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Predictors of a sustained beneficial response to interferon alfa therapy in chronic hepatitis C
Editorial Predictors of a Sustained Beneficial Response to Interferon Alfa Therapy in Chronic Hepatitis C Interferon alfa was first reported to have beneficial effects in chronic hepatitis C in the mid-1980s, ~ effects that were subsequently verified in multiple randomized controlled trials performed in many countries throughout the world. 2-~ This agent was approved for use as therapy in chronic hepatitis C in 1991, the first and still the only approved therapy for a disease that accounts for at least 30% of chronic liver disease and cirrhosis in the United States. In the several years since the licensing of interferon alfa for chronic hepatitis C, the enthusiasm for this therapy has been tempered by experience. A high proportion of patients have improvements in serum aminotransferases, hepatitis C virus (HCV) RNA levels, and hepatic histology during therapy, but only a small percentage have a long-term beneficial response. 6 For instance, in a recent European multicenter trial using the standard regimen of interferon alfa recommended in the United States (3 million units thrice weekly for 6 months), the long-term response rate was only 14%. 7 In our own experience from the Clinical Center of the National Institutes of Health, only 11 of 59 treated patients (19%) maintained a sustained response when assessed 1 to 5 years after therapy. Thus, many patients are treated but few have a long-term benefit. Of course, if one could predict which patients would ultimately have a long-term beneficial response to interferon alfa therapy, one might treat only those whose likelihood of a response warranted the expense and discomforts of the 6 months of therapy. It is for this reason that clinical trials as well as most published large series of treatment usually include secondary analyses of predictive factors for a response; comparing the response to therapy according to pretreatment clinical, biochemical, histological, and virological features. Despite many differences in design of these s t u d i e s - in types of interferon used, doses and drug regimens, patient populations, definitions of response, duration of follow-up, and serological and virological tests methods u s e d - - s e v e r a l predictive factors have been found repeatedly to be associated with a high likelihood of a
Abbreviations: HCV, hepatitis C virus. From the Liver Diseases Section, Digestive Diseases Branch, and the Epidemiology and Clinical Trials Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. Received May 15, 1995; accepted June 19, 1995. Address reprint requests to: Hari S. Conjeevaram, MD, Liver Diseases Section, Bldg 10, Room 4D52, NIH, Bethesda, MD 20892-1372. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2204-004353.00/0
long-term sustained response. T M Most prominent have been young age, short duration of disease, absence of cirrhosis, viral genotype, and low HCV RNA levels. In some instances, predictors of a response have also included lower body weight, 4'11'25-26low gamma-glutamyl transpeptidase (GGTP) levels, 11 mild activity on liver biopsy, 16'25'26 and source of HCV infection. In two studies, the presence of high levels of hepatic iron before treatment correlated with a lack of an initial response. 27,2s What is not always clear, however, is whether the individual factors identified in these studies are independent predictors of response or whether they are interrelated. Thus, young age may not be an independent predictive factor but may merely reflect patients with a shorter duration of illness or the absence of cirrhosis (which is more common in older patients who have had chronic hepatitis C for a longer time). Similarly, hepatic iron concentrations and GGTP levels p e r s e may not be predictive features of a response but rather merely reflect long duration of disease and presence of cirrhosis. Sorting out whether a factor is an independent determinant of response is important for several reasons. The predictive factor for a response to interferon alfa reflects on the cause of a response (biological significance) and can lead to approaches to enhance responsiveness (clinical significance). Furthermore, clinical use requires that the predictive features are accurate, are appropriately categorized, and are applicable to patients outside of the setting of a controlled trial. For example, it is not enough to know that response is less frequent with increasing duration of disease; to use this information, the clinician needs to know how duration of disease was measured and what the response rate was for various periods of duration. Among the approaches to identify independent predictors of a response, the most rigorous is the statistical device of multivariate analysis. In multivariate analysis, factors that appear to be associated in univariate analysis are analyzed together, controlling alternately for each. Thus, after controlling for genotype, one can assess whether the presence of cirrhosis correlates with a response to treatment. Several factors can be controlled for contemporaneously, and multiple analyses can be done, varying the factors in the model, adding or subtracting sequentially to test the robustness of the various associations. When applied and interpreted appropriately, multivariate analysis is a potent and valuable technique, but like all statistical analyses, it can be misinterpreted and lead to mistaken conclusions. Three im-
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HEPATOLOGYVol. 22, No. 4, 1995
CONJEEVARAM, EVERHART, AND HOOFNAGLE
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TABLE 1. P e r c e n t a g e o f P a t i e n t s W i t h C h r o n i c H e p a t i t i s C W i t h a L o n g - T e r m B e n e f i c i a l R e s p o n s e (LTR) to a Course of Interferon Alfa by Pretreatment Features of Disease
Author
Chemello et a129 Martinot-Peignoux et al so
No. of Patients
Overall Response Rate
Yes
No
High
Low
la & lb
Others
174
36%
19%
40%
28%
66%
16%
53%
141
20%
6%
22%
12%
39%
6%
Response rate odds ratio (95% CI) P
Cirrhosis
3.1 (1.3-8.6) .012
HCV RNA
4.9 (2.6-8.9) <.001
Genotype
32% 6.4 (3.2-13.1) <.001
NOTE. Response is defined by normal alanine transaminase levels 6 months after stopping therapy. Abbreviations: 95% CI, 95% confidence intervals; HCV RNA, hepatitis C virus RNA with low levels defined as undetecta.ble by PCR in the study by Chemello et al and undetectable by branched DNA test in the study by Martinot-Peignoux et al.
portant factors should be stressed in interpreting multivariate analyses. First, multivariate analysis uncovers correlations, not causality; just because a factor correlates with a response does not mean that that factor causes the response. Second, multivariate analysis may exclude important predictive factors if they are interrelated; thus, if GGTP levels increase both with age and with cirrhosis, the GGTP and not age or cirrhosis may appear to have the strongest correlation with outcome. The reason may have more to do with the statistical distribution of the variables than with biological importance. Finally, multivariate analysis requires large numbers of patients and, because of the multiplicity of comparisons made, lowers the power of the statistical analyses (making type II errors more common). A general rule of thumb is that for every factor analyzed, there should be at least 10 cases with the outcome of interest. Thus for analyzing factors predictive of a response to interferon alfa in chronic hepatitis C, series with fewer than 30 responders will rarely be useful; adequate confidence requires studies with 50 or more responders. It is rare for all of these factors to be considered when applying multivariate analysis to clinical studies. The various issues raised by the secondary analyses of predictors of response are well exemplified in two articles published in recent issues of HEPATOLOGY. Chemello et al from Padua, Italy, provided an analysis of their randomized trial of three regimens of interferon alfa (Roferon: alfa-2a) among 174 Italian patients with chronic hepatitis C. 20 A long-term beneficial response (defined by normal alanine transaminase (ALT) 6 months after stopping therapy) occurred in 63 patients (36%). The univariate analysis of clinical and virologic features identified five features that correlated with a higher rate of response: (1) young age, (2) short duration of disease, (3) normal GGTP levels, (4) absence of cirrhosis, and (5) HCV genotypes 2 and 3 (as contrasted to 1 and particularly lb). In multivariate analysis, genotype was the feature most closely associated with a long-term response, and cirrhosis no longer correlated with response. Similarly, in this issue Martinot-Peignoux et al from Clichy, France, provided an analysis of two trials of interferon alfa therapy (Intron A: alfa-2b
in one and Wellferon: alfa-ln in the second) among 141 patients with chronic hepatitis C. 3° A long-term beneficial response (defined similarly) occurred in 28 patients (20%). Although univariate analysis showed several important predictors of response (including young age and short duration of disease), multivariate analysis showed again the predominant importance of genotype as well as HCV RNA levels (which was analyzed in this trial using the branched DNA amplification assay, which provides reliable quantitation of virus levels). Indeed, in multivariate analyses the two virologic measures were the only variables that independently predicted the likelihood of response. Such results indicate viral factors are the major determinants of responsiveness to interferon alfa in chronic hepatitis C. The results of these two studies and multiple previous smaller studies bring into better focus the importance of viral genotype and titer in the clinical management of patients with chronic hepatitis C. However, the ability to apply the results of these studies to management of patients remains problematical. First, genotyping of HCV is not standardized and is not generally available. Second, the analyses in these studies have not adequately documented that the factors of young age, short duration of disease, and absence of cirrhosis are not actually important factors, being lost in the final analysis because of inadequate numbers or because of incorrect categorization of groups. To demonstrate these difficulties, the results of the two studies with an analysis of the odds-ratio for a long-term response (and confidence intervals) are shown in Table 1. From these findings, one would question why HCV genotype and HCV titer appeared to be important and the presence of cirrhosis not. The answer to this points again to the shortcomings of multivariate analysis. Favorable outcomes among cases with cirrhosis were too infrequent (6 of 31 in the Italian study and 1 of 18 in the French study) and may have been limited to patients with certain genotypes, making analysis of the association of cirrhosis and outcome independent of genotype difficult. These possibilities might have been addressed if the relative risk and confidence intervals for each of these factors had been given and if specific
1328
CONJEEVARAM, EVERHART, AND HOOFNAGLE
models had been tested, such as the probability of a response in patients with cirrhosis and specific genotypes (bivariate analysis, analyzing cirrhosis while controlling for genotype). The factors of duration of disease and age in both articles were analyzed as continuous variables. More helpful would have been to classify patients into groups (young and old, short and long duration) to optimize the differences in response rates and again to provide the relative risk and confidence intervals for these clinical factors. To use these features clinically, one needs to know what is considered a "young" age in chronic hepatitis C and what is considered a short duration of illness. Even the analyses of genotypes in these two studies, although showing significant correlations, were limited by small numbers. Only 6 patients in the Italian and 11 in the French study had the HCV genotype la, which is the most common genotype found in the United States. Thus, this genotype occurred too infrequently to analyze its independent association with a nonresponse. These problems aside, these two reports provide a basis for making recommendations to patients as well as needs for future research. Based on these and other reports on predictive factors for a response to therapy, one can recommend a course of interferon alfa for all patients with chronic hepatitis C (as defined by the presence of anti-HCV in serum, abnormal serum aminotransferases, and liver biopsy showing chronic hepatitis) infected with HCV genotypes 2 and 3 regardless of age, duration of disease, or even HCV RNA titer. In patients with genotype 1 and those in whom the genotype is unknown, the presence of other predictive factors should be used in the decision to initiate interferon; therapy can be confidently recommended only for those patients with low levels ofHCV RNA, especially if they are young (<40 years of age), have a short duration of known disease (<5 years), and are without cirrhosis. The findings of these multivariate analyses are also helpful in directing future studies of therapy, including studies of higher doses or more prolonged courses of interferon alfa. Obviously, enrollment in studies of interferon should focus on subjects with genotype 1. In the United States, where 75% to 80% of patients are genotype l a or lb, is this limitation does not present a problem. In such studies, a continued effort should be made to identify characteristics that predict a favorable response to treatment. HARI S. CONJEEVARAM, M D 1
JAMES E. EVERHART, MD, M P H 2 JAY H. HOOFNAGLE, MD 1 ~Liver Diseases Section Digestive Diseases Branch 2Epidemiology and Clinical Trials Branch Division of Digestive Diseases and Nutrition National Institutes of Health Bethesda, MD
HEPATOLOGYOctober 1995 REFERENCES
1. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, et al. Treatment of chronic non-A, nonB hepatitis with recombinant human alpha interferon. N Engl J Med 1986;315:1575-1578. 2. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP, Carey W, et al. Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter randomized, controlled trial. N Engl J Med 1989;321:1501-1506. 3. DiBisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, et al. Recombinant interferon alpha therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321:1506-1510. 4. Weiland O, Schvarz R, Wejstal R, Norkrans G, Fryden A. Therapy of chronic post-transfusion non-A, non-B hepatitis with interferon alfa-2b: Swedish experience. J Hepatol 1990; 11:$57-$62. 5. Marcellin P, Boyer N, Giostra E, Degott C, Courouce AM, Degos F, Coppere H, et al. Recombinant human-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. HEPATOLOGY1991; 13:393-397. 6. Shindo M, Di Bisceglie AM, Hoofnagle JH. Long-term follow-up of patients with chronic hepatitis C treated with alpha-interferon. HEPATOLOGY1992; 15:1013-1016. 7. Brouwer JT, Nevens F, Kleter GEM, Elewaut A, Adler M, Brenard R, Chamuleau RAFM, et al. Treatment of chronic hepatitis C: efficacy of interferon dose and analysis of factors predictive of response: interim report of 350 patients treated in a Benelux multicenter study. HEPATOLOGY1993; 18:110A. 8. Jouet P, Roudot-Thoraval F, Dhumeax D, Metreau J-M, Le Groupe Francais Pour L'Etude Du Traitement Des Hepatites Chroniques NANB/C. Comparative efficacy of interferon alpha in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 1994; 106:686-690. 9. Camma C, Craxi A, Tine F, Almasio P, Di Marco V, Lo Iacono 0, Bruno R, et al. Predictors of response to alpha-interferon (IFN) in chronic hepatitis C: a multivariate analysis on 361 treated patients. J Hepatol 1992; 17($1):$20. 10. Saracco G, Rosina F, Abate ML, Chiandussi L, Gallo V, Cerutti E, Napoli AD, et al. Long-term follow-up of patients with chronic hepatitis C treated with different doses of interferon-2b. HEPATOLOGY1993; 18:1300-1305. 11. 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;34:1714-1717. 12. Tsubata A, Chayama K, Ikeda K, Yasuji A, Koida I, Saitoh S, Hashimoto M, et al. Factors predictive of response to interferona therapy in hepatitis C virus infection. HEPATOLOGY 1994; 19:1088-1094. 13. Hayashi J, Ohmiya M, Kishihara Y, Tani Y, Kinukawa N, Ikematsu H, Kashiwagi S. A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C. Am J Gastroenterol 1994;89:2151-2156. 14. Yamada G, Takahashi M, Miyamoto R, Tsuji T, Yoshizawa H, Okamoto H. Prediction of interferon effect in chronic hepatitis C by both quantification and genotyping of HCV-RNA. Dig Dis Sci 1994;39:441. 15. Mita E, Hayashi N, Hagiwara H, Ueda K, Kanazawa Y, Kasahara A, Fusamoto H, et al. Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer. Dig Dis Sci 1994;39:977-982. 16. Matsumoto A, Tanaka E, Suzuki T, Ogata H, Kiyosawa K. Viral and host factors that contribute to efficacy of interferon-alpha2a therapy in patients with chronic hepatitis C. Dig Dis Sci 1994;39:1273-1280. 17. Diodati G, Bonetti P, Tagger A, Casarin C, Noventa F, Ribero M, Fasola M, et al. Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C. Dig Dis Sci 1994;39:2497-2502. 18. Mahaney K, Tedeschi V, Maertens G, DiBisceglie AM, Vergalla J, Hoofnagle JH, Sallie R. Gonotypic analysis of hepatitis C virus in American patients. HEPATOLOGY1994;20:1405-1411.
HEPATOLOGYVol. 22, No. 4, 1995 19. Hino K, Sainokami S, Shimoda K, Iino S, Wang Y, Okamoto H, Miyakawa Y, et al. Genotypes and titres of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C. J Med Virol 1994;42:299-305. 20. Nousbaum J-B, Pol S, Nalpas B, Landais P, Berthelot P, Brechot C, Collaborative Study Group. Hepatitis C virus type lb infection in France and Italy. Ann Intern Med 1995; 122:161-168. 21. Garson JA, Brillanti S, Whitby K, Foli M, Deaville R, Masci C, Miglioli M, et al. Analysis of clinical and virological factors associated with response to alpha interferon therapy in chronic hepatitis C. J Med Virol 1995;45:348-353. 22. Kasahara A, Hayashi N, Hiramatsu N, Oshita M, Hagiwara H, Katayama K, Kato M, et al. Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: a multicenter randomized controlled trial. HEPATOLOGY1995;21:291-297. 23. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, et al. Detection of hepatitis C virus by polymerase chain reaction and response to interferon-a therapy: relationship to genotypes of hepatitis C virus. HEPATOLOGY 1992; 16:293-299. 24. Kobayashi Y, Watanabe K, Yokoi M, Kakehashi R, Kaito M, Kondo M, Hayashi Y, et al. Quantitation and typing of serum hepatitis C virus RNA in patients with chronic hepatitis C treated with inteferon-B. HEPATOLOGY1993; 18:1319-1325.
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25. Lam NP, DeGuzman I.J, Pitrak D, Layden TJ. Clinical and histologic predictors of response to interferon-alpha in patients with chronic hepatitis C viral infection. Dig Dis Sci 1994;39:26602664. 26. Davis GL, Lindasy K, Albrecht J, Bodenheimer HC, Balart LA, Perillo RP, Dienstag JL, et al. Clinical predictors of response to recombinant interferon-alpha treatment in patients with chronic hepatitis non-A, non-B hepatitis (hepatitis C). J Viral Hepatitis 1994; 1:55-63. 27. Van Thiel DH, Friedlander L, Fagiuoli S, Wright HI, Irish W, Gavaler JS. Response to interferon a therapy is influenced by the iron content of the liver. J Hepatol 1994;20:410-415. 28. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers I_J, Parker TI, Radick JL, Schiff ER, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995;108:1104-1109. 29. Chemello L, Bonetti P, Cavalletto L, Talato F, Donadon V, Casarin P, Belussi F, et al. Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C. HEPATOLOGY1995;22:700-706. 30. Martinot-Peignoux M, Marcellin P, Pouteau M, Castelnau C, Boyer N, Poliquin M, Degott C, et al. Pretreatment serum HCV RNA levels and HCV genotype are the main and independent prognostic factors of sustained response to alpha interferon therapy in chronic hepatitis C. HEPATOLOGY1995;22:1050-1056.
Abbreviations: HCV, hepatitis C virus. From the Liver Diseases Section, Digestive Diseases Branch, and the Epidemiology and Clinical Trials Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. Received May 15, 1995; accepted June 19, 1995. Address reprint requests to: Hari S. Conjeevaram, MD, Liver Diseases Section, Bldg 10, Room 4D52, NIH, Bethesda, MD 20892-1372. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2204-004353.00/0
long-term sustained response. T M Most prominent have been young age, short duration of disease, absence of cirrhosis, viral genotype, and low HCV RNA levels. In some instances, predictors of a response have also included lower body weight, 4'11'25-26low gamma-glutamyl transpeptidase (GGTP) levels, 11 mild activity on liver biopsy, 16'25'26 and source of HCV infection. In two studies, the presence of high levels of hepatic iron before treatment correlated with a lack of an initial response. 27,2s What is not always clear, however, is whether the individual factors identified in these studies are independent predictors of response or whether they are interrelated. Thus, young age may not be an independent predictive factor but may merely reflect patients with a shorter duration of illness or the absence of cirrhosis (which is more common in older patients who have had chronic hepatitis C for a longer time). Similarly, hepatic iron concentrations and GGTP levels p e r s e may not be predictive features of a response but rather merely reflect long duration of disease and presence of cirrhosis. Sorting out whether a factor is an independent determinant of response is important for several reasons. The predictive factor for a response to interferon alfa reflects on the cause of a response (biological significance) and can lead to approaches to enhance responsiveness (clinical significance). Furthermore, clinical use requires that the predictive features are accurate, are appropriately categorized, and are applicable to patients outside of the setting of a controlled trial. For example, it is not enough to know that response is less frequent with increasing duration of disease; to use this information, the clinician needs to know how duration of disease was measured and what the response rate was for various periods of duration. Among the approaches to identify independent predictors of a response, the most rigorous is the statistical device of multivariate analysis. In multivariate analysis, factors that appear to be associated in univariate analysis are analyzed together, controlling alternately for each. Thus, after controlling for genotype, one can assess whether the presence of cirrhosis correlates with a response to treatment. Several factors can be controlled for contemporaneously, and multiple analyses can be done, varying the factors in the model, adding or subtracting sequentially to test the robustness of the various associations. When applied and interpreted appropriately, multivariate analysis is a potent and valuable technique, but like all statistical analyses, it can be misinterpreted and lead to mistaken conclusions. Three im-
1326
HEPATOLOGYVol. 22, No. 4, 1995
CONJEEVARAM, EVERHART, AND HOOFNAGLE
1327
TABLE 1. P e r c e n t a g e o f P a t i e n t s W i t h C h r o n i c H e p a t i t i s C W i t h a L o n g - T e r m B e n e f i c i a l R e s p o n s e (LTR) to a Course of Interferon Alfa by Pretreatment Features of Disease
Author
Chemello et a129 Martinot-Peignoux et al so
No. of Patients
Overall Response Rate
Yes
No
High
Low
la & lb
Others
174
36%
19%
40%
28%
66%
16%
53%
141
20%
6%
22%
12%
39%
6%
Response rate odds ratio (95% CI) P
Cirrhosis
3.1 (1.3-8.6) .012
HCV RNA
4.9 (2.6-8.9) <.001
Genotype
32% 6.4 (3.2-13.1) <.001
NOTE. Response is defined by normal alanine transaminase levels 6 months after stopping therapy. Abbreviations: 95% CI, 95% confidence intervals; HCV RNA, hepatitis C virus RNA with low levels defined as undetecta.ble by PCR in the study by Chemello et al and undetectable by branched DNA test in the study by Martinot-Peignoux et al.
portant factors should be stressed in interpreting multivariate analyses. First, multivariate analysis uncovers correlations, not causality; just because a factor correlates with a response does not mean that that factor causes the response. Second, multivariate analysis may exclude important predictive factors if they are interrelated; thus, if GGTP levels increase both with age and with cirrhosis, the GGTP and not age or cirrhosis may appear to have the strongest correlation with outcome. The reason may have more to do with the statistical distribution of the variables than with biological importance. Finally, multivariate analysis requires large numbers of patients and, because of the multiplicity of comparisons made, lowers the power of the statistical analyses (making type II errors more common). A general rule of thumb is that for every factor analyzed, there should be at least 10 cases with the outcome of interest. Thus for analyzing factors predictive of a response to interferon alfa in chronic hepatitis C, series with fewer than 30 responders will rarely be useful; adequate confidence requires studies with 50 or more responders. It is rare for all of these factors to be considered when applying multivariate analysis to clinical studies. The various issues raised by the secondary analyses of predictors of response are well exemplified in two articles published in recent issues of HEPATOLOGY. Chemello et al from Padua, Italy, provided an analysis of their randomized trial of three regimens of interferon alfa (Roferon: alfa-2a) among 174 Italian patients with chronic hepatitis C. 20 A long-term beneficial response (defined by normal alanine transaminase (ALT) 6 months after stopping therapy) occurred in 63 patients (36%). The univariate analysis of clinical and virologic features identified five features that correlated with a higher rate of response: (1) young age, (2) short duration of disease, (3) normal GGTP levels, (4) absence of cirrhosis, and (5) HCV genotypes 2 and 3 (as contrasted to 1 and particularly lb). In multivariate analysis, genotype was the feature most closely associated with a long-term response, and cirrhosis no longer correlated with response. Similarly, in this issue Martinot-Peignoux et al from Clichy, France, provided an analysis of two trials of interferon alfa therapy (Intron A: alfa-2b
in one and Wellferon: alfa-ln in the second) among 141 patients with chronic hepatitis C. 3° A long-term beneficial response (defined similarly) occurred in 28 patients (20%). Although univariate analysis showed several important predictors of response (including young age and short duration of disease), multivariate analysis showed again the predominant importance of genotype as well as HCV RNA levels (which was analyzed in this trial using the branched DNA amplification assay, which provides reliable quantitation of virus levels). Indeed, in multivariate analyses the two virologic measures were the only variables that independently predicted the likelihood of response. Such results indicate viral factors are the major determinants of responsiveness to interferon alfa in chronic hepatitis C. The results of these two studies and multiple previous smaller studies bring into better focus the importance of viral genotype and titer in the clinical management of patients with chronic hepatitis C. However, the ability to apply the results of these studies to management of patients remains problematical. First, genotyping of HCV is not standardized and is not generally available. Second, the analyses in these studies have not adequately documented that the factors of young age, short duration of disease, and absence of cirrhosis are not actually important factors, being lost in the final analysis because of inadequate numbers or because of incorrect categorization of groups. To demonstrate these difficulties, the results of the two studies with an analysis of the odds-ratio for a long-term response (and confidence intervals) are shown in Table 1. From these findings, one would question why HCV genotype and HCV titer appeared to be important and the presence of cirrhosis not. The answer to this points again to the shortcomings of multivariate analysis. Favorable outcomes among cases with cirrhosis were too infrequent (6 of 31 in the Italian study and 1 of 18 in the French study) and may have been limited to patients with certain genotypes, making analysis of the association of cirrhosis and outcome independent of genotype difficult. These possibilities might have been addressed if the relative risk and confidence intervals for each of these factors had been given and if specific
1328
CONJEEVARAM, EVERHART, AND HOOFNAGLE
models had been tested, such as the probability of a response in patients with cirrhosis and specific genotypes (bivariate analysis, analyzing cirrhosis while controlling for genotype). The factors of duration of disease and age in both articles were analyzed as continuous variables. More helpful would have been to classify patients into groups (young and old, short and long duration) to optimize the differences in response rates and again to provide the relative risk and confidence intervals for these clinical factors. To use these features clinically, one needs to know what is considered a "young" age in chronic hepatitis C and what is considered a short duration of illness. Even the analyses of genotypes in these two studies, although showing significant correlations, were limited by small numbers. Only 6 patients in the Italian and 11 in the French study had the HCV genotype la, which is the most common genotype found in the United States. Thus, this genotype occurred too infrequently to analyze its independent association with a nonresponse. These problems aside, these two reports provide a basis for making recommendations to patients as well as needs for future research. Based on these and other reports on predictive factors for a response to therapy, one can recommend a course of interferon alfa for all patients with chronic hepatitis C (as defined by the presence of anti-HCV in serum, abnormal serum aminotransferases, and liver biopsy showing chronic hepatitis) infected with HCV genotypes 2 and 3 regardless of age, duration of disease, or even HCV RNA titer. In patients with genotype 1 and those in whom the genotype is unknown, the presence of other predictive factors should be used in the decision to initiate interferon; therapy can be confidently recommended only for those patients with low levels ofHCV RNA, especially if they are young (<40 years of age), have a short duration of known disease (<5 years), and are without cirrhosis. The findings of these multivariate analyses are also helpful in directing future studies of therapy, including studies of higher doses or more prolonged courses of interferon alfa. Obviously, enrollment in studies of interferon should focus on subjects with genotype 1. In the United States, where 75% to 80% of patients are genotype l a or lb, is this limitation does not present a problem. In such studies, a continued effort should be made to identify characteristics that predict a favorable response to treatment. HARI S. CONJEEVARAM, M D 1
JAMES E. EVERHART, MD, M P H 2 JAY H. HOOFNAGLE, MD 1 ~Liver Diseases Section Digestive Diseases Branch 2Epidemiology and Clinical Trials Branch Division of Digestive Diseases and Nutrition National Institutes of Health Bethesda, MD
HEPATOLOGYOctober 1995 REFERENCES
1. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, et al. Treatment of chronic non-A, nonB hepatitis with recombinant human alpha interferon. N Engl J Med 1986;315:1575-1578. 2. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP, Carey W, et al. Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter randomized, controlled trial. N Engl J Med 1989;321:1501-1506. 3. DiBisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, et al. Recombinant interferon alpha therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321:1506-1510. 4. Weiland O, Schvarz R, Wejstal R, Norkrans G, Fryden A. Therapy of chronic post-transfusion non-A, non-B hepatitis with interferon alfa-2b: Swedish experience. J Hepatol 1990; 11:$57-$62. 5. Marcellin P, Boyer N, Giostra E, Degott C, Courouce AM, Degos F, Coppere H, et al. Recombinant human-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. HEPATOLOGY1991; 13:393-397. 6. Shindo M, Di Bisceglie AM, Hoofnagle JH. Long-term follow-up of patients with chronic hepatitis C treated with alpha-interferon. HEPATOLOGY1992; 15:1013-1016. 7. Brouwer JT, Nevens F, Kleter GEM, Elewaut A, Adler M, Brenard R, Chamuleau RAFM, et al. Treatment of chronic hepatitis C: efficacy of interferon dose and analysis of factors predictive of response: interim report of 350 patients treated in a Benelux multicenter study. HEPATOLOGY1993; 18:110A. 8. Jouet P, Roudot-Thoraval F, Dhumeax D, Metreau J-M, Le Groupe Francais Pour L'Etude Du Traitement Des Hepatites Chroniques NANB/C. Comparative efficacy of interferon alpha in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 1994; 106:686-690. 9. Camma C, Craxi A, Tine F, Almasio P, Di Marco V, Lo Iacono 0, Bruno R, et al. Predictors of response to alpha-interferon (IFN) in chronic hepatitis C: a multivariate analysis on 361 treated patients. J Hepatol 1992; 17($1):$20. 10. Saracco G, Rosina F, Abate ML, Chiandussi L, Gallo V, Cerutti E, Napoli AD, et al. Long-term follow-up of patients with chronic hepatitis C treated with different doses of interferon-2b. HEPATOLOGY1993; 18:1300-1305. 11. 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;34:1714-1717. 12. Tsubata A, Chayama K, Ikeda K, Yasuji A, Koida I, Saitoh S, Hashimoto M, et al. Factors predictive of response to interferona therapy in hepatitis C virus infection. HEPATOLOGY 1994; 19:1088-1094. 13. Hayashi J, Ohmiya M, Kishihara Y, Tani Y, Kinukawa N, Ikematsu H, Kashiwagi S. A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C. Am J Gastroenterol 1994;89:2151-2156. 14. Yamada G, Takahashi M, Miyamoto R, Tsuji T, Yoshizawa H, Okamoto H. Prediction of interferon effect in chronic hepatitis C by both quantification and genotyping of HCV-RNA. Dig Dis Sci 1994;39:441. 15. Mita E, Hayashi N, Hagiwara H, Ueda K, Kanazawa Y, Kasahara A, Fusamoto H, et al. Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer. Dig Dis Sci 1994;39:977-982. 16. Matsumoto A, Tanaka E, Suzuki T, Ogata H, Kiyosawa K. Viral and host factors that contribute to efficacy of interferon-alpha2a therapy in patients with chronic hepatitis C. Dig Dis Sci 1994;39:1273-1280. 17. Diodati G, Bonetti P, Tagger A, Casarin C, Noventa F, Ribero M, Fasola M, et al. Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C. Dig Dis Sci 1994;39:2497-2502. 18. Mahaney K, Tedeschi V, Maertens G, DiBisceglie AM, Vergalla J, Hoofnagle JH, Sallie R. Gonotypic analysis of hepatitis C virus in American patients. HEPATOLOGY1994;20:1405-1411.
HEPATOLOGYVol. 22, No. 4, 1995 19. Hino K, Sainokami S, Shimoda K, Iino S, Wang Y, Okamoto H, Miyakawa Y, et al. Genotypes and titres of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C. J Med Virol 1994;42:299-305. 20. Nousbaum J-B, Pol S, Nalpas B, Landais P, Berthelot P, Brechot C, Collaborative Study Group. Hepatitis C virus type lb infection in France and Italy. Ann Intern Med 1995; 122:161-168. 21. Garson JA, Brillanti S, Whitby K, Foli M, Deaville R, Masci C, Miglioli M, et al. Analysis of clinical and virological factors associated with response to alpha interferon therapy in chronic hepatitis C. J Med Virol 1995;45:348-353. 22. Kasahara A, Hayashi N, Hiramatsu N, Oshita M, Hagiwara H, Katayama K, Kato M, et al. Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: a multicenter randomized controlled trial. HEPATOLOGY1995;21:291-297. 23. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, et al. Detection of hepatitis C virus by polymerase chain reaction and response to interferon-a therapy: relationship to genotypes of hepatitis C virus. HEPATOLOGY 1992; 16:293-299. 24. Kobayashi Y, Watanabe K, Yokoi M, Kakehashi R, Kaito M, Kondo M, Hayashi Y, et al. Quantitation and typing of serum hepatitis C virus RNA in patients with chronic hepatitis C treated with inteferon-B. HEPATOLOGY1993; 18:1319-1325.
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25. Lam NP, DeGuzman I.J, Pitrak D, Layden TJ. Clinical and histologic predictors of response to interferon-alpha in patients with chronic hepatitis C viral infection. Dig Dis Sci 1994;39:26602664. 26. Davis GL, Lindasy K, Albrecht J, Bodenheimer HC, Balart LA, Perillo RP, Dienstag JL, et al. Clinical predictors of response to recombinant interferon-alpha treatment in patients with chronic hepatitis non-A, non-B hepatitis (hepatitis C). J Viral Hepatitis 1994; 1:55-63. 27. Van Thiel DH, Friedlander L, Fagiuoli S, Wright HI, Irish W, Gavaler JS. Response to interferon a therapy is influenced by the iron content of the liver. J Hepatol 1994;20:410-415. 28. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers I_J, Parker TI, Radick JL, Schiff ER, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995;108:1104-1109. 29. Chemello L, Bonetti P, Cavalletto L, Talato F, Donadon V, Casarin P, Belussi F, et al. Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C. HEPATOLOGY1995;22:700-706. 30. Martinot-Peignoux M, Marcellin P, Pouteau M, Castelnau C, Boyer N, Poliquin M, Degott C, et al. Pretreatment serum HCV RNA levels and HCV genotype are the main and independent prognostic factors of sustained response to alpha interferon therapy in chronic hepatitis C. HEPATOLOGY1995;22:1050-1056.