but none in the other two groups still had a complete response six months after the end of treatment.
Long-Term Follow-up
Thirty-nine of the 42 patients (93 percent), including all 14 in the high-dose group, 13 in the low-dose group, and 12 in the untreated group, were followed for a mean period of 32 months (range, 24 to 48) after the completion of therapy. In the high-dose group, five of the seven patients with normal serum alanine aminotransferase levels 6 months after treatment continued to have normal values throughout the observation period, for a mean of 39 months (range, 36 to 48) after termination of therapy. One patient had a relapse 7 months after the termination of treatment, and the other had a relapse 21 months after the termination of treatment. During the long-term follow-up, we observed no correlation between the pattern of serum alanine aminotransferase values and the presence or absence of serum HDV RNA. In three of the five patients with alanine aminotransferase values that remained normal, serum HDV RNA was again detectable within 12 months after the termination of therapy and then was either detectable or undetectable, in no particular pattern, throughout the observation period. In the other two patients, serum HDV RNA continued to be detectable during treatment and throughout the follow-up period (Figure 1). Thus, none of the patients treated with 9 million units of interferon had a sustained clearance of HDV RNA, despite long intervals of seronegativity (range, two to six months). None of the patients treated with 3 million units and none of the controls had a sustained biochemical or virologic response.
Serologic Markers
During the study, we did not observe a marked change in the titers of IgG and IgM antibody to hepatitis delta antigen in any of the groups. Assays for serum HBsAg remained positive in all patients. Neutralizing antibodies to interferon became detectable at the end of treatment in seven patients receiving 3 million units of interferon (50 percent) and in two receiving 9 million units (14 percent, P = 0.051) but in none of the controls. The appearance of these antibodies had no notable effect on the course of the disease or the response to therapy.
Liver-Biopsy Studies
The mean total histologic scores did not differ significantly among the three study groups before the initiation of therapy. Of the 28 patients treated with either high- or low-dose interferon, 26 (93 percent) underwent a second liver biopsy at the end of treatment, and 22 (79 percent) underwent a third biopsy a mean of eight months after the completion of treatment. For ethical reasons, only two liver biopsies were performed in the untreated controls. Thus, the scores for the biopsies performed during follow-up (mean, 7 months after treatment) in 11 of the 14 controls were compared with the scores for the biopsies performed in the treated patients both at the end of treatment and during follow-up. The changes in the total score between the first and second biopsies and between the first and third are shown in Table 3Table 3
Comparison of Liver-Biopsy Findings in Treated Patients and Untreated Controls.. Patients treated with 9 million units of interferon had significant histologic improvement both at the end of treatment (P = 0.006) and during follow-up (P = 0.027), as compared with the controls. The difference between the changes in the total score for the high- and low-dose groups was not significant. However, changes in the scores for individual histopathological variables did differ significantly between groups. Patients in the high-dose group had significantly greater improvement in periportal necrosis (P = 0.027), portal inflammation (P = 0.034), and lobular inflammation (P = 0.05), as compared with the controls, and the improvement in periportal necrosis was also significantly greater in the high-dose group than in the low-dose group. A comparison of the first and third liver-biopsy specimens showed a significant reduction of portal inflammation (P = 0.05) in patients treated with the higher dose of interferon, as compared with the controls. A comparison of the first and second liver biopsies in the controls showed a significant increase in portal inflammation(P = 0.029), lobular inflammation (P = 0.04), and fibrosis (P = 0.04). A blind subjective comparison of paired biopsy specimens confirmed that the histologic improvement occurred significantly more frequently in the patients treated with high-dose interferon than in the controls (Table 3).Markers in Hepatic Cells
Hepatitis delta antigen was undetectable in four patients at the end of therapy (three treated with 9 million units of interferon, and one with 3 million units) but was detectable in all patients during follow-up. Moreover, at the end of treatment, there was a reduction in the percentage of cells that were positive for hepatitis delta antigen in 73 percent of the patients treated with 9 million units and in 54 percent of those treated with 3 million units. This reduction was more marked in the high-dose group (range, 50 to 90 percent reduction) than in the low-dose group (range, 30 to 70 percent), and it persisted, though it was less pronounced, during follow-up. Although hepatitis delta antigen was detectable in all the controls throughout the study, a reduction in the percentage of positive cells was seen in 27 percent of the untreated group (range, 30 to 50 percent reduction). In all except two patients, HBcAg was undetectable both before and after therapy. Intrahepatic HBsAg was detectable in most of the patients at the time of enrollment and throughout the study.
Side Effects
The symptoms commonly attributed to interferon therapy,27 which were more frequently observed in the high-dose group than in the low-dose group, were generally mild or moderate. Treatment was not interrupted in any patient, and all patients completed the 48-week course of therapy. Two patients required a reduction from 9 million units to 3 million units after five and six months of therapy because of asthenia and anemia, respectively. One of the two had no response to therapy, and the other had a transient biochemical response. Besides flulike symptoms, asthenia and mild alopecia were the most common side effects observed in the high-dose group (71 and 57 percent, respectively), and the low-dose group (29 percent for both side effects).
Discussion
Chronic hepatitis D is a severe form of liver disease in which spontaneous resolution is rare. Long-term studies have shown that cirrhosis develops in 60 to 70 percent of patients with hepatitis D,8 which is a much higher incidence than that observed in patients with hepatitis B or C. The disease may be rapidly progressive, and in about 15 percent of patients cirrhosis develops within one to two years after the onset of acute hepatitis28.
Because of its antiviral and immunomodulatory properties, interferon is the most promising therapeutic agent for the treatment of various chronic viral infections, including chronic viral hepatitis29. In the past decade, several randomized controlled trials have documented the effectiveness of interferon alfa in treating chronic hepatitis B and, more recently, chronic hepatitis C30-32. However, there is uncertainty about the therapeutic value of interferon alfa as a treatment for chronic hepatitis D. Overall, the results of the small number of controlled clinical trials that have been conducted19 suggest that interferon alfa can induce an amelioration, albeit transient, of chronic hepatitis D. However, variations in the enrollment criteria, doses of interferon, schedules of administration, duration of treatment, and patient populations make it difficult to compare the results of these trials19. Furthermore, the criteria used to evaluate the response to therapy have not been uniform, and the various criteria (i.e., the decrease in serum alanine aminotransferase levels, histologic findings, and HDV replication) have rarely been combined to evaluate the overall effectiveness of interferon alfa19.
In this randomized controlled trial, we compared the efficacy of high versus low doses of interferon alfa in the long-term treatment of patients with chronic hepatitis D who were followed for up to four years after the termination of therapy. Multiple factors were analyzed simultaneously to evaluate the response to treatment. High doses of interferon alfa given three times a week for 48 weeks induced a complete response in 50 percent of the patients, whereas the rate of response was higher (71 percent) when the biochemical and virologic responses were analyzed separately. The rate of response was significantly lower in patients treated with 3 million units of interferon, suggesting that the efficacy of the treatment is related to the dose of the drug. Histologic improvement was also significantly more frequent in patients treated with 9 million units of interferon. Moreover, the change from chronic active hepatitis to chronic persistent or lobular hepatitis observed in two patients suggests that treatment with high-dose interferon may be effective in preventing the progression of the disease and underscores the importance of early recognition and treatment of chronic hepatitis D.
Although a large proportion of the patients receiving high doses of interferon had a sustained biochemical response, the pattern of viremia during follow-up was not correlated with this response. The discrepancy, initially noted at the end of treatment, became more evident thereafter and persisted during the long-term follow-up. The lack of correlation between the pattern of HDV replication and the alanine aminotransferase levels was confirmed by the persistence of intrahepatic delta antigen in the majority of the patients both at the end of treatment and during follow-up, despite a reduction in the percentage of positive cells. This discrepancy is difficult to interpret, although the pathogenic mechanism of HDV infection is still unknown, and the direct clinical consequences of HDV replication are uncertain. In chronic HBV infection, the lack of correlation between viremia and liver damage suggests that HBV is not directly cytopathic33. Similarly, the persistence of HDV viremia despite alanine aminotransferase values that remained normal in some of our patients may indicate that HDV is not directly cytopathic or, possibly, that genetic variants of the virus with altered pathogenic potential may emerge over time. We cannot, however, exclude the possibility that treatment with interferon induces a reduction in the level of viremia.
It is remarkable that half the patients treated with 9 million units who had a biochemical response still had normal alanine aminotransferase values a mean of 39 months (range, 32 to 48) after the termination of therapy, despite the persistence of viremia. Although low doses of interferon induced biochemical and histologic improvement more frequently than occurs spontaneously, the effects of the lower dose were not sustained, and there was no significant difference between the long-term course of the disease in the low-dose group and the long-term course in the untreated controls.
Our study demonstrates that interferon alfa, given in a dose of 9 million units three times a week for 48 weeks, is generally well tolerated and results in normal alanine aminotransferase values, clearance of serum HDV RNA, and histologic improvement in 50 percent of patients with chronic hepatitis D. A complete biochemical response persisted for up to four years in half the patients who had normal alanine aminotransferase values at the end of therapy, whereas the effects on viral replication were not sustained. Our data provide evidence that the efficacy of interferon as a treatment for chronic hepatitis D is related to the dose, even though a substantial proportion of our patients had a relapse within six months after the termination of therapy, despite the use of high doses. Further studies will be necessary to determine whether long-term treatment with high doses of interferon followed by maintenance therapy with low doses can increase the duration of the response and ultimately change the natural history of chronic hepatitis D.
Presented in part at the annual meeting of the American Association for the Study of Liver Diseases, Chicago, November 3-6, 1990.
We are indebted to Drs. David M. Novick and Robert H. Purcell for helpful critical comments; Dr. David Alling for helpful advice on the statistical analysis; Ms. Patrizia Chessa and Ms. Ornella De Martis for taking exceptional care of the patients; Ms. Elena Acerbi for technical support; Ms. Carla Molinas, Mr. Antonello Strazzera, Dr. Daniela De Gioannis, Ms. Maria Piras, and Ms. Rosetta Scioscia for laboratory work; and Mr. Todd Heishman for editorial assistance.
Source Information
From the Istituto di Medicina Interna, University of Cagliari, Cagliari, Italy (P.F., A.M., A.C., M.E.L., A.B.); the Department of Pathology, University of Leuven, Leuven, Belgium (V.D., P.V.E., Y.G.); the Istituto di Medicina Interna, University of Catania, Catania, Italy (L.C.); Clinical Research, Roche S.p.A., Milan, Italy (S.S., D.C.); and Clinical Research, Hoffman-LaRoche, Ltd., Basel, Switzerland (J.-C.R.).
Address reprint requests to Dr. Farci at the Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 7, Rm. 200, 9000 Rockville Pike, Bethesda, MD 20892.
The following investigators also participated in this study: Anna Maria Giulia Farci, M.D., Giovanna Peddis, Ph.D., Giuseppina Orgiana, Ph.D., Anna Paola Mazzoleni, Ph.D., and Aldo Casti, M.D., Istituto di Medicina Interna, and Gavino Faa, M.D., Istituto di Anatomia Patologica, University of Cagliari, Cagliari, Italy; Caterina Trischitta, M.D., Istituto di Medicina Interna, University of Catania, Catania, Italy; and Monique Chaneac, Ph.D., Clinical Research, Hoffmann-LaRoche, Ltd., Basel, Switzerland.
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- Citing Articles (93)
Citing Articles
1
C. Triantos, M. Kalafateli, V. Nikolopoulou, A. Burroughs. (2012) Meta-analysis: antiviral treatment for hepatitis D. Alimentary Pharmacology & Therapeutics 35:6, 663-673
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Mario Rizzetto, Alessia Ciancio. 2012. Hepatitis D. , 599-604.
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Anna S. F. Lok, Francesco Negro. 2011. Hepatitis B and D. , 537-581.
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Zaigham Abbas, Muhammad Arsalan Khan, Mohammad Salih, Wasim Jafri, Zaigham Abbas. 2011. Interferon alpha for chronic hepatitis D. .
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Vincent Soriano, Daniel Grint, Antonella d’Arminio Monforte, Andrzej Horban, Clifford Leen, Eva Poveda, Francisco Antunes, Stephane de Wit, Jens Lundgren, Juergen Rockstroh, Lars Peters. (2011) Hepatitis delta in HIV-infected individuals in Europe. AIDS 25:16, 1987-1992
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Raymund R. Razonable. (2011) Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus. Mayo Clinic Proceedings 86:10, 1009-1026
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Irene N Rapti, Stephanos J Hadziyannis. (2011) Treatment of special populations with chronic hepatitis B infection. Expert Review of Gastroenterology & Hepatology 5:3, 323-339
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Patrizia Farci. 2011. Hepatitis D. , 393-405.
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Wedemeyer, Heiner, Yurdaydìn, Cihan, Dalekos, George N., Erhardt, Andreas, Çakaloğlu, Yilmaz, Değertekin, Halil, Gürel, Selim, Zeuzem, Stefan, Zachou, Kalliopi, Bozkaya, Hakan, Koch, Armin, Bock, Thomas, Dienes, Hans Peter, Manns, Michael P., . (2011) Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta. New England Journal of Medicine 364:4, 322-331
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Heiner Wedemeyer. (2011) Hepatitis D revival. Liver International 31, 140-144
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Grazia Anna Niro, Domenica Gioffreda, Rosanna Fontana. (2011) Hepatitis delta virus infection: Open issues. Digestive and Liver Disease 43, S19-S24
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Stéphanie Pascarella, Francesco Negro. (2011) Hepatitis D virus: an update. Liver International 31:1, 7-21
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Grazia Anna Niro, Antonina Smedile, Antonio Massimo Ippolito, Alessia Ciancio, Rosanna Fontana, Antonella Olivero, Maria Rosa Valvano, Maria Lorena Abate, Domenica Gioffreda, Gian Paolo Caviglia, Mario Rizzetto, Angelo Andriulli. (2010) Outcome of chronic delta hepatitis in Italy: A long-term cohort study. Journal of Hepatology 53:5, 834-840
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C. Yurdaydın, R. Idilman, H. Bozkaya, A. M. Bozdayi. (2010) Natural history and treatment of chronic delta hepatitis. Journal of Viral Hepatitis 17:11, 749-756
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Ellen Sloth Andersen, Jan Gerstoft, Nina Weis. (2010) Reactivation of hepatitis D virus after chemotherapy for diffuse large B cell lymphoma despite lamivudine prophylaxis. International Journal of Hematology 92:2, 378-380
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Heiner Wedemeyer, Michael P. Manns. (2010) Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nature Reviews Gastroenterology & Hepatology 7:1, 31-40
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D.J. Hu, W.A. Bower, J.W. Ward. 2010. Viral Hepatitis. , 203-229.
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MARGARET JAMES KOZIEL, CHLOE LYNNE THIO. 2010. Hepatitis B Virus and Hepatitis Delta Virus. , 2059-2086.
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JULES L. DIENSTAG. 2010. Chronic Viral Hepatitis. , 1593-1617.
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FRED Y. AOKI, FREDERICK G. HAYDEN, RAPHAEL DOLIN. 2010. Antiviral Drugs (Other than Antiretrovirals). , 565-610.
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Manuel Mendizabal, Bertram Bengsch, K. Rajender Reddy. (2009) Management of HBV, HCV, and HDV coinfection. Current Hepatitis Reports 8:3, 111-118
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Fulya Gunsar. (2009) Delta hepatitis. Expert Review of Anti-infective Therapy 7:5, 499-501
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Raffaella Romeo, Ersilio Del Ninno, Mariagrazia Rumi, Antonio Russo, Angelo Sangiovanni, Roberto de Franchis, Guido Ronchi, Massimo Colombo. (2009) A 28-Year Study of the Course of Hepatitis Δ Infection: A Risk Factor for Cirrhosis and Hepatocellular Carcinoma. Gastroenterology 136:5, 1629-1638
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Rong-Nan Chien. (2008) Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B. Hepatology International 2:3, 296-303
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C. Yurdaydın, H. Bozkaya, F. O. Önder, H. Şentürk, H. Karaaslan, M. Akdoğan, H. Çetinkaya, E. Erden, Ö. Erkan-Esin, K. Yalçın, A. M. Bozdayı, R. F. Schinazi, J. L. Gerin, Ö. Uzunalimoğlu, A. Özden. (2008) Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. Journal of Viral Hepatitis 15:4, 314-321
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Elif S. Koytak, Cihan Yurdaydin, Jeffrey S. Glenn. (2007) Hepatitis D. Current Treatment Options in Gastroenterology 10:6, 456-463
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P. Farci, L. Chessa, C. Balestrieri, G. Serra, M. E. Lai. (2007) Treatment of chronic hepatitis D. Journal of Viral Hepatitis 14:s1, 58-63
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C. Yurdaydın, H. Bozkaya, H. Karaaslan, F. O. Önder, Ö. E. Erkan, K. Yalçın, H. Değertekin, A. M. Bozdayı, Ö. Uzunalimoğlu. (2007) A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis. Journal of Viral Hepatitis 14:11, 812-816
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(2007) Viral Hepatitis in HIV Infection. New England Journal of Medicine 357:1, 90-91
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Anna S. F. Lok, Brian J. McMahon. (2007) Chronic hepatitis B. Hepatology 45:2, 507-539
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Patrizia Farci. (2006) Treatment of chronic hepatitis D: New advances, old challenges. Hepatology 44:3, 536-539
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Andreas Erhardt, Wolfram Gerlich, Christine Starke, Ulrike Wend, Andreas Donner, Abdurrahman Sagir, Tobias Heintges, Dieter Haussinger. (2006) Treatment of chronic hepatitis delta with pegylated interferon-α2b. Liver International 26:7, 805-810
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Grazia Anna Niro, Alessia Ciancio, Giovanni Battista Gaeta, Antonina Smedile, Aldo Marrone, Antonella Olivero, Maria Stanzione, Ezio David, Giuseppina Brancaccio, Rosanna Fontana, Francesco Perri, Angelo Andriulli, Mario Rizzetto. (2006) Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 44:3, 713-720
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Corinne Castelnau, Frédéric Le Gal, Marie-Pierre Ripault, Emmanuel Gordien, Michelle Martinot-Peignoux, Nathalie Boyer, Bach-Nga Pham, Sarah Maylin, Pierre Bedossa, Paul Dény, Patrick Marcellin, Elyanne Gault. (2006) Efficacy of peginterferon alpha-2b in chronic hepatitis delta: Relevance of quantitative RT-PCR for follow-up. Hepatology 44:3, 728-735
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Zaigham Abbas, Mohammad Salih, Wasim Jafri, Zaigham Abbas. 2006. Interferon-alpha for hepatitis D. .
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Billur Canbakan, Hakan Senturk, Fehmi Tabak, Meral Akdogan, Veysel Tahan, Ali Mert, Necdet Sut, Resat Ozaras, Kenan Midilli, Gulsen Ozbay. (2006) Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: A randomized trial. Journal of Gastroenterology and Hepatology 21:4, 657-663
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Morris Sherman. (2006) Optimizing Management Strategies in Special Patient Populations. The American Journal of Gastroenterology 101:S1, S26-S31
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Giovanni B. Gaeta, Davide F. Precone, Alessandro Cozzi-Lepri, Paola Cicconi, Antonella D'Arminio Monforte. (2006) Multiple viral infections. Journal of Hepatology 44, S108-S113
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Isabelle Rosa, Laurent Costes, Valérie Garrait, Michel Chousterman. (2005) Efficacy of pegylated interferon alpha-2b for the treatment of chronic delta hepatitis in a patient co-infected with HIV. AIDS 19:18, 2177-2178
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Scott K Fung, Anna S. F Lok. (2005) Update on viral hepatitis in 2004. Current Opinion in Internal Medicine 4:4, 359-366
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G. A. NIRO, A. CIANCIO, H. L. TILLMAN, M. LAGGET, A. OLIVERO, F. PERRI, R. FONTANA, N. LITTLE, F. CAMPBELL, A. SMEDILE, M. P. MANNS, A. ANDRIULLI, M. RIZZETTO. (2005) Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Alimentary Pharmacology and Therapeutics 22:3, 227-232
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Peter Ferenci, Elisabeth Formann, Raffaella Romeo. (2005) Successful Treatment of Chronic Hepatitis D with a Short Course of Peginterferon alfa-2a. The American Journal of Gastroenterology 100:7, 1626-1627
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G. A. Niro, F. Rosina, M. Rizzetto. (2005) Treatment of hepatitis D. Journal of Viral Hepatitis 12:1, 2-9
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Dirk Hartwig, Lutz Schoeneich, Jobst Greeve, Claudia Schütte, Isabel Dorn, Holger Kirchner, Holger Hennig. (2004) Interferon-α stimulation of liver cells enhances hepatitis delta virus RNA editing in early infection. Journal of Hepatology 41:4, 667-672
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V. Vargas Blasco. (2004) Hepatitis por otros virus hepatotropos. Medicine - Programa de Formación Médica Continuada Acreditado 9:11, 666-673
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Necati Örmeci. (2003) Short- and long-term effects of treatment of chronic hepatitis B and delta virus by IFN. Fundamental & Clinical Pharmacology 17:6, 651-658
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Kendal Yalcin, Halil Degertekin, Cihan Yurdaydin, Mithat Bozdayi, Hakan Bozkaya. (2003) The role of HBeAg seroconversion in acute exacerbation of liver disease with termination of hepatitis B and D virus infection in a chronic hepatitis D patient during α-interferon therapy. European Journal of Gastroenterology & Hepatology 15:7, 819-823
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Kendal Yalcin, Halil Degertekin, Cihan Yurdaydin, Mithat Bozdayi, Hakan Bozkaya. (2003) The role of HBeAg seroconversion in acute exacerbation of liver disease with termination of hepatitis B and D virus infection in a chronic hepatitis D patient during ??-interferon therapy. European Journal of Gastroenterology & Hepatology 15:7, 819-823
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Patrick Marcellin, Nathalie Boyer. (2003) Chronic viral hepatitis. Best Practice & Research Clinical Gastroenterology 17:2, 259-275
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The EASL Jury. (2003) EASL INTERNATIONAL CONSENSUS CONFERENCE ON HEPATITIS B. Journal of Hepatology 39, 3-25
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Patrizia Farci. (2003) Delta hepatitis: an update. Journal of Hepatology 39, 212-219
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Tricia J. Brown, Monica McCrary, Stephen K. Tyring. (2002) Antiviral agents: Nonantiviral drugs. Journal of the American Academy of Dermatology 47:4, 581-599
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Brent D Lemberg, Thomas A Shaw-Stiffel. (2002) Hepatic disease in injection drug users. Infectious Disease Clinics of North America 16:3, 667-679
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Cihan Yurdaydin, Hakan Bozkaya, Selım Gürel, Hans L Tillmann, Nuray Aslan, A Okçu-Heper, Esra Erden, Kendal Yalçin, Nevzat Iliman, Özden Uzunalımoǧlu, Michael P Manns, A.Mithat Bozdayi. (2002) Famciclovir treatment of chronic delta hepatitis. Journal of Hepatology 37:2, 266-271
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Ryo Fukuda, Norihisa Ishimura, Sachiko Hamamoto, Makoto Moritani, Yasushi Uchida, Shunji Ishihara, Shuji Akagi, Makoto Watanabe, Yoshikazu Kinoshita. (2001) Co-infection by serologically-silent hepatitis B virus may contribute to poor interferon response in patients with chronic hepatitis C by down-regulation of type-I interferon receptor gene expression in the liver. Journal of Medical Virology 63:3, 220-227
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Otto S. Lin, Emmet B. Keeffe. (2001) C
URRENT TREATMENT STRATEGIES FOR CHRONIC HEPATITIS BAND C. Annual Review of Medicine 52:1, 29-49
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Anne Gervais, Nathalie Boyer, Patrick Marcellin. (2001) Tolerability of Treatments for Viral Hepatitis. Drug Safety 24:5, 375-384
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L. M. M. Wolters, A. B. van Nunen, P. Honkoop, A. C. T. M. Vossen, H. G. M. Niesters, P. E. Zondervan, R. A. de Man. (2000) Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus. Journal of Viral Hepatitis 7:6, 428-434
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Tiffany Weakley, K. Rajender Reddy. (1999) Hepatitis B. Current Treatment Options in Gastroenterology 2:6, 463-472
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Daryl T.-Y. Lau, David E. Kleiner, Yoon Park, Adrian M. di Bisceglie, Jay H. Hoofnagle. (1999) Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology 117:5, 1229-1233
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Daryl T. Lau, Edward Doo, Yoon Park, David E. Kleiner, Peter Schmid, Mary C. Kuhns, Jay H. Hoofnagle. (1999) Lamivudine for chronic delta hepatitis. Hepatology 30:2, 546-549
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Ryo Fukuda, Norihisa Ishimura, Misa Niigaki, Sachiko Hamamoto, Shuichi Satoh, Shino Tanaka, Yoshinori Kushiyama, Yasushi Uchida, Shunji Ihihara, Shuji Akagi, Makoto Watanabe, Yoshikazu Kinoshita. (1999) Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: Clinical and virological significance. Journal of Medical Virology 58:3, 201-207
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Regino P González-Peralta, George J Galasso, Thierry Poynard, Solko Schalm, Howard C Thomas, Teresa L Wright. (1999) Summary of the first international symposium on viral hepatitis. Antiviral Research 42:2, 77-96
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Jayant N Dhuley, Suresh R Naik. (1999) Moderate protective effect of 6-MFA, a microbial metabolite obtained from Aspergillus ochraceus on immunological liver injury in mice. Comparative Immunology, Microbiology and Infectious Diseases 22:1, 15-25
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Jayant N Dhuley, Suresh R Naik. (1998) Modulation of rifampicin toxicity by 6 MFA, an interferon inducer obtained from fungus Aspergillus ochraceus. Environmental Toxicology and Pharmacology 5:4, 237-243
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Elisabetta Borghesio, Floriano Rosina, Antonina Smedile, Marco Lagget, Maria Grazia Niro, Giovanni Marinucci, Mario Rizzetto. (1998) Serum immunoglobulin M antibody to hepatitis D as a surrogate marker of hepatitis D in interferon-treated patients and in patients who underwent liver transplantation. Hepatology 27:3, 873-876
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Edward De Maeyer, Jaqueline De Maeyer-Guignard. (1998) Type I Interferons. International Reviews of Immunology 17:1-4, 53-73
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P. Karayiannis. (1998) Hepatitis D virus. Reviews in Medical Virology 8:1, 13-24
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Lee, William M., . (1997) Hepatitis B Virus Infection. New England Journal of Medicine 337:24, 1733-1745
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PEI-JER CHEN, HUI-LIN WU, CHUAN-JEN WANG, JU-HSIN CHIA, DING-SHINN CHEN. (1997) Molecular biology of hepatitis D virus: Research and potential for application. Journal of Gastroenterology and Hepatology 12:9-10, S188-S192
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YUN-FAN LIAW, RONG-NAN CHIEN, SHI-MING LIN, CHAU-TING YEH, SUN-LUNG TSAI, I.-SHYAN SHEEN, CHIA-MING CHU. (1997) Response of Patients with Dual Hepatitis B Virus and C Virus Infection to Interferon Therapy. Journal of Interferon & Cytokine Research 17:8, 449-452
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Menno D. de Jong, Charles A.B. Boucher, David A. Cooper, George J. Galasso, Brian Gazzard, Joep M.A. Lange, Julio S. Montaner, Douglas D. Richman, Howard C. Thomas. (1997) Summary of the II international consensus symposium on combined antiviral therapy and implications for future therapies. Antiviral Research 35:2, 65-82
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Trong-zong Chen, Jaw-ching Wu, Lo-chun Au, Kong-bung Choo. (1997) Specific inhibition of delta antigen by in vitro system by antisense oligodeoxynucleotide: implications for translation mechanism and treatment. Journal of Virological Methods 65:2, 183-189
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STEPHANOS J HADZIYANNIS. (1997) REVIEW: Hepatitis delta. Journal of Gastroenterology and Hepatology 12:4, 289-298
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Brian J G Pereira, Andrew S Levey. (1997) Hepatitis C virus infection in dialysis and renal transplantation. Kidney International 51:4, 981-999
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Anna Linda Zignego, Rossana Fontana, Silvia Puliti, Susanna Barbagli, Monica Monti, Grazia Careccia, Francesca Giannelli, Carlo Giannini, Giampiero Buzzelli, Maurizia Rossana Brunetto, Ferruccio Bonino, Paolo Gentilini. (1997) Relevance of inapparent coinfection by hepatitis B virus in alpha interferon-treated patients with hepatitis C virus chronic hepatitis. Journal of Medical Virology 51:4, 313-318
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Wood, Alastair J.J., , Hoofnagle, Jay H., Di Bisceglie, Adrian M., . (1997) The Treatment of Chronic Viral Hepatitis. New England Journal of Medicine 336:5, 347-356
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Claudio Zavaglia, Riccardo Bottelli, Antonina Smedile, Gianmaria Iamoni, Luca Mondazzi, Aldo Airoldi, Francesco Lanzani, Gaetano Idéo. (1996) A Pilot Study of Thymosin-α1 Therapy for Chronic Hepatitis D. Journal of Clinical Gastroenterology 23:2, 162-163
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Maureen M. Jonas. (1996) Interferon-α for Viral Hepatitis. Journal of Pediatric Gastroenterology & Nutrition 23:2, 93-106
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V. Di Marco, R. Giacchino, A. Timitilli, F. Bortolotti, C. Crivellaro, R. Calzia, C. Iannuzzi, T. Prestileo, P. Vajro, G. Nebbia, C. Stringhi, F. Rosina, D. Biassoni, F. Callea, M. Rizzetto, A. Craxi. (1996) Long-term interferon-α treatment of children with chronic hepatitis delta: a multicentre study. Journal of Viral Hepatitis 3:3, 123-128
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Robert A. de Man, Renate P. Sprey, Hubert G.M. Niesters, Ruud A. Heijtink, Pieter E. Zondervan, Wim Hop, Solko W. Schalm. (1995) Survival and complications in a cohort of patients with anti-Delta positive liver disease presenting in a tertiary referral clinic. Journal of Hepatology 23:6, 662-667
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Jaw-Ching Wu, Trong-Zong Chen, Yi-Shin Huang, Fu-Shun Yen, Ling-Tan Ting, Wen-Yung Sheng, Shyh-Haw Tsay, Shou-Dong Lee. (1995) Natural history of hepatitis D viral superinfection: Significance of viremia detected by polymerase chain reaction. Gastroenterology 108:3, 796-802
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L. Dinolfo, M. L. Abate, P. Bertolo, P. Bosio, F. Rosina, A. Cavicchini, M. Rizzetto, F. Negro. (1995) Detection of hepatitis D virus RNA in serum by a reverse transcription, polymerase chain reaction-based assay. International Journal of Clinical & Laboratory Research 25:1, 35-39
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Jean-Louis Gaudin, Pascal Faure, Hubert Godinot, Françoise Gerard, Christian Trepo. (1995) The French experience of treatment of chronic type D hepatitis with a 12-month course of interferon alpha-2B. Results of a randomized controlled trial. Liver 15:1, 45-52
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Norah Terrault, S. Victor Feinman. (1995) Interferons for viral hepatitis. Transfusion Medicine Reviews 9:1, 29-52
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Teresa L. Wright, Brian Pereira. (1995) Liver transplantation for chronic viral hepatitis. Liver Transplantation and Surgery 1:1, 30-42
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Manuel Battegay, Lisa H. Simpson, Jay H. Hoofnagle, Richard Sallie, Adrian M. di Bisceglie. (1994) Elimination of hepatitis delta virus infection after loss of hepatitis B surface antigen in patients with chronic delta hepatitis. Journal of Medical Virology 44:4, 389-392
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Floriano Rosina, Raffaele Cozzolongo. (1994) Interferon in HDV infection. Antiviral Research 24:2-3, 165-174
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A. Garripoli, V. Marco, R. Cozzolongo, C. Costa, A. Smedile, A. Fabiano, F. Bonino, M. Rizzetto, G. Verme, A. Craxi, F. Rosina. (1994) Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 14:3, 154-157
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Di Bisceglie, Adrian M., . (1994) Interferon Therapy for Chronic Viral Hepatitis. New England Journal of Medicine 330:2, 137-138
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Richard A. McPherson. (1994) Laboratory diagnosis of human hepatitis viruses. Journal of Clinical Laboratory Analysis 8:6, 369-377
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David K.H. Wong, Jenny Heathcote. (1994) The role of interferon in the treatment of viral hepatitis. Pharmacology & Therapeutics 63:2, 177-186
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P. Dény, G. Fattovich, F. Le Gal, G. Giustina, C. Lecot, G. Morsica, H. Poinsot, A. Alberti, C. Bréchot. (1994) Polymerase-chain-reaction-based semi-quantification of hepatitis D viraemia in patients treated with high doses of α2b interferon. Research in Virology 145, 287-295
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