Therapy for chronic viral hepatitis

Fernando Alvarez, MD

Clin Invest Med 1996; 19 (5): 381-8.

[résumé]

From the Division of Gastroenterology­Nutrition, Hôpital Sainte-Justine, and the Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Que.

Paper reprints may be obtained from: Dr. Fernando Alvarez, Division of Gastroenterology­Nutrition, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montreal QC H3T 1C5; fax 514 345-4999; alvarezf@ERE.UMontreal.ca

Contents

Abstract

Treatment of chronic hepatitis B and C aims to achieve viral eradication. Decreasing the number of carriers subsequently reduces the transmission of the viruses. For an individual patient, therapy is aimed at preventing cirrhosis, liver failure and hepatocarcinoma. Among potential therapies, interferon alfa offers the best results. In one study involving the treatment of children from a region of intermediate endemicity, interferon alfa accelerated the clearance of hepatitis B virus (HBV) replication. In long-term follow-up, the study did not show a significant difference between patients who were treated and those who were not in the rate of disappearance of serum HBV-DNA, normalization of alanine aminotransferase (ALT) levels or seroconversion to antibodies to hepatitis B e antigen. The most important factors in predicting a rapid decrease in HBV replication were ALT levels more than twice normal, low levels of serum HBV-DNA (less than 100 pg/mL) and inflammatory activity on liver biopsy (chronic active hepatitis). A select group of children with HBV infection has thus been shown to benefit from interferon alfa therapy. Treatment should be administered in a dosage of 6 MU/m2 three times each week for 6 months. Chronic active hepatitis develops in approximately 30% of children with a chronic hepatitis C virus (HCV) infection. Cirrhosis due to HCV appears to be a very rare complication among children. Results of interferon alfa treatment for children with HCV are scarce. A pilot study of 12 children treated with interferon alfa in a dosage of 3 MU/m2 three times each week for 6 months showed that ALT levels normalized in approximately 90% of the patients after 15 months of follow-up. All of the patients had a decrease in the histological activity of the disease. Factors predictive of a favourable response in adults were: low levels of gamma-glutamyl transferase, young age, female sex, short duration of disease, absence of cirrhosis and low histological activity of the disease. Controlled randomized studies are needed to determine the indications for interferon alfa therapy in children infected with HCV. Available data suggest that children may have a better response than adults.

Résumé

Le traitement de l'hépatite B et C chronique a pour but l'éradication virale. La diminution du nombre de porteurs conduit à la diminution de la transmission virale. Chez un sujet donné, le traitement a pour but de prévenir la cirrhose, l'insuffisance hépatique et le cancer hépato-cellulaire. Parmi les traitements potentiels, l'interféron alpha offre les meilleurs résultats. Dans une étude chez des enfants dans une région endémique intermédiaire, le traitement avec l'interféron alpha accéléra la clairance de la réplication du virus de l'hépatite B (VHB). À long terme, cette étude n'a pas démontré de différence significative entre les sujets traités et non-traités quant au taux de disparition sérique de l'ADN viral, la normalisation de l'alanine aminotransférase (ALT) ou la séroconversion des anticorps contre l'antigène E de l'hépatite B. Les meilleurs facteurs prédictifs d'une diminution rapide de la réplication du VHB étaient un niveau d'ALT plus de deux fois supérieur à la normale avec un faible niveau sérique d'ADN viral (moins de 100 pg/mL) et l'activité inflammatoire à la biopsie hépatique (hépatite chronique active). Certains enfants avec une infection au VHB ont donc répondu au traitement à l'interféron alpha. Ce traitement doit être administré à la dose de 6 MU/m2 trois fois par semaine durant 6 mois. L'hépatite chronique active survient chez 30 % des enfants avec une infection au virus de l'hépatite chronique C (VHC). La cirrhose due au VHC semble très rare chez les enfants. Il y a peu de données quant au résultat du traitement à l'interféron alpha chez les enfants infectés au VHC. Une étude pilote portant sur 12 enfants traités avec interféron alpha à la dose de 3 MU/m2 trois fois par semaine pour 6 mois a démontré que le niveau de l'ALT est normalisé chez 90 % des sujets 15 mois après le début du traitement. Une diminution de l'activité histologique de la maladie a été observée chez tous les sujets. Chez les adultes, les facteurs prédictifs d'une bonne réponse thérapeutique sont les suivants : bas niveau de gamma-glutamyl transférase, sujets plus jeunes et de sexe féminin, courte durée de la maladie, absence de cirrhose, et faible activité histologique de la maladie. Il est nécessaire de procéder à des études randomisées afin d'établir les indications de traitement avec l'interféron alpha chez les enfants infectés au VHC. D'après les données courantes, les enfants pourraient avoir une meilleure réponse thérapeutique que les adultes.

[Table of contents]

Introduction

Chronic viral hepatitis is a necroinflammatory liver disorder that may progress for years without the patient having any evident symptoms. Two viruses are currently detected in patients with chronic liver infection: hepatitis B virus (HBV) and hepatitis C virus (HCV). Hepatitis delta virus is a defective virus that may coinfect patients with an HBV infection.

HBV infection is endemic in East Asia and Africa and is of intermediate endemicity in the Mediterranean area, Eastern Europe and some areas of Central and South America. Recently, it has become more common to see patients with an HBV infection in some Western countries, in large part as a result of the adoption of children from the Far East and Eastern Europe.

HCV infection in children can be acquired through blood transfusion or, less frequently, through the community. Although HCV may also be acquired through vertical transmission, such transmission is infrequent among mothers who do not have an HIV infection. In our milieu, most children have been infected through blood transfusions or blood products administered in the course of cancer treatment, surgery or treatment of coagulopathies or other hematologic disorders.

Long-term complications of chronic viral infections are cirrhosis, with or without hepatic failure, and hepatocellular carcinoma. These complications are very rare in children with an HBV or HCV infection. However, it seems reasonable to suggest that eradication of the infection during childhood could prevent further complications during adulthood.

[Table of contents]

Natural history

An understanding of the spontaneous, long-term outcome is useful in the design of treatment protocols as well as the interpretation of their potential results.

Chronic hepatitis B

Bortolotti and associates[1] published results of a longitudinal study involving 76 patients who acquired HBV infection during childhood. Children with biopsy-proven chronic hepatitis who also had positive results of serum tests for HBV-DNA and hepatitis B e antigen (HBeAg) were followed for 1 to 12 years (mean 5 years). Seventy percent of this group seroconverted to antibody to HBeAg (anti-HBe) and had a negative result of a test for HBV-DNA. In these cases, modification of the circulating viral markers was associated with normalization of serum transaminase activity. Hepatitis B surface antigen (HBsAg) was cleared in 6.6% of children. The seroconversion rate to anti-HBe was 12% per year and to antibody to HBsAg (anti-HBs) 1.9% per year. In this series, the only significant predictive factor for spontaneous seroconversion was the presence of IgM to antibody to hepatitis B core antigen (anti-HBc). To interpret these results adequately, we should consider that they were derived in a population in northern Italy, a region of intermediate endemicity. Thus, only 10% percent of the children were infected through vertical transmission. Most children with this infection lose circulating HBV-DNA and HBeAg before adulthood, although in some the virus may subsequently be reactivated several years after anti-HBe seroconversion. Whether this reversion of HBV-replication status is due to replication of HBV mutant forms that escape from immune control or to factors that modify the immune response itself is still a matter of speculation.

A similar study[2] was carried out in Taiwan, in an area where HBV infection is highly endemic and vertical transmission is the most common mode of infection. In this study, 420 children were followed for 1 to 12 years (mean 4.7 years). The rate of seroconversion to anti-HBe was 6% per year. The rate of seroconversion to anti-HBs was 1.7% each year in the patients who had a positive test result for anti-HBe at the beginning of the study. The rate of seroconversion to anti-HBe was half that observed in the study in northern Italy. However, once a child in Taiwan had a negative result for HBeAg, his or her probability of converting to anti-HBs was the same as that for a child in Italy. In addition, in the study from Taiwan, high levels of transaminase activity (twice the normal values) predicted seroconversion to anti-HBs.

Long-term complications of HBV infection -- including hepatocellular carcinoma, cirrhosis and hepatic failure -- are very rare in children. Most studies of the natural outcome of HBV infection in adults have been carried out in regions of the world with high endemicity. Recently, Villeneuve and associates[3] carried out a prospective study of 317 asymptomatic carriers with positive test results for HBsAg in the Montreal area, a region of low endemicity. The mean length of follow-up of these patients was 16.2 years. More than half of the patients were infected during infancy. The annual rate of loss of HBsAg in this group was only 0.7%. Only three carriers (aged 53, 56 and 68) died of cirrhosis related to HBV infection, and none had hepatocellular carcinoma during the follow-up period. A previous study by researchers in northern Italy involving asymptomatic carriers showed similar results after a follow-up of more than 10 years.[4]

Chronic hepatitis C

In an international longitudinal study, 77 children with chronic HCV infection were evaluated.[5] In 15.5% of the patients, their mothers were found to have antibody to HCV, indicating probable vertical transmission; in 60%, blood transfusions were the probable cause; 9% had other potential percutaneous exposure; and in 15.5%, no source of infection was evident. During the 6-year follow-up period, 19% of the children complained of symptoms and 27% of those who underwent a liver biopsy had histologic signs of disease activity. However, only two patients had chronic active hepatitis and cirrhosis. In one of them, liver­kidney microsome type 1 (LKM1) antibodies were found. None of the children had liver failure during the observation period. Sustained remission, as established by normalization of serum transaminase activity, was observed in 10% of the patients. There were no differences between children with an HCV infection acquired through transfusion and those with community-acquired infection. However, one fact to be considered in future treatment protocols is that the disease appeared to be more aggressive in children with cancer or aplastic anemia.

Spontaneous, long-term outcome of HCV infection in adulthood is still a controversial issue. Seeff and associates[6] studied a large group of patients (568 adults) with transfusion-related non-A, non-B hepatitis for a mean follow-up period of 18 years. When these patients were compared with a population without infection, no increased mortality from any cause was found. However, a small but significantly higher number of deaths in the patient group were related to liver disease. Since the mean age of the patients in this study was 49.1 years (mean 49.1 years, standard deviation 12.6 years), results should be interpreted cautiously and should not be extrapolated to patients infected during childhood. In contradiction to this study, a study by Kiyosawa and associates[7] showed that symptoms of chronic liver disease became evident after a mean of 13.6 years of infection. Cirrhosis appeared after a mean of 17.8 years of follow-up, and hepatocellular carcinoma was seen after a mean of 23.4 years. Among patients with an HCV infection, hepatocellular carcinoma is uncommon (7.7% of cases) in livers without cirrhosis, whereas, among patients with HBV infection, carcinoma develops in 40% of livers without cirrhosis.

Chronic delta hepatitis

This is a defective hepatotropic virus that requires the helper functions of HBV. In children, delta virus infection can cause severe liver disease. In a prospective study in a region with a high prevalence of HBV­delta-virus coinfection, 23 children aged 3 to 15 years with coinfection were followed for 5 to 12 years.[8] Active hepatitis and cirrhosis were observed frequently (in 26% of these children). Most patients remained stable during the follow-up period. Despite the histologic aggressiveness of the disease, 74% of these children had serum anti-HBe at the first observation, and 91% had serum anti-HBe at the last observation. One may thus deduce that the aggressiveness of the disease depends more on the replication of delta virus than of HBV.

[Table of contents]

Therapy for chronic viral hepatitis

Treatment of chronic viral hepatitis B or C is aimed at eradicating the relevant virus. Decreasing the number of chronic carriers subsequently reduces the possibility of transmission of these viruses. For an individual patient, therapy is aimed at preventing progression to cirrhosis, liver failure and hepatocellular carcinoma.

Interferon

Interferon alfa is the most effective therapy currently available for chronic viral hepatitis. Interferons are produced rapidly by the body as a defence against viral infections. The use of exogenous interferon in patients with a chronic HBV infection is based on the decreased production of alpha-interferon in their livers,[9­11] and the observation that lymphocytes in these patients appear to be poor producers of alpha-interferon.[11]

Interferons exert their antiviral activities by inhibiting intracellular viral replication and especially by stimulating the immune response against infected cells.[11] They inhibit viral replication by inducing the expression of intracellular antiviral proteins, such as: (1) 2'-5' oligoadenylate synthetase, which indirectly breaks down viral single-stranded RNA; (2) double-stranded, RNA-dependent protein kinase, which inhibits the formation of the 40s initiation complex; and (3) Mx protein, which blocks viral replication in the cell nucleus. Stimulation of the immune response is the result of: (1) induction of the production of other cytokines; (2) expression of major histocompatibility complexes at the cell surface; (3) expression of Fc receptors; (4) an increase in natural-killer-cell activity; and (5) an increase in B lymphocyte function.[11]

The use of corticosteroids diminishes the immunological response and consequently increases viral replication and the expression of viral antigenic peptides at the surface of infected cells. Once this treatment is withdrawn, the elimination of infected cells should be facilitated, producing what has been called an "immunological rebound," which is magnified by the administration of interferon alfa.

Immunotherapy

HBV vaccination is expected to induce an anti-HBs response in patients with an infection, facilitating the elimination of the HBV. A recent pilot study found that a regular vaccination schedule induced a decrease in serum levels of HBV-DNA in a group of adults with HBV infection.[12]

Other antiviral therapies

Many other antiviral agents have been used to decrease viral replication in chronic viral hepatitis, but these have not significantly modified the long-term outcome. Some of these agents could be useful, when administered along with interferon alfa, in preventing the replication of mutant forms of hepatitis viruses. Studies of alternative antiviral agents may have particular interest for patients who also have an HIV infection or who have received transplants.

[Table of contents]

Interferon alfa therapy for chronic hepatitis B

In a prospective randomized controlled trial, Ruiz-Moreno and associates[13] evaluated the efficacy of interferon alfa in 36 children who had a positive test result for serum HBV-DNA and an increased serum level of alanine aminotransferase (ALT). Treatment consisted of either 5 or 10 MU/m2 of interferon alfa three times a week for 6 months. Approximately 50% of those treated lost serum HBV-DNA. This sign of reduction of liver HBV replication was associated with seroconversion to anti-HBe, improvement in histological activity and normalization of ALT levels. The dose of interferon alfa did not have a significant influence on the response to treatment. Only 17% of untreated children in the control group spontaneously seroconverted to anti-HBe during the observation period.

Recently, Barbera and associates[14] published a similar prospective controlled trial of interferon alfa treatment involving a larger group of 77 children, all of whom had positive results of tests for HBeAg. The treatment consisted of 3 or 7.5 MU/m2 of interferon alfa three times each week for 6 months. After treatment was completed, 24% of the patients in the group receiving 7.5 MU/m2 had seroconverted to anti-HBe, but only 5% in the group receiving 3 MU/m2 and only 3% in the control (untreated) group had done so. The differences between the treatment groups were statistically significant. However, when the follow-up was continued for 18 months, these differences disappeared. The authors concluded that interferon alfa treatment hastened the seroconversion to anti-HBe, although seroconversion occurred spontaneously later on, anyway. This study identified characteristics of children who were more likely to seroconvert either with treatment or spontaneously: (1) ALT activity levels of more than twice normal values; (2) serum levels of HBV-DNA of less than 100 pg/mL; and (3) high titres of anti-HBc of IgM type. (See also Table 1.)

Differences in the results between these two protocols may be explained by the way children were selected for study. In the study by Ruiz-Moreno and associates, treated and untreated children showed elevated levels of ALT before therapy. Barbera and associates considered such levels as a favourable prognostic indicator of seroconversion to anti-HBe, but they did not use these levels as selection criteria for patients in their study.

Utili and associates[15] evaluated the modification of response to interferon alfa (given in a dosage of 3 MU/m2 three times a week for 12 months) as a result of prior treatment with prednisone (0.3 to 0.6 mg/kg per day for 1 month). Results of this trial showed that the final rate of seroconversion to anti-HBe was not influenced by previous steroid treatment. Low viral replication levels (less than 100 pg/mL of HBV-DNA in serum) before any treatment predicted a favourable response, with disappearence of HBe-Ag from the serum of 75% of patients with low levels. It could be speculated that a group of children with low replication levels would really benefit from a prior prednisone or 12-month interferon alfa treatment, since the rate of seroconversion in children with low levels of viral replication in this study was higher than rates in previously reported studies. An international randomized controlled trial is now being carried out. Criteria for children entering this study include positive results of tests for serum HBV-DNA and HBeAg as well as ALT activity levels higher than twice normal.

No irreversible adverse effects and few serious ones have been described among children given interferon alfa at the doses used in the series described above. In most cases, a transient influenza-like syndrome was reported. Abdominal pain, headache, transient hair loss, mild depression and moderate leukocytopenia or thrombocytopenia were also noted.[13,15] Only one case of severe thrombocytopenia, requiring treatment with prednisone and gamma-globulins was described by Barbera and associates.[14] In most children in whom serum HBV-DNA disappears and HBe seroconversion occurs, whether spontaneously or with interferon alfa treatment, an increase of ALT activity levels typically precedes the modification of the HBV markers (Fig. 1).

Unresolved problems

Children who have acquired an HBV infection through vertical transmission commonly show high levels of liver HBV replication and serum HBV-DNA, often associated with normal ALT levels. Such patients have low rates of spontaneous seroconversion or response to interferon alfa treatment. New forms of treatment are needed for such cases, as well as for other nonresponders to interferon alfa.

Clearance of HBsAg obviously leads to an improvement in the prognosis for the liver disease. However, it is not clearly established that the disappearence of signs of viral expression in the liver means that hepatocellular carcinoma is prevented. HBV behaves like a retrovirus, integrating into the host's genomic DNA and thus potentially leading to cancer. Integrated HBV-DNA has been found in the livers of children suffering an acute or chronic B infection.[16] The presence in the liver of integrated HBV-DNA is therefore independent of the patient's serologic status for HBsAg or anti-HBs.[16] Thus, depending on on the location of integrated HBV-DNA, the risk of hepatocellular carcinoma does not disappear once HBV replication has stopped.

[Table of contents]

Interferon alfa therapy for chronic hepatitis C

Few reports are available on the efficacy of interferon alfa treatment in children with chronic hepatitis C. A pilot trial was carried out by Ruiz-Moreno and associates[17] involving 12 children with non-A, non-B chronic hepatitis who were treated with 3 MU/m2 of interferon alfa three times a week for 6 months and were followed-up for 24 months. One of these children was dropped from the study because of a 16-fold increase in ALT levels and the appearance of LKM1 antibodies 4 months after beginning the treatment. At the end of the follow-up period, 45% of the children had normal levels of ALT, and all of them showed a decrease in histological activity on liver biopsy.

A larger randomized controlled trial of interferon alfa treatment in children with chronic hepatitis C is clearly needed. Some points should be considered in the design of such a study and the evaluation of the results. First, on the basis of a recent study of children with thalassemia and chronic HCV infection,[18] the hepatic iron concentration should be measured before beginning treatment. Second, patients with chronic hepatitis C and cancer in remission have more aggressive liver disease[19] and generally do not respond favourably to interferon alfa.[20] These two characteristics are relevant in a pediatric population, considering that almost half of our patients (at least in the Western world) have been infected with HCV as a result of multiple transfusions with blood products during the treatment of cancer or chronic hematological disorders (mainly hemophilia or chronic hemolytic anemia). On the basis of interferon alfa treatment of adults with an HCV infection, several factors that are likely to predict a good response must be considered (Table 2), such as: (1) short duration of the disease;[21] (2) young age at the time of treatment;[22] (3) absence of cirrhosis;[21,22] (4) low levels of gamma-glutamyl transferase;[22] (5) low serum levels of HCV-RNA;[23,24] and (6) HCV genotype 2.[25­27]

Unresolved problems

Several problems have been identified in adults treated with interferon alfa, among which are: (1) a high rate of relapse; (2) relapse during treatment; and (3) difficulties in defining the response to treatment. Normalization of ALT activity levels was the marker used in most studies to establish the response to interferon alfa treatment. However, this biochemical response does not necessarily mean that the virus has been eradicated. Replication of HCV in the liver and persistence of inflammatory changes have been reported in patients with sustained normalization of ALT levels.[28,29] In addition, replication of HCV at extrahepatic sites, mainly peripheral blood mononuclear cells, appears to be an important factor in resistance to interferon alfa.[30] In 30% of patients who have a relapse after therapy, a second course of interferon alfa appears to be effective.[31]

In patients with positive results of tests for LKM1 and HCV, interferon alfa treatment can have adverse effects; in particular, it can aggravate the liver disease.[32] Some researchers have proposed to treat these patients with immunosuppressive therapy.[33] In other cases, despite the presence of LKM1 autoantibodies, interferon alfa produced a sustained normalization of ALT levels. It has been speculated that the specificity of LKM1 antibodies may predict the response to either treatment.[34] Although this area is still controversial, all children with chronic hepatitis C should be systematically tested for LKM1 antibodies in their serum before the beginning of interferon alfa treatment. Close follow-up should be ensured during the treatment of patients who have both LKM1 antibodies and an HCV infection.

[Table of contents]

Interferon alfa therapy for chronic hepatitis delta

Very few controlled trials evaluating the response to interferon alfa in chronic delta virus infection in adult patients are available.[35] Only anecdotal cases have been published in the pediatric literature to date.[36] In adult patients, treatment of delta virus needs to be longer than that of HBV or HCV. Sustained response (persistent normalization of ALT levels) is rare, occurring in patients in whom HBsAg is cleared from serum.[35]

[Table of contents]

Conclusions

Interferon alfa treatment for chronic HBV infection in children accelerates seroconversion from HBcAg to anti-HBc. This phenomenon is associated with a decrease in HBV replication in the liver and in ALT activity levels. The treatment appears to be well tolerated in children. Nevertheless, since interferon alfa therapy is lengthy and costly and requires administration by subcutaneous injection, studies of the cost-effectiveness of this therapy in children with chronic hepatitis B are still needed.

There has been very limited experience with the treatment of chronic hepatitis C with interferon alfa in children. Although most of our knowledge of factors predicting a good response to treatment have been derived from adult populations, their analysis allows us to be optimistic about the treatment of children with an HCV infection. Since cirrhosis is infrequent in chronic hepatitis C among children, a higher rate of response may be expected among children. Properly conducted studies of the influence of viral load and previous cancer on the response to therapy must be conducted to establish which patients benefit most from interferon alfa therapy. Autoimmunity and chronic hepatitis C infection is also another area of controversy, which is propitious for original and exciting research.

Acknowledgements

The publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. I also thank Hoffmann­La Roche (Canada) for its sponsorship of the invited speakers' program.

[Table of contents]

References

  1. Bortolotti F, Cadrobbi P, Crivellaro C, et al. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood. Gastroenterology 1990; 99: 805-10.
  2. Hsu HY, Chang MH, Lee CY, Chen JS, Hsu HC, Chen DS. Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology 1992; 15: 382-6.
  3. Villeneuve JP, Desrochers M, Infante-Rivard C, et al. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal. Gastroenterology 1994; 106: 1000-5.
  4. De Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993; 118: 191-4.
  5. Bortolotti F, Jara P, Diaz C, et al. Posttransfusion and community-acquired hepatitis C in childhood. J Pediatr Gastroenterol Nutr 1994; 18: 279-83.
  6. Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med 1992; 327: 1906-11.
  7. Kiyosawa K, Akahame Y, Nagata A, et al. Significance of blood transfusion in non-A, non-B chronic liver disease in Japan. Vox Sanguinis 1982; 43: 45-52.
  8. Bortolotti F, Di Marco V, Vajro P, et al. Long-term evolution of chronic delta hepatitis in children. J Pediatr 1993; 122: 736-8.
  9. Tolentino P, Dianzani F, Zucca M, Giacchino R. Decreased interferon response by lymphocytes from children with chronic hepatitis. J Infect Dis 1975; 132: 459-63.
  10. Ikeda T, Lever AML, Thomas HC. Evidence for a deficiency of interferon production in patients with chronic hepatitis B virus infection acquired in adult life. Hepatology 1986; 6: 962-5.
  11. Dianzani F, Antonelli G, Capobianchi MR. The biological basis for clinical use of interferon. J Hepatol 1990; 11: S5-10.
  12. Pol S, Driss F, Carnot F, Michel ML, Berthelot P, Brechot C. Efficacité d'une immunothérapie par vaccination contre le virus de l'hépatite B sur la multiplication virale B. Life Sci 1993; 316: 688-91.
  13. Ruiz-Moreno M, Rua MJ, Molina J, et al. Prospective, randomized controlled trial of interferon-a in children with chronic hepatitis B. Hepatology 1991; 13: 1035-9.
  14. Barbera C, Bortolotti F, Crivellaro C, et al. Recombinant interferon-alpha hastens the rate of HBeAg clearance in children with chronic hepatitis B. Hepatology 1994; 20: 287-90.
  15. Utili R, Sagnelli E, Gaeta GB, et al. Treatment of chronic hepatitis B in children with prednisone followed by alfa-interferon: a controlled randomized study. J Hepatol 1994; 20: 163-7.
  16. Scotto J, Hadchouel M, Hery C, et al. Hepatitis B virus DNA in children's liver diseases: detection by blot hybridisation in liver and serum. Gut 1983; 24: 618-24.
  17. Ruiz-Moreno M, Rua MJ, Castillo I, et al. Treatment of children with chronic hepatitis C with recombinant interferon-alpha: a pilot study. Hepatology 1992; 16: 882-5.
  18. Clemente MG, Congia M, Lai ME, et al. Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 1994; 125: 123-8.
  19. Inui A, Fujisawa T, Miyagawa Y, et al. Histologic activity of the liver in children with transfusion-associated chronic hepatitis C. J Hepatol 1994; 21: 748-53.
  20. Fujisawa T, Ohkawa T, Inui A, Yokota S. Effect of interferon therapy on serum hepatitis C virus RNA levels in children with chronic hepatitis C. Int Hepatol Commun 1994; 2: 316-20.
  21. Tiné F, Magrin S, Craxi A, Pagliaro L. Interferon for non-A, non-B chronic hepatitis. A meta-analysis of randomized cinical trials. J Hepatol 1991; 13: 192-9.
  22. Camps J, Crisostomo S, Garcia-Granero M, Riezu-Boj JI, Civeira MP, Prieto J. Prediction of the response of chronic hepatitis C to interferon alfa: a statistical analysis of pretreatment variables. Gut 1993; 34: 1714-7.
  23. Lau JYN, Davis GL, Kniffen J, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 1993; 341: 1501-4.
  24. Hagiwara H, Hayashi N, Mita E, et al. Quantitative analysis of hepatitis C virus RNA in serum during interferon alfa therapy. Gastroenterology 1993; 104: 877-83.
  25. Tsubota A, Chayama K, Ikeda K, et al. Factors predictive of response to interferon-alpha therapy in hepatitis C virus infection. Hepatology 1994; 19: 1088-94.
  26. Orito E, Mizokami M, Mizoguchi N, et al. Hepatitis C virus serotype II responds more favorably to interferon-alpha therapy. J Hepatol 1994; 21: 130-2.
  27. Kanazawa Y, Hayashi N, Mita E, et al. Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients. Hepatology 1994; 20: 1121-30.
  28. Kakumu S, Yoshika K, Tanaka K, et al. Long-term carriage of hepatitis C virus with normal aminotransferase after interferon treatment in patients with chronic hepatitis C. J Med Virol 1993; 41: 65-70.
  29. Johnson Y, Lau N, Mizokami M, et al. Serum ALT: tarnished gold standard for interferon response in hepatitis C virus infection. Lancet 1993; 342: 1208-9.
  30. Saleh MG, Tibbs CJ, Koskinas J, et al. Hepatic and extrahepatic hepatitis C virus replication in relation to response to interferon therapy. Hepatology 1994; 20: 1399-1404.
  31. Marcellin P, Boyer N, Routeau M, Benhamou JP, Erlinger S. Retreatment with interferon-alpha of chronic hepatitis C virus infection. Lancet 1994; 344: 690-1.
  32. Muratori L, Lenzi M, Cataleta M, et al. Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C. J Hepatol 1994; 21: 199-203.
  33. Bellary S, Schiano T, Hartman G, Black M. Chronic hepatitis with combined features of autoimmune chronic hepatitis and chronic hepatitis C: favorable response to prednisone and azathioprine. Ann Intern Med 1995; 123: 32-4.
  34. Yamamoto AM, Cresteil D, Homberg JC, Alvarez F. Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera. Gastroenterology 1993; 104: 1762-7.
  35. Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994; 330: 88-94.
  36. Kay MH, Wyllie R, Deimler C, Caulfield M, Steffen R, Baetz-Greenwalt B. Alpha interferon therapy in children with chronic active hepatitis B and delta virus infection. J Pediatr 1993; 123: 1001-4.

[Table of contents]

| CIM: October 1996 / MCE: octobre 1996
CMA Webspinners / >