To the Editor: In their article on hepatitis C virus (HCV) infection(July 5 issue),1 Lauer and Walker note that the pegylated interferonpeginterferon alfa-2a has been approved by the Food and DrugAdministration (FDA), when in fact it is peginterferon alfa-2bthat has received FDA approval. Large studies in the UnitedStates and Europe of the use of either brand of pegylated interferonplus ribavirin have been completed and found sustained virologicresponse rates of 56 percent and 61 percent.2,3 The combinationof peginterferon alfa-2b plus ribavirin has been approved inEurope and is expected to be approved soon in the United States.
The comments about the lack of value of retreatment in patientswith no response to interferon monotherapy are inaccurate; numerousstudies have found sustained virologic response rates of 20to 30 percent among such patients.4 Approximately 30 percentof patients with chronic HCV infection have normal alanine aminotransferaselevels.4,5 Studies have shown that the sustained virologic responserates for either interferon monotherapy or combination therapyare equivalent to those among patients with elevated alanineaminotransferase levels. Although it is recognized that cirrhosisdevelops in only a small percentage of patients with normalalanine aminotransferase levels, as many as 20 percent of suchpatients will have stage 3 or stage 4 fibrosis. It is importantto direct therapy to prevent progressive liver disease, butgiven the improvements in antiviral therapy and the opportunityto eradicate virus in an increasing number of patients, mosthepatologists believe that patients with mild disease shouldalso be treated.
Bruce R. Bacon, M.D. Adrian M. Di Bisceglie, M.D. Saint Louis University St. Louis, MO 63110-0250 baconbr{at}slu.edu
Editor's note: Drs. Bacon and Di Bisceglie receive research support from and have consulting relationships with Schering-Ploughand Roche Laboratories.
References
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41-52. [Free Full Text]
Fried MW, Shiffman ML, Reddy RK, et al. Pegylated (40 kDa) interferon alfa-2a (PEGASYS) in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively-controlled, multicenter study. Gastroenterology 2001;120:Suppl 1:A-55.
Manns MP, McHutchinson JG, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multicenter, multinational phase III randomized controlled trial. Hepatology 2000;32:297A-297A. [CrossRef][Web of Science]
Di Bisceglie AM, Thompson J, Smith-Wilkaitis N, Brunt EM, Bacon BR. Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon. Hepatology 2001;33:704-707. [CrossRef][Web of Science][Medline]
Di Bisceglie AM. Chronic hepatitis C viral infection in patients with normal serum alanine aminotransferases. Am J Med 1999;107:53S-55S. [CrossRef][Medline]
To the Editor: Lauer and Walker did not answer the followingquestion: Do persons with HCV infection and normal liver-functionresults need a liver biopsy?
James R. Korb, M.D. Southern California Permanente Medical Group Los Angeles, CA 90034 james.r.korb{at}kp.org
To the Editor: Drs. Lauer and Walker overestimate the importance of HCV as a cause of chronic liver disease by concentratingon review articles, consensus statements, and retrospectivestudies while ignoring the prospective studies. Currently thereare four large, long-term, retrospective–prospective studiesinvolving patients who have received transfusions. These studiesdemonstrate a rather favorable outcome of HCV-associated liverdisease.1,2,3,4 In contrast to the consensus statement the authorscite indicating that liver cirrhosis develops in 20 to 30 percentof patients with HCV, much lower rates of cirrhosis have beendocumented in the four prospective studies.1,2,3,4
Hans L. Tillmann, M.D. Stolze Str. 41 30171 Hannover, Germany hansltillmann{at}web.de
References
Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 1999;340:1228-1233. [Free Full Text]
Wiese M, Berr F, Lafrenz M, Porst H, Oesen U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany: a 20-year multicenter study. Hepatology 2000;32:91-96. [CrossRef][Web of Science][Medline]
Rodger AJ, Roberts S, Lanigan A, Bowden S, Brown T, Crofts N. Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975. Hepatology 2000;32:582-587. [CrossRef][Web of Science][Medline]
Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000;132:105-111. [Free Full Text]
To the Editor: Drs. Lauer and Walker do not discuss the association between HCV infection and diabetes mellitus. This associationwas described in 1995 and has been supported by more recentcross-sectional studies in which patients with HCV infectionwere matched according to age, sex, and severity of cirrhosis.In one study, the prevalence of diabetes mellitus was 23.6 percentamong patients with HCV infection but 9.4 percent among thoseinfected with hepatitis B virus, and the prevalence was associatedwith the Child–Pugh score among patients with cirrhosis.1A similar prevalence has been found in other studies and inthe experience at our institution.2 Persons older than 40 yearsof age with HCV infection have a risk of diabetes that is threetimes that of those without HCV infection.3 Furthermore, HCV-relatedcirrhosis was found to be a predictor of the development ofdiabetes after liver transplantation.2
Kevan C. Herold, M.D. Columbia University New York, NY 10032 kh318{at}columbia.edu
References
Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999;30:1059-1063. [CrossRef][Web of Science][Medline]
Bigam DL, Pennington JJ, Carpentier A, et al. Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology 2000;32:87-90. [CrossRef][Web of Science][Medline]
Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133:592-599. [Free Full Text]
To the Editor: Lauer and Walker report that current psychosis or a history of psychosis is an absolute contraindication totreatment with interferon alfa and ribavirin in persons whoare infected with HCV. To support this conclusion, the authorscite the consensus statement on hepatitis C from the EuropeanAssociation for the Study of the Liver.1 Yet a clear justificationfor such a conclusion is lacking. The 1997 consensus statementfrom the National Institutes of Health on the management ofhepatitis C2 does not include psychosis as a contraindicationto treatment with interferon alfa. In fact, a survey of 11,241patients with chronic viral hepatitis treated with interferonalfa reported only 10 adverse events relating to psychosis.3None of these events were considered life-threatening, and allremitted with the discontinuation of interferon or with treatmentwith appropriate psychiatric medication.
Seth Himelhoch, M.D. Johns Hopkins University Baltimore, MD 21287-6220 shimelh1{at}jhmi.edu
References
EASL International Consensus Conference on Hepatitis C: Paris, 26-28, February 1999, consensus statement. J Hepatol 1999;30:956-961. [CrossRef][Medline]
National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology 1997;26:Suppl 1:2S-10S. [CrossRef][Medline]
Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996;24:38-47. [CrossRef][Web of Science][Medline]
To the Editor: The review on HCV infection indicates that hemoglobinopathies are considered absolute contraindications to treatment withribavirin. We think that patients with hemoglobinopathies cantolerate ribavirin, but they require close monitoring.
Hemoglobinopathies are the most common autosomal recessive diseases.The high prevalence of positivity for HCV antibodies among patientswith hemoglobinopathies is related to increased requirementsfor blood transfusion,1 and the increased iron stores mightaccelerate the progression of the disease. Therefore, antiviraltherapy in patients with HCV infection and concomitant hemoglobinopathyis warranted.
A study from the United Kingdom demonstrated the feasibilityof combination therapy with interferon and ribavirin in patientswith thalassemia.2 Five of 11 patients had a sustained virologicresponse. Transfusion requirements were increased during therapy.We also successfully treated two patients with -thalassemia;both had a sustained virologic response. With regard to antiviraltreatment in patients with HCV infection and sickle cell disease,a single successful case report is available.3 Thus, interferonand ribavirin therapy appears feasible and should be consideredin patients with HCV infection and hemoglobinopathy.
Robert J. de Knegt, M.D. Arie P. van den Berg, M.D. Groningen University Hospital 9700 RB Groningen, the Netherlands r.j.de.knegt{at}int.azg.nl
References
Erer B, Angelucci E, Lucarelli G, et al. Hepatitis C virus infection in thalassemia patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14:369-372. [Medline]
Swaim MW, Agarwal S, Rosse WF. Successful treatment of hepatitis C in sickle-cell disease. Ann Intern Med 2000;133:750-751. [Free Full Text]
Telfer PT, Garson JA, Whitby K, et al. Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients. Br J Haematol 1997;98:850-855. [CrossRef][Medline]
To the Editor: In the article on HCV infection, hepatitis A vaccine is incorrectly described as a recombinant vaccine. Bothhepatitis A vaccines licensed by the FDA and available in theUnited States are inactivated vaccines, prepared by propagatingcell-culture–adapted virus in human fibroblasts and inactivatingthe purified product with formalin.1,2 To my knowledge, thereare no recombinant hepatitis A vaccines available anywhere inthe world.
Beth P. Bell, M.D., M.P.H. Centers for Disease Control and Prevention Atlanta, GA 30333
References
Peetermans J. Production, quality control and characterization of an inactivated hepatitis A vaccine. Vaccine 1992;10:Suppl 1:S99-S101.
Armstrong ME, Giesa PA, Davide JP, et al. Development of the formalin-inactivated hepatitis A vaccine, VAQTA from the live attenuated virus strain CR326F. J Hepatol 1993;18:Suppl 2:S20-S26.
The authors reply:
To the Editor: We agree with Bacon and Di Bisceglie that preliminaryabstracts of studies in which pegylated interferons plus ribavirinare being used are promising, but final recommendations shouldawait peer review. We also agree that their own study revealedrelatively good results (a sustained virological response rateof 30 percent) after retreatment in patients who had no responseto interferon. However, three other studies1,2,3 have showna sustained virologic response to combination therapy in only4 to 14 percent of patients who previously had no response tointerferon alone.
The issue of which patients require a biopsy was raised by Korb,and the question of whom to treat was raised by Bacon and DiBisceglie. We recommend a liver biopsy for patients with viremiawho have persistently normal aminotransferase levels, sincethe results of a biopsy can greatly influence decisions regardingtreatment. We recommend treatment for those with a biopsy specimenshowing liver disease,4 but we believe that close observationis an option that can be discussed with those whose biopsy specimensshow very mild disease activity. We do not recommend therapyoutside of controlled clinical trials for patients with viremiawho have normal liver-function results and normal liver histology.
In response to Tillmann: we indeed discussed prospective studiesand their limitations in the review. We did not state that cirrhosisdevelops in 20 to 30 percent of patients; the numbers we gavewere 15 to 20 percent. These are still estimates but are inagreement with more recent reports.5
We appreciate the comments by Herold about the possible associationof HCV infection with diabetes mellitus. Because of space limitations,we were not able to discuss this interesting issue.
We agree with Himelhoch and de Knegt and van den Berg that somecontraindications to interferon and ribavirin should be addressedagain in the future, especially since groups of patients thatare currently excluded from therapy may have a high prevalenceof HCV infection. Our review was intended for a general audience,and pending additional studies, we would not recommend treatingpatients with a history of psychosis or with hemoglobinopathiesexcept in specialized centers.
We apologize for the errors that were noted. Indeed, peginterferonalfa-2b, not peginterferon alfa-2a, has been approved by theFDA. Although the dose of ribavirin must be reduced for a substantialnumber of patients, less than 1 percent, not 20 percent, haveto discontinue ribavirin therapy because of drug-induced anemia.As Bell correctly notes, hepatitis A vaccine is an inactivatedvaccine.
Bruce D. Walker, M.D. Georg M. Lauer, M.D. Massachusetts General Hospital Charlestown, MA 02129-2000 bwalker{at}helix.mgh.harvard.edu
References
Cavalletto L, Chemello L, Donada C, et al. The pattern of response to interferon alpha (alpha-IFN) predicts sustained response to a 6-month alpha-IFN and ribavirin retreatment for chronic hepatitis C. J Hepatol 2000;33:128-134. [CrossRef][Web of Science][Medline]
Pol S, Couzigou P, Bourliere M, et al. A randomized trial of ribavirin and interferon-alpha vs. interferon-alpha alone in patients with chronic hepatitis C who were non-responders to a previous treatment. J Hepatol 1999;31:1-7. [Web of Science][Medline]
Spadaro A, Freni MA, Ajello A, et al. Interferon retreatment of patients with chronic hepatitis C: a long-term follow-up. Hepatogastroenterology 1999;46:3229-3233. [Medline]
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41-52.
Seeff LB, Hollinger FB, Alter HJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001;33:455-463. [CrossRef][Web of Science][Medline]
Correction
to
Lauer and Walker, 
-thalassemia; both had a sustained virologic response. With regard to antiviral treatment in patients with HCV infection and sickle cell disease, a single successful case report is available.3 Thus, interferon and ribavirin therapy appears feasible and should be considered in patients with HCV infection and hemoglobinopathy. 
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