Correspondence
Treatment of Acute Hepatitis C with Interferon Alfa-2b
N Engl J Med 2002; 346:1091-1092April 4, 2002
- Article
To the Editor:
Jaeckel and colleagues (Nov. 15 issue)1 report that treatment of acute hepatitis C virus (HCV) infection with interferon alfa-2b prevents chronic infection. Their conclusion is based on the finding that in 42 of 43 patients who could be evaluated, HCV RNA in serum was undetectable 24 weeks after the end of treatment with interferon alfa-2b. To measure HCV RNA in serum, the authors used the Cobas Amplicor HCV C monitor, version 2.0 (Roche Diagnostics, Mannheim, Germany). This assay has a lower limit of detection of 600 IU per milliliter, not 600 copies per milliliter, as stated in the article. The international unit is an internationally accepted standard of measurement; 100,000 IU is defined as the amount of virus in 1 ml of the World Health Organization's International Standard for Nucleic Acid Amplification Technology Assays for HCV RNA (Standard 96/790).2
Jaeckel et al. should have used an assay that is more sensitive for the detection of HCV RNA. The study specimens should be retested with a more sensitive assay, such as the Cobas Amplicor HCV Test, version 2.0 (Roche Diagnostics), or the Versant HCV RNA Qualitative Assay (Bayer Diagnostics, Emeryville, Calif.). The findings reported by Jaeckel and colleagues are important but require confirmation with a more sensitive assay.
2 ReferencesRobin Patel, M.D.
Jeffrey J. Germer
Mayo Clinic, Rochester, MN 55905
patel.robin@mayo. edu 1
Jaeckel E ,Cornberg M ,Wedemeyer H , et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345:1452-1457
Full Text | Web of Science | Medline2
Saldanha J ,Lelie N ,Heath A . Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA. Vox Sang 1999;76:149-158
CrossRef | Web of Science | Medline
To the Editor:
The short follow-up period in the study by Jaeckel et al. may have resulted in an overestimate of the true rate of eradication of HCV. Transient periods of undetectable viremia are not uncommon in patients with acute hepatitis C.1
No data are provided on the evolution of the antibody response. In subjects with spontaneous clearance of HCV infection, levels of specific antibodies decrease, and the antibodies eventually disappear.2,3 This process may be accelerated in patients treated with interferon. Lack of seroconversion, with transient, weak antibody reactivity, has been reported in a patient with acute hepatitis C who was successfully treated with interferon alfa and ribavirin.4
4 ReferencesGuido Tocci, M.D.
Ubaldo Visco-Comandini, M.D., Ph.D.
Giorgio Antonucci, M.D.
National Institute for Infectious Diseases Lazzaro Spallanzani– IRCCS, 00149 Rome, Italy
giudo50@libero.it 1
Villano SA ,Vlahov D ,Nelson KE ,Cohn S ,Thomas DL . Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999;29:908-914
CrossRef | Web of Science | Medline2
Takaki A ,Wiese M ,Maertens G , et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000;6:578-582
CrossRef | Web of Science | Medline3
Beld M ,Penning M ,van Putten M , et al. Quantitative antibody response to structural (Core) and nonstructural (NS3, NS4, NS5) hepatitis C virus proteins among seroconverting injecting drug users: impact of epitope variation and relationship to detection of HCV RNA in blood. Hepatology 1999;29:1288-1298
CrossRef | Web of Science | Medline4
Morand P ,Dutertre N ,Minazzi H , et al. Lack of seroconversion in a health care worker after polymerase chain reaction-documented acute hepatitis C resulting from a needlestick injury. Clin Infect Dis 2001;33:727-729
CrossRef | Web of Science | Medline
To the Editor:
The study reported by Jaeckel et al. was a prospective case series without a control group. Therefore, selection bias is an important consideration. For example, we do not know the number of patients who were screened. As in any case series, the concern is that patients who are poor candidates for therapy are not invited to participate in the study. As a result, an analysis based on a case series is likely to overestimate the response rate. Although we recognize that the infrequent presentation of acute HCV infection may have made it impossible to perform a large, randomized, controlled trial, it is important to know more about the number of patients screened and about the study population.
Andrew J. Muir, M.D., M.H.S.
Don C. Rockey, M.D.
Duke University Medical Center, Durham, NC 27710
andrew.muir@duke. edu To the Editor:
For historical controls, Jaeckel et al. cite only one small study (involving 28 patients), which was fraught with methodologic flaws.1 Historical controls are inappropriate for comparison, since the patients in the study by Jaeckel et al. were not typical of patients with early HCV infection. All their patients had clinical features of infection, and 68 percent even had icterus; however, 80 percent of acute infections are clinically silent.2 In addition, observational studies suggest that symptomatic acute disease is more likely to resolve spontaneously than silent acute disease.3,4 Does the extremely high rate of response (with the use of interferon alfa-2b alone) reflect the natural history of symptomatic acute HCV infection or the effect of treatment?
Jaeckel et al. could have reported the base-line, 24-week, and 48-week levels of HCV RNA in the patients with identified cases of infection who were excluded from the study. Although the excluded patients probably differed in some respects from the treated patients, a comparison of data in this similar population would have been valuable.
4 ReferencesHilary K. Seligman, M.D.
Rena K. Fox, M.D.
University of California–San Francisco, San Francisco, CA 94143
rfox@medicine.ucsf. edu 1
Santantonio T ,Mazzola M ,Guastadisegni A ,Casalino C ,Pastore G . A cohort study of acute hepatitis C virus (HCV) infection: natural course and outcome. Hepatology 1999;30:Suppl:205A-205A abstract.
CrossRef | Web of Science2
Alter MJ ,Margolis HS ,Krawczynski K , et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med 1992;327:1899-1905
Full Text | Web of Science | Medline3
Giuberti T ,Marin MG ,Ferrari C , et al. Hepatitis C virus viremia following clinical resolution of acute hepatitis C. J Hepatol 1994;20:666-671
CrossRef | Web of Science | Medline4
Villano SA ,Vlahov D ,Nelson KE ,Cohn S ,Thomas DL . Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999;29:908-914
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Patel and Germer that more sensitive assays for the detection of HCV RNA have become available. However, these more sensitive tests were not available during the enrollment period for our study.
For chronic HCV infection, it is generally accepted that undetectable HCV RNA in serum 24 weeks after the end of therapy predicts a sustained response.1 We agree with Tocci et al. that this has not been formally proved for the follow-up of acute HCV infection after therapy. However, none of our patients had had a relapse as of February 2002. Twenty-three of our 44 patients had seroconversion to anti-HCV antibodies during the study; the other 21 were positive for anti-HCV antibodies at the time of referral.
Tocci et al. point out that anti-HCV antibodies may disappear after recovery. Our research group has shown that this occurs after a period of decades.2 Long-term studies will determine whether the decline in the level of antibodies after interferon therapy is accelerated in patients with acute hepatitis C.
We agree with Muir and Rockey that inclusion of a control group would have strengthened our study. Our screening strategy of distributing more than 7000 brochures nationwide may have resulted in a better representation of the overall spectrum of patients with acute hepatitis C than the use of referrals from major centers in multicenter studies. We did not plan to include a control group initially because we did not expect to recruit a sufficiently large number of patients.
As Muir and Rockey state, selection bias is always a concern in a case series. Every patient with acute hepatitis C infection who was referred to our center received therapy; no one was excluded. Therefore, we cannot provide any data on excluded, untreated patients, as Seligman and Fox request. However, it is possible that primary care physicians saw patients with acute HCV infection and did not refer them to our center. A recently established national network (Hep-Net), sponsored by the German Ministry of Education and Research, will work with all physicians caring for patients with viral hepatitis to identify those who have acute hepatitis C.
We agree with Seligman and Fox that a comparison with historical controls is problematic, since the typical routes of infection with HCV have changed. In most recent, prospective follow-up studies, including ours, the prevalence of symptoms and the prevalence of icterus have been higher than in cohorts of patients infected through blood transfusions. Patients with symptoms and those with icterus may be more likely to have self-limited disease.3
3 ReferencesMarkus Cornberg, M.D.
Elmar Jaeckel, M.D.
Michael P. Manns, M.D.
Medical School of Hannover, 30623 Hannover, Germany
manns.michael@mh-hannover. de 1
McHutchison JG ,Davis GL ,Esteban-Mur R , et al. Durability of sustained virologic response in patients with chronic hepatitis C after treatment with interferon α-2b alone or in combination with ribavirin. Hepatology 2001;34:Suppl:244A-244A abstract.
Web of Science2
Takaki A ,Wiese M ,Maertens G , et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000;6:578-582
CrossRef | Web of Science | Medline3
Gerlach TJ ,Zachoval R ,Gruener N , et al. Acute hepatitis C: natural course and response to antiviral treatment. Hepatology 2001;34:Suppl:341A-341A abstract.
Web of Science
- Citing Articles (1)
Citing Articles
1
Mindie H. Nguyen, Huy N. Trinh, Ruel Garcia, Gloria Nguyen, Khoa D. Lam, Emmet B. Keeffe. (2008) Higher Rate of Sustained Virologic Response in Chronic Hepatitis C Genotype 6 Treated With 48 Weeks Versus 24 Weeks of Peginterferon Plus Ribavirin. The American Journal of Gastroenterology 103:5, 1131-1135
CrossRef
