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Keywords:

  • thalassaemia;
  • hepatitis C;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Summary.  Hepatitis C virus (HCV) infection is common in transfusion-dependent thalassaemia. The clinical usefulness of 12-month treatment, using interferon alpha 3 MIU/m2 thrice weekly and oral ribavirin 16 mg/kg/d, was evaluated in 18 previously untreated thalassaemia patients. The median age at start of treatment was 16 years (range 7–29). Fourteen were infected with genotype 1b and 4 with genotype 6a. The sustained biochemical and virological response rates 6 months after stopping treatment were both 72·2%. Blood consumption was temporarily increased by 30% due to ribavirin-associated haemolysis. This study demonstrated a high, sustained response rate to combination treatment despite infection with genotype 1b.

Thalassaemia major (TM) is the commonest transfusion-dependent anaemia in the southern Chinese population. Transfusion-transmitted chronic hepatitis C virus (HCV) infection was common before the implementation of screening of blood products. A combination of interferon and ribavirin has been shown to be superior to interferon monotherapy as frontline treatment in non-thalassaemia patients (Poynard et al, 1998). However data on combination treatment in TM patients are limited and most reports have been based on interferon monotherapy. About 40% of TM patients responded to interferon monotherapy (Donohue et al, 1993; Di Marco et al, 1997). The 1999 Consensus Statement of the European Association for the Study of the Liver (EASL) listed anaemia as ‘an absolute contraindication to ribavirin’ in hepatitis C (EASL, 1999). Only a few TM patients have been treated with combination treatment and these patients had failed initial monotherapy (Telfer et al, 1997). This study aimed to investigate the efficacy and complications of combination treatment in a group of Chinese TM patients who were naïve to HCV treatment.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This was a multicentre study involving three regional hospitals in Hong Kong. The patients were managed with regular blood transfusion and desferrioxamine. The inclusion criteria were that the patients were HCV antibody and HCV RNA positive, and had persistent elevation of serum alanine aminotransferase (ALT) levels for at least 6 months before treatment. Liver biopsy was performed for liver iron content and hepatitis activity before the start of treatment. Virological investigations were performed centrally. Serum HCV RNA was detected by reverse transcription–polymerase chain reaction (RT–PCR) using nested primers 209, 211, 939 and 940 targeting the 5′ non-coding region, as previously described (Chan et al, 1992). The analytical sensitivity of the RT–PCR was determined by testing standards with known levels of HCV RNA (HCV RNA Quantification Panel QHW702, Boston Biomedica, MA, USA). The RT–PCR produced a consistently lower detection limit of 100 copies/ml. The HCV genotypes were identified by PCR with combinations of genotype-specific primers, targeting the core region as previously described. (Ohno et al, 1997)

Treatment and monitoring.  Patients were treated with a combination of interferon and ribavirin for 12 months. Interferon alpha (Intron A; Schering Plough, Kenilworth, NJ, USA) was given at 3 MIU/m2 subcutaneously three times per week. Ribavirin (Rebetol; Schering Plough) was given orally at 16 mg/kg/d in two divided doses. Dosage adjustment was allowed for interferon if the patient developed leucopenia or thrombocytopenia. Ribavirin dosage was not adjusted as these patients were all transfusion-dependent. Biochemical monitoring included monthly ALT testing and serum ferritin measurement at 3 monthly intervals. The virological response was assessed by serum HCV RNA detection at 3 monthly intervals during treatment and for at least 6 months after completion of treatment. Sustained virological response was defined as disappearance of HCV RNA at 6 months after completion of treatment. Sustained biochemical response was defined as normalization of ALT for 6 months after completion of treatment.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Eighteen HCV infected patients fulfilled the inclusion criteria and consented to treatment. The patients were diagnosed with TM at a median age of 12 months. At the time of antiviral treatment, the median age was 16 years (range 7–29). There were 10 men and eight women. Fourteen had genotype 1b while the others had genotype 6a. The median serum ferritin level before treatment was 2142 µg/l (range 980–7157), and the liver iron content was 5·4 mg/g dry weight (range 2–41·8). The median dose of interferon administered was 3 MIU/m2 (range 2·7–3·4) and median dose of ribavirin was 17·3 mg/kg (range 13·5–21·3). Three patients required transient reduction of interferon dose for 1 month because of mild neutropenia (neutrophils 1–1·1 × 109/l). All patients completed the 12 month treatment.

Sustained biochemical response was achieved in 13 patients (72·2%). The biochemical response was usually observed at 1 month after starting treatment. Serum HCV RNA became undetectable in 12 patients at 3 months, and two more patients had disappearance of HCV RNA by 6 months. However, two initially RNA negative patients had reappearance of viral RNA at 12 months, and one patient had a late response by 12 months. Thus, there were 13 responders at the end of treatment, and they all remained RNA negative without recurrence at 6 months after stopping treatment. The sustained virological response rate was 72·2%. (Table I)

Table I.  Response to ribavirin and interferon in HCV patients.
PatientAge (years)GenotypePre-treatment ferritin (µg/l)Pre-treatment liver iron (mg/g)Biochemical ResponseHCV RNABlood Consumption Increase Liver iron at end of treatment (mg/g)
3 months6 months12 months6 months post*
  • *

    6 months after stopping treatment.

  • These patients had a splenectomy during the same year of treatment.

 1 8·31b1498 8·7No+++ 39% 
 2 9·51b387341·8Yes  0% 
 319·21b613921·6No++++ 32% 
 415·01b715715·2No++++ 26% 
 513·41b4678 4·2Yes130%11·7
 621·91b4675 4·5Yes+152% 9·6
 716·71b1311 9·8Yes 36%12·1
 828·81b5601 5·3Yes140% 3·5
 918·71b2142Yes  8% 7·2
1016·21b 981 2Yes 55% 8·1
1110·01b2003 2Yes 33% 
12 7·21b1895 5·4Yes 38% 
1319·71b1150 2·5No++++ 15% 
1410·51b2748 3·5Yes−30% 
15246b5197 9·2Yes 88% 
1621·46a799727·4Yes++ 30% 
1724·46a3502 6·1Yes 48% 
1821·26a2430 4·2No++ 31% 

Serum ferritin declined or remained static in the sustained responders. The non-responders had markedly increased serum ferritin levels at the end of treatment. Side-effects of fever, chills, anorexia and malaise were common but usually transient. The median reduction in body weight was 6% (range 2–16%) during treatment. The most significant complication was ribavirin-associated haemolysis. The patients required more frequent transfusions to maintain a pretransfusion haemoglobin level of around 9·5 g/dl. Compared with the transfusion requirement during the 2 years prior to treatment, the annual blood consumption during treatment increased by a median of 30%, ranging from 8% to 152%. After stopping treatment, blood consumption returned to the pretreatment level.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

HCV infection is common in transfusion-dependent TM patients. The prevalence of HCV infection was reported to be 60% in Italian patients (Lai et al, 1993). The prevalence of HCV infection in Hong Kong TM was 16·3% (unpublished data). Since the screening of blood products for HCV began in the early 1990s, there have been no new cases detected. Combination treatment of interferon and ribavirin is now the standard treatment for non-thalassaemic HCV-infected adults. Interferon monotherapy has been reported to achieve a virological response rate of 40% in TM patients, following 6–18 months of treatment (Donohue et al, 1993; Di Marco et al, 1997). In TM patients who failed interferon treatment or relapsed after interferon, combination treatment could achieve sustained virological response in about 40% (Telfer et al, 1997). However, there has been no report on the use of combination treatment in previously untreated TM patients. Whether combination treatment should be used as frontline treatment, with complications such as haemolysis due to ribavirin, has to be considered. This study demonstrated that there was 30% increase of blood consumption during treatment. The patients are thus at risk of a further increase in iron overload during treatment. The patients should be instructed to intensify desferrioxamine chelation during treatment. In the responders, there was a decline of serum ferritin levels but that might just reflect a decrease in hepatitis activity.

The overall sustained response rate in this cohort of patients is high. Genotype is an important prognostic factor for response and genotype 1b is associated with poorer response (Bell et al, 1997). In this study, patients with genotype 1b had good sustained response to treatment, with a 71·4% response rate. The high response rate may be a result of the relatively young age of this cohort, and the liver disease was also less advanced. Iron overload is another factor that may adversely affect the response of TM patients to interferon (Clemente et al, 1994). The iron overload was mild to moderate in most of our patients and this might also account for a higher response rate. For patients who fail combination treatment, the newer agents with a longer half-life, such as pegylated interferon, may be considered (Zeuzem et al, 2000).

In conclusion, combination treatment with interferon and ribavirin achieved a high, sustained response rate in previously untreated TM patients, despite the unfavourable genotypes of most patients. Young TM patients infected with hepatitis C deserve early treatment as the toxicity from the combination treatment is low.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We thank Dr Ching Yin Lee and Anselm Lee for referring patients to the study, and Professor Christopher Lam for performing the liver iron content assay.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • Bell, H., Hellum, K., Harthug, S., Maeland, A., Ritland, S., Myrvang, B., Von Der Lippe, B., Raknerud, N., Skaug, K., Gutigard, B.G., Skjaerven, R., Prescott, L.E., Simmonds, P. & Group, C. (1997) Genotype, viral load and age as independent predictors of treatment outcome of interferon-α2a treatment in patients with chronic hepatitis C. Scandinavian Journal of Infectious Disease, 29, 1722.
  • Chan, S.W., McOmish, F., Holmes, E.C., Dow, B., Peutherer, J.E., Follett, E., Yap, P.L. & Simmonds, P. (1992) Analysis of a new hepatitis C virus type and its phylogenetic relationship to existing variants. Journal of General Virology, 73, 11311141.
  • Clemente, M.G., Congia, M., Lai, M.E., Lilliu, F., Lampis, R., Frau, F., Frau, M.R., Faa, G., Diana, G., Dessi, C., Melis, A., Mazzoleni, A.P., Cornacchia, G., Cao, A. & De Virgiliis, S. (1994) Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. Journal of Pediatrics, 125, 123128.
  • Di Marco, V., Lo lacono, O., Almasio, P., Ciaccio, C., Capra, M., Rizzo, M., Malizia, R., Maggio, A., Fabiano, C., Barbaria, F. & Craxi, A. (1997) Long-term efficacy of α-Interferon in β-thalassaemia with chronic hepatitis C. Blood, 90, 22072212.
  • Donohue, S.M., Wonke, B., Hoffbrand, A.V., Reittie, J., Ganeshaguru, K., Scheuer, P.J., Brown, D. & Dusheiko, G. (1993) Alpha interferon in the treatment of chronic hepatitis C infection in thalassaemia major. British Journal of Haematology, 83, 491497.
  • EASL International Consensus Conference on Hepatitis C (1999) Consensus Statement. Journal of Hepatology, 30, 956961.
  • Lai, M.E., De Virgilis, S., Argiolu, F., Farci, P., Mazzoleni, A.P., Lisci, V., Rapicetta, M., Clemente, M.G., Nurchis, P., Arnone, M., Balestrieri, A. & Cao, A. (1993) Evaluation of antibodies to hepatitis C virus in a long-term prospective study of posttransfusion hepatitis among thalassemic children: comparison between first- and second-generation assay. Journal of Pediatric Gastroenterology and Nutrition, 16, 458464.
  • Ohno, O., Mizokami, M., Wu, R.R., Saleh, M.G., Ohba, K., Orito, E., Mukaide, M., Williams, R. & Lau, J.Y. (1997) New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. Journal of Clinical Microbiology, 35, 201207.
  • Poynard, T., Marcellin, P., Lee, S.S., Niederau, C., Minuk, G.S., Ideo, G., Bain, V., Heathcote, J., Zeuzem, S., Trepo, C. & Albrecht, J. (1998) Randomised trial of interferon α 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet, 352, 14261432.
  • Telfer, P.T., Garson, J.A., Whitby, K., Grant, P.R., Yardemian, A., Hoffbrand, A.V. & Wonke, B. (1997) Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients. British Journal of Haematology, 98, 850855.
  • Zeuzem, S., Feinman, S.V., Rasenack, J., Heathcote, J., Lai, M.Y., Gane, E., O'Grady, J., Reichen, J., Diago, M., Lin, A., Hofman, J. & Brunda, M.J. (2000) Peginterferon Alfa-2a in patients with chronic hepatits C. New England Journal of Medicine, 343, 16661672.