Peginterferon plus Ribavirin for Hepatitis C in HIV-Infected Patients
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Torriani and colleagues' report of the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) and Chung and colleagues' report of the Adult AIDS Clinical Trials Group (ACTG) A5071 trial of treatment for hepatitis C virus (HCV) infection in patients coinfected with the human immunodeficiency virus (HIV) (July 29 issue)1,2 may provide data to refute the recommendation that pegylated interferon and ribavirin be prescribed when the CD4+ cell count is above 350 per cubic millimeter and deferred when it is less than 200 per cubic millimeter.3 APRICOT enrolled 51 patients with a CD4+ cell count of less than 200 per cubic millimeter, but the authors do not provide information about these patients' outcomes. What was their rate of sustained virologic response? Did the baseline CD4+ cell count predict the development of AIDS-defining events? The CD4+ cell count did not predict the rate of sustained virologic response in the ACTG A5071 trial, but was it a predictor of the histologic response? In a previous investigation,4 it was not. Answers to these questions would help steer the development of guidelines and ensure that persons in whom elevated CD4+ cell counts cannot be achieved, despite antiretroviral therapy, will not be denied treatment for HCV without supporting evidence.
Lynn E. Taylor, M.D.
Josiah D. Rich, M.D., M.P.H.
Karen T. Tashima, M.D.
Brown Medical School
Providence, RI 02912
ltaylor@lifespan.org
References
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-450.
Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-459.
Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004;18:1-12.
Di Martino V, Thevenot T, Boyer N, et al. HIV coinfection does not compromise liver histological response to interferon therapy in patients with chronic hepatitis C. AIDS 2002;16:441-445.
To the Editor: Torriani et al. and Chung et al. report substantially different rates of sustained virologic response among HIV-infected subjects with HCV genotype 1 infection. The lower rate of sustained virologic response reported by Chung et al. may be partially explained by the higher percentage of black patients enrolled in their study than in the study by Torriani et al. Recent work shows that black persons are less likely to have a sustained virologic response than non-Hispanic whites, even when both groups have similar proportions of patients with genotype 1 infection.1
Another possible explanation is a difference in body-mass index (the weight in kilograms divided by the square of the height in meters) between the patients in the two studies. A body-mass index greater than 30 has previously been shown to be an independent risk factor for the absence of a response to therapy with pegylated interferon and ribavirin.2 The exact causes for this association remain unclear, although there is evidence that use of a weight-based dosage of ribavirin is particularly important in preventing relapse among persons with genotype 1 infection.3 Neither Torriani et al. nor Chung et al. examined the effect of body-mass index or the dose of ribavirin per unit of body weight on the probability of a sustained virologic response. Addressing these important issues may help further refine treatment regimens in this "difficult-to-treat" population.
Pierre M. Gholam, M.D.
Brown Medical School
Providence, RI 02912
pierre_gholam@brown.edu
References
Muir AJ, Bornstein JD, Killenberg PG, et al. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-2271.
Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355.
Drs. Torriani and Dieterich reply: Dr. Taylor and colleagues highlight the importance of considering CD4+ cell counts in deciding whether to treat hepatitis C in HIV-infected patients. Small studies have demonstrated lower rates of sustained virologic response than those observed in APRICOT among patients randomly assigned to receive peginterferon alfa-2a and have discouraged physicians from treating HCV infection in patients with CD4+ cell counts below 200 per cubic millimeter.1 In APRICOT, 51 patients had a CD4+ cell count below 200 per cubic millimeter, and 17 of them were randomly assigned to receive peginterferon alfa-2a and ribavirin. The rate of sustained virologic response was higher in this group than in the overall study group assigned to receive this treatment (47 percent vs. 40 percent). We chose not to include this result because of the small number of patients on which it was based. AIDS-defining events occurred in 1 percent of the patients in our study, and the incidence was not increased in patients with CD4+ cell counts below 200 per cubic millimeter. Lastly, in our prospectively defined, multiple logistic-regression analysis, the baseline CD4+ cell count was not predictive of a sustained virologic response when included as a continuous variable or as a binary variable (<200 vs. 200 cells per cubic millimeter). We agree that treatment for HCV should not be withheld from HIV-infected patients with low CD4+ cell counts on the basis of arbitrary thresholds.
Dr. Gholam remarks that sustained response rates obtained with peginterferon alfa-2a and ribavirin in patients with HIV and HCV genotype 1 infection were strikingly different in APRICOT and ACTG A5071. We agree that the lower overall response rates in ACTG A5071 may be partially explained by the higher number of black patients, the higher body-mass index, the higher percentage of patients with genotype 1 infection, and the lower initial ribavirin dose during the first month of treatment (600 mg per day) in that study. These factors are known to be associated with decreased response rates.2,3,4
Twenty-one of 66 patients in ACTG A5071 (32 percent) and 31 of 289 patients in APRICOT (11 percent) who were randomly assigned to peginterferon alfa-2a and ribavirin were black. In APRICOT, the mean body-mass index was 24 (i.e., normal), corresponding to a ribavirin dose of 10 to 11 mg per kilogram of body weight. In our prospectively defined, multiple logistic-regression analysis, neither race nor body-surface area predicted sustained virologic response.
Francesca J. Torriani, M.D.
University of California, San Diego
San Diego, CA 92103-8951
ftorriani@ucsd.edu
Douglas T. Dieterich, M.D.
Mount Sinai Medical Center
New York, NY 10029-6574
References
Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004;18:1-12.
Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-2271.
Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355.
Dr. Chung and colleagues reply: In response to Dr. Taylor and colleagues: we found no relationship in our study between the CD4+ cell count at baseline and the rate of sustained virologic response to peginterferon and ribavirin in patients coinfected with HCV and HIV. Similarly, we found no relationship between the CD4+ cell count at baseline and the histologic response at week 24 among patients who did not have a virologic response to peginterferon and ribavirin. Although the total number of black patients in our study was small, we observed a sustained virologic response in 11 percent of the 44 blacks. Although this appears to represent a sizable drop-off from the result in patients of other races (24 percent rate of sustained virologic response), the difference is not significant, even among patients with genotype 1 infection, in this study of moderate size. However, it remains possible that the higher proportion of blacks in our study cohort may still have contributed to the observed disparity between our study and that of Torriani et al. in sustained virologic responses overall and for patients with genotype 1 infection. Another possible factor may have been the timing of ribavirin administration in our study (i.e., the dose-escalation schedule), which limited the dose received during the potentially critical initial period of treatment, although it appears that the planned cumulative dose of ribavirin for patients completing therapy was actually higher in our study than in the study by Torriani et al.
Body-mass index had no effect on the overall rate of sustained virologic response. The complexity of our dose-escalation study design, the required early discontinuation at week 24 for patients who did not have a response, and the small numbers who had a sustained virologic response make it difficult to interpret this negative finding. Further study will be required to determine whether optimizing the ribavirin dose improves the overall rate of sustained virologic response in coinfected persons.
Raymond T. Chung, M.D.
Massachusetts General Hospital
Boston, MA 02114
rtchung@partners.org
Janet Andersen, Sc.D.
Harvard School of Public Health
Boston, MA 02115
Paul Volberding, M.D.
University of California, San Francisco
San Francisco, CA 94143
for the AIDS Clinical Trials Group A5071 Study Team
Lynn E. Taylor, M.D.
Josiah D. Rich, M.D., M.P.H.
Karen T. Tashima, M.D.
Brown Medical School
Providence, RI 02912
ltaylor@lifespan.org
References
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-450.
Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-459.
Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004;18:1-12.
Di Martino V, Thevenot T, Boyer N, et al. HIV coinfection does not compromise liver histological response to interferon therapy in patients with chronic hepatitis C. AIDS 2002;16:441-445.
To the Editor: Torriani et al. and Chung et al. report substantially different rates of sustained virologic response among HIV-infected subjects with HCV genotype 1 infection. The lower rate of sustained virologic response reported by Chung et al. may be partially explained by the higher percentage of black patients enrolled in their study than in the study by Torriani et al. Recent work shows that black persons are less likely to have a sustained virologic response than non-Hispanic whites, even when both groups have similar proportions of patients with genotype 1 infection.1
Another possible explanation is a difference in body-mass index (the weight in kilograms divided by the square of the height in meters) between the patients in the two studies. A body-mass index greater than 30 has previously been shown to be an independent risk factor for the absence of a response to therapy with pegylated interferon and ribavirin.2 The exact causes for this association remain unclear, although there is evidence that use of a weight-based dosage of ribavirin is particularly important in preventing relapse among persons with genotype 1 infection.3 Neither Torriani et al. nor Chung et al. examined the effect of body-mass index or the dose of ribavirin per unit of body weight on the probability of a sustained virologic response. Addressing these important issues may help further refine treatment regimens in this "difficult-to-treat" population.
Pierre M. Gholam, M.D.
Brown Medical School
Providence, RI 02912
pierre_gholam@brown.edu
References
Muir AJ, Bornstein JD, Killenberg PG, et al. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-2271.
Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355.
Drs. Torriani and Dieterich reply: Dr. Taylor and colleagues highlight the importance of considering CD4+ cell counts in deciding whether to treat hepatitis C in HIV-infected patients. Small studies have demonstrated lower rates of sustained virologic response than those observed in APRICOT among patients randomly assigned to receive peginterferon alfa-2a and have discouraged physicians from treating HCV infection in patients with CD4+ cell counts below 200 per cubic millimeter.1 In APRICOT, 51 patients had a CD4+ cell count below 200 per cubic millimeter, and 17 of them were randomly assigned to receive peginterferon alfa-2a and ribavirin. The rate of sustained virologic response was higher in this group than in the overall study group assigned to receive this treatment (47 percent vs. 40 percent). We chose not to include this result because of the small number of patients on which it was based. AIDS-defining events occurred in 1 percent of the patients in our study, and the incidence was not increased in patients with CD4+ cell counts below 200 per cubic millimeter. Lastly, in our prospectively defined, multiple logistic-regression analysis, the baseline CD4+ cell count was not predictive of a sustained virologic response when included as a continuous variable or as a binary variable (<200 vs. 200 cells per cubic millimeter). We agree that treatment for HCV should not be withheld from HIV-infected patients with low CD4+ cell counts on the basis of arbitrary thresholds.
Dr. Gholam remarks that sustained response rates obtained with peginterferon alfa-2a and ribavirin in patients with HIV and HCV genotype 1 infection were strikingly different in APRICOT and ACTG A5071. We agree that the lower overall response rates in ACTG A5071 may be partially explained by the higher number of black patients, the higher body-mass index, the higher percentage of patients with genotype 1 infection, and the lower initial ribavirin dose during the first month of treatment (600 mg per day) in that study. These factors are known to be associated with decreased response rates.2,3,4
Twenty-one of 66 patients in ACTG A5071 (32 percent) and 31 of 289 patients in APRICOT (11 percent) who were randomly assigned to peginterferon alfa-2a and ribavirin were black. In APRICOT, the mean body-mass index was 24 (i.e., normal), corresponding to a ribavirin dose of 10 to 11 mg per kilogram of body weight. In our prospectively defined, multiple logistic-regression analysis, neither race nor body-surface area predicted sustained virologic response.
Francesca J. Torriani, M.D.
University of California, San Diego
San Diego, CA 92103-8951
ftorriani@ucsd.edu
Douglas T. Dieterich, M.D.
Mount Sinai Medical Center
New York, NY 10029-6574
References
Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004;18:1-12.
Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-2271.
Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639-644.
Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355.
Dr. Chung and colleagues reply: In response to Dr. Taylor and colleagues: we found no relationship in our study between the CD4+ cell count at baseline and the rate of sustained virologic response to peginterferon and ribavirin in patients coinfected with HCV and HIV. Similarly, we found no relationship between the CD4+ cell count at baseline and the histologic response at week 24 among patients who did not have a virologic response to peginterferon and ribavirin. Although the total number of black patients in our study was small, we observed a sustained virologic response in 11 percent of the 44 blacks. Although this appears to represent a sizable drop-off from the result in patients of other races (24 percent rate of sustained virologic response), the difference is not significant, even among patients with genotype 1 infection, in this study of moderate size. However, it remains possible that the higher proportion of blacks in our study cohort may still have contributed to the observed disparity between our study and that of Torriani et al. in sustained virologic responses overall and for patients with genotype 1 infection. Another possible factor may have been the timing of ribavirin administration in our study (i.e., the dose-escalation schedule), which limited the dose received during the potentially critical initial period of treatment, although it appears that the planned cumulative dose of ribavirin for patients completing therapy was actually higher in our study than in the study by Torriani et al.
Body-mass index had no effect on the overall rate of sustained virologic response. The complexity of our dose-escalation study design, the required early discontinuation at week 24 for patients who did not have a response, and the small numbers who had a sustained virologic response make it difficult to interpret this negative finding. Further study will be required to determine whether optimizing the ribavirin dose improves the overall rate of sustained virologic response in coinfected persons.
Raymond T. Chung, M.D.
Massachusetts General Hospital
Boston, MA 02114
rtchung@partners.org
Janet Andersen, Sc.D.
Harvard School of Public Health
Boston, MA 02115
Paul Volberding, M.D.
University of California, San Francisco
San Francisco, CA 94143
for the AIDS Clinical Trials Group A5071 Study Team