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Long-term efficacy of interferon alpha treatment in chronic hepatitis C
Correspondence 2. Honkoop P, Niesters HGM, Man RA de, Osterhaus ADME, Schalm SW. Lamivudine resistance in immunocompetent chronic hepatitis B: incidence and patterns. J Hepatol 1997; 26: 1393–5. 3. Niesters HGM, Honkoop P, Haagsma EB, Man RA de, Schalm SW, Osterhaus ADME. Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine therapy. J Infect Dis 1998; 177: 1382–5. 4. Man RA de, Bartholomeusz A, Niesters HGM, Zondervan P, Locarnini SA. The sequential occurrence of viral muta-
tions in a liver transplant recipient reinfected with hepatitis B: hepatitis B immune globulin escape famciclovir non-response, followed by lamivudine resistance in graft loss. J Hepatol 1998: In press. 5. Leung NWY, Lai CL, Liaw YF, Chang TT, Guan R, Tai DI. Lamivudine (100 mg od) for 1 year significantly improves necro-inflammatory activity and reduces progression in fibrosis stage: results of a placebo-controlled multicentre study in Asia of lamivudine for chronic hepatitis B infection [abstract]. Hepatology 1997; 26: (Suppl); 357.
Long-term efficacy of interferon alpha treatment in chronic hepatitis C To the Editor: Interferon alpha (IFNa) has become a well-established therapy of chronic hepatitis C, with an initial response rate of 50%. However, sustained remission of chronic hepatitis C is rarely achieved, and occurs only in about 20% of treated patients. Concerning the long-term effect of IFNa therapy, only a few and contradictory studies have been presented (1–5). In one of the longest follow-up studies yet reported, covering a period of 6–8 years, all patients relapsed as shown by re-appearance of HCV RNA in the serum (1). However, other authors demonstrated long-lasting remission extending from 2–6 years in patients who had received IFNa for 6–12 months (2–5). In this study we have therefore analysed the long-term efficacy of IFNa treatment in patients with sustained response observed 12 months after stopping INFa therapy, covering a period of 24–84 months. One hundred and seventy-six patients with chronic hepatitis C (73 female, 103 male; mean age 46 years; 20–68), who were anti-HCV
positive and HCV RNA positive by polymerase chain reaction (PCR) were treated with IFNa, at our hospital between July 1989 and December 1994. All patients received at least 3 MU IFNa tiw for at least 6 months (total IFNa dose 216–720 MU, mean 360). Treatment duration was 6–12 months (mean 8). Twenty-eight (16%) of the 176 patients achieved a sustained response, as documented by normal alanine aminotransferase (ALT) levels and negative PCR for HCV RNA 1 year after stopping IFNa treatment. Twenty-three of these 28 patients were followed for a period of 2–7 years (median 58 months), and ALT levels and HCV RNA by PCR (HCV-AmplicorTM assay, Roche Diagnostic Systems Inc., Branchburg NJ, USA) were measured at least at 1year intervals. As shown in Table 1, only three of the 23 patients initially defined as having sustained remission suffered a late relapse, which became evident 16, 28, and 32 months after cessation of IFNa therapy. In
TABLE 1 Analysis of the long-lasting efficacy of IFNa therapy in patients with sustained response followed during a period of 2–7 years No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age
52 25 23 32 29 73 34 37 30 41 30 63 55 43 32 46 27 29 37 47 30 47 60
Sex
f f f f f f f m f f m m f m m m m m m f f m m
Length of follow-up period (months) 24 25 26 27 30 31 35 41 42 46 57 58 58 59 62 63 70 76 78 78 80 82 84
Clinical presentation of patients with hepatitis C before starting IFNa HCV genotype
HCV RNA level ALT U/l (copies¿105)
Histological activity (Knodell)
2a 3a 3a 1b 3a 2b 3a 3a 1a 3a n.d 2b 1b 1b 3a 1b 1 3 3 1 1 2 1b
6.9 0.3 3.0 ∞0.1 ∞0.1 1.7 1.9 0.1 ∞0.1 ∞0.1 ∞0.1 5.7 1.0 0.9 ∞0.1 0.2 n d. n d. n.d. n d. n.d. n d. n.d.
6 2 6 10 4 11 2 3 9 8 4 12 10 11 6 10 4 8 4 11 8 8 11
91 14 37 28 37 102 118 32 21 96 28 72 267 82 28 30 65 48 150 276 75 52 36
Total IFNa dose (MU)
Occurrence of relapse (months after stopping IFNa)
216 218 216 216 72 216 216 216 216 432 720 216 360 720 720 720 432 432 432 432 432 432 432
yes (16) no no no no no no no no yes (28) no yes (32) no no no no no no no no no no no
ALT, alanine aminotransferase. f,female; m, male; IFNa, inteferon alpha. MU, million units. n.d., not done.
511
Correspondence two of these three patients, HCV RNA could be detected about 2 years before the disease exacerbated, while in the third patient the recurrence of hepatitis C viremia and rise in ALT levels occurred at the same time. Interestingly, ALT elevation was pronounced in all patients, resembling acute hepatitis. Comparing the 23 patients with sustained response and the 148 patients with non-response or relapse, it became evident that the patients with sustained response were significantly younger, had lower viremia level, and were less frequently infected with genotype 1 than the non-responders or responders with relapse (mean 39 vs. 47 years; mean 137 000 vs. 555 000 copies/ml [nΩ92]; and 39% vs. 83% genotype 1, p∞0.05). In contrast, the ALT levels (75∫68 vs. 69∫32 U/l) and the histological activity (8.6∫3 vs. 8.3∫3) as assessed by Knodell score showed no significant differences. Also, dosage (380∫193 vs. 362∫145 MU IFNa) and duration of IFNa therapy (9∫3 vs. 9∫3 months) had no influence on the clinical outcome. In conclusion, our data strongly imply that IFNa can induce a sustained remission of chronic hepatitis C, and that relapses may no longer occur after the phase of remission has lasted for more than 3 years. Thomas Berg1, Thomas Kaul1, Hans-Gerd Heuft1, Uta Naumann1, Hartmut Lobeck2, Bertram Wiedenmann1 and Uwe Hopf1 1 Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie and 2Pathologisches Institut, Universita¨tsklinikum Charite´, Campus Virchow-Klinikum, Humboldt-Universita¨t, Berlin, Germany
References 1. Vento S, Concia E, Ferraro T. Lack of sustained efficacy of interferon in patients with chronic hepatitis C. N Engl J Med 1996; 334: 1479. 2. Reichard O, Glaumann H, Fryden A, Norkrans G, Schvarcz R, Sonnerborg A, et al. Two-year biochemical, virological and histological follow-up in patients with chronic hepatitis C responding in a sustained fashion to interferon alfa-2b treatment. Hepatology 1995; 21: 918–22. 3. Teuber G, Dienes HP, Meyer zum Bu¨schenfelde KH, Gerken G. Long-term follow-up of patients with chronic hepatitis C after interferon-alpha treatment. Digestion 1996; 57: 464–71. 4. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-a therapy. Ann Intern Med 1997; 127: 875–81. 5. Camma` C, Di Marco V, Lo Iacono O, Almasio P, Giunta M, Fuschi P, et al. Long-term course of interferon-treated chronic hepatitis C. J Hepatol 1998; 28: 531–7.
Increased serum nitrite and nitrate concentrations in chronic hepatitis To the Editor: We read with interest the review article by Simpson et al. about cytokines and the liver (1). As mentioned in the article, circulating levels of cytokines, such as TNFa and IL6, increase during hepatitis, and in many studies enhanced hepatic expression of a variety of different cytokines has been demonstrated in patients with hepatic inflammation. There are many studies in the literature demonstrating that hepatocytes express iNOS following exposure to various cytokines such as TNF, IL1, IFN gamma and IL6 (2–4). Increased NO production and plasma nitrite/nitrate levels have also been found during chronic hepatic inflammation, suggesting a role for NO in mediating the hepatic response to inflammatory stimuli (5). We investigated serum nitrite/nitrate levels in patients with chronic hepatitis. Serum pools were prepared from 21 patients and 10 age/ sex-matched healthy control subjects. The etiology was hepatitis B in eight patients and hepatitis C in 13, while all had HAI scores between 6–8 and serum ALT levels between 65–80 u/l. All the patients had naive chronic hepatitis disease and had not received any treatment including interferon alpha. There were no cirrhotic patients in the study group; the fibrosis scores were between 1–3 in liver biopsies. Serum samples were deproteinized by zinc sulphate and, after reducing nitrate to nitrite (incubation in the presence of 20 mU nitrate reductase, 5 ml FAD, 0.6 nM NADPH in 50 nm phosphate buffer, pH 7.5 for 1 h at 37æC) total nitrite was measured by a procedure based on the Griess reaction (6,7). The mean serum nitrite/nitrate concentrations in patients and control subjects were 72.1∫6.91 mmol/l and 29.0∫4.6 mmol/l, respectively (Fig. 1). Thus, we concluded that serum nitrite/nitrate concentrations are increased in chronic hepatitis. There is a discrepancy between our results and previously reported studies which concluded that nitric oxide production was reduced or unchanged in chronic hepatitis (8–10). In the study reported by Moriyama et al., normal serum nitrite/nitrate levels were found in chronic hepatitis (8). However, interestingly, these authors found even higher values of nitrite and nitrate levels in patients with hepatocellular carcinoma based on chronic hepatitis than in patients with carcinoma
512
based on liver cirrhosis. A similar finding was also reported by Mihm et al. (10). These authors found that iNOS transcript expression was increased in chronic hepatitis C and, although this increase was not
Fig. 1. Total serum nitrite and nitrate concentrations (mmol/l in patients with chronic hepatitis and controls.
tions in a liver transplant recipient reinfected with hepatitis B: hepatitis B immune globulin escape famciclovir non-response, followed by lamivudine resistance in graft loss. J Hepatol 1998: In press. 5. Leung NWY, Lai CL, Liaw YF, Chang TT, Guan R, Tai DI. Lamivudine (100 mg od) for 1 year significantly improves necro-inflammatory activity and reduces progression in fibrosis stage: results of a placebo-controlled multicentre study in Asia of lamivudine for chronic hepatitis B infection [abstract]. Hepatology 1997; 26: (Suppl); 357.
Long-term efficacy of interferon alpha treatment in chronic hepatitis C To the Editor: Interferon alpha (IFNa) has become a well-established therapy of chronic hepatitis C, with an initial response rate of 50%. However, sustained remission of chronic hepatitis C is rarely achieved, and occurs only in about 20% of treated patients. Concerning the long-term effect of IFNa therapy, only a few and contradictory studies have been presented (1–5). In one of the longest follow-up studies yet reported, covering a period of 6–8 years, all patients relapsed as shown by re-appearance of HCV RNA in the serum (1). However, other authors demonstrated long-lasting remission extending from 2–6 years in patients who had received IFNa for 6–12 months (2–5). In this study we have therefore analysed the long-term efficacy of IFNa treatment in patients with sustained response observed 12 months after stopping INFa therapy, covering a period of 24–84 months. One hundred and seventy-six patients with chronic hepatitis C (73 female, 103 male; mean age 46 years; 20–68), who were anti-HCV
positive and HCV RNA positive by polymerase chain reaction (PCR) were treated with IFNa, at our hospital between July 1989 and December 1994. All patients received at least 3 MU IFNa tiw for at least 6 months (total IFNa dose 216–720 MU, mean 360). Treatment duration was 6–12 months (mean 8). Twenty-eight (16%) of the 176 patients achieved a sustained response, as documented by normal alanine aminotransferase (ALT) levels and negative PCR for HCV RNA 1 year after stopping IFNa treatment. Twenty-three of these 28 patients were followed for a period of 2–7 years (median 58 months), and ALT levels and HCV RNA by PCR (HCV-AmplicorTM assay, Roche Diagnostic Systems Inc., Branchburg NJ, USA) were measured at least at 1year intervals. As shown in Table 1, only three of the 23 patients initially defined as having sustained remission suffered a late relapse, which became evident 16, 28, and 32 months after cessation of IFNa therapy. In
TABLE 1 Analysis of the long-lasting efficacy of IFNa therapy in patients with sustained response followed during a period of 2–7 years No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age
52 25 23 32 29 73 34 37 30 41 30 63 55 43 32 46 27 29 37 47 30 47 60
Sex
f f f f f f f m f f m m f m m m m m m f f m m
Length of follow-up period (months) 24 25 26 27 30 31 35 41 42 46 57 58 58 59 62 63 70 76 78 78 80 82 84
Clinical presentation of patients with hepatitis C before starting IFNa HCV genotype
HCV RNA level ALT U/l (copies¿105)
Histological activity (Knodell)
2a 3a 3a 1b 3a 2b 3a 3a 1a 3a n.d 2b 1b 1b 3a 1b 1 3 3 1 1 2 1b
6.9 0.3 3.0 ∞0.1 ∞0.1 1.7 1.9 0.1 ∞0.1 ∞0.1 ∞0.1 5.7 1.0 0.9 ∞0.1 0.2 n d. n d. n.d. n d. n.d. n d. n.d.
6 2 6 10 4 11 2 3 9 8 4 12 10 11 6 10 4 8 4 11 8 8 11
91 14 37 28 37 102 118 32 21 96 28 72 267 82 28 30 65 48 150 276 75 52 36
Total IFNa dose (MU)
Occurrence of relapse (months after stopping IFNa)
216 218 216 216 72 216 216 216 216 432 720 216 360 720 720 720 432 432 432 432 432 432 432
yes (16) no no no no no no no no yes (28) no yes (32) no no no no no no no no no no no
ALT, alanine aminotransferase. f,female; m, male; IFNa, inteferon alpha. MU, million units. n.d., not done.
511
Correspondence two of these three patients, HCV RNA could be detected about 2 years before the disease exacerbated, while in the third patient the recurrence of hepatitis C viremia and rise in ALT levels occurred at the same time. Interestingly, ALT elevation was pronounced in all patients, resembling acute hepatitis. Comparing the 23 patients with sustained response and the 148 patients with non-response or relapse, it became evident that the patients with sustained response were significantly younger, had lower viremia level, and were less frequently infected with genotype 1 than the non-responders or responders with relapse (mean 39 vs. 47 years; mean 137 000 vs. 555 000 copies/ml [nΩ92]; and 39% vs. 83% genotype 1, p∞0.05). In contrast, the ALT levels (75∫68 vs. 69∫32 U/l) and the histological activity (8.6∫3 vs. 8.3∫3) as assessed by Knodell score showed no significant differences. Also, dosage (380∫193 vs. 362∫145 MU IFNa) and duration of IFNa therapy (9∫3 vs. 9∫3 months) had no influence on the clinical outcome. In conclusion, our data strongly imply that IFNa can induce a sustained remission of chronic hepatitis C, and that relapses may no longer occur after the phase of remission has lasted for more than 3 years. Thomas Berg1, Thomas Kaul1, Hans-Gerd Heuft1, Uta Naumann1, Hartmut Lobeck2, Bertram Wiedenmann1 and Uwe Hopf1 1 Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie and 2Pathologisches Institut, Universita¨tsklinikum Charite´, Campus Virchow-Klinikum, Humboldt-Universita¨t, Berlin, Germany
References 1. Vento S, Concia E, Ferraro T. Lack of sustained efficacy of interferon in patients with chronic hepatitis C. N Engl J Med 1996; 334: 1479. 2. Reichard O, Glaumann H, Fryden A, Norkrans G, Schvarcz R, Sonnerborg A, et al. Two-year biochemical, virological and histological follow-up in patients with chronic hepatitis C responding in a sustained fashion to interferon alfa-2b treatment. Hepatology 1995; 21: 918–22. 3. Teuber G, Dienes HP, Meyer zum Bu¨schenfelde KH, Gerken G. Long-term follow-up of patients with chronic hepatitis C after interferon-alpha treatment. Digestion 1996; 57: 464–71. 4. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-a therapy. Ann Intern Med 1997; 127: 875–81. 5. Camma` C, Di Marco V, Lo Iacono O, Almasio P, Giunta M, Fuschi P, et al. Long-term course of interferon-treated chronic hepatitis C. J Hepatol 1998; 28: 531–7.
Increased serum nitrite and nitrate concentrations in chronic hepatitis To the Editor: We read with interest the review article by Simpson et al. about cytokines and the liver (1). As mentioned in the article, circulating levels of cytokines, such as TNFa and IL6, increase during hepatitis, and in many studies enhanced hepatic expression of a variety of different cytokines has been demonstrated in patients with hepatic inflammation. There are many studies in the literature demonstrating that hepatocytes express iNOS following exposure to various cytokines such as TNF, IL1, IFN gamma and IL6 (2–4). Increased NO production and plasma nitrite/nitrate levels have also been found during chronic hepatic inflammation, suggesting a role for NO in mediating the hepatic response to inflammatory stimuli (5). We investigated serum nitrite/nitrate levels in patients with chronic hepatitis. Serum pools were prepared from 21 patients and 10 age/ sex-matched healthy control subjects. The etiology was hepatitis B in eight patients and hepatitis C in 13, while all had HAI scores between 6–8 and serum ALT levels between 65–80 u/l. All the patients had naive chronic hepatitis disease and had not received any treatment including interferon alpha. There were no cirrhotic patients in the study group; the fibrosis scores were between 1–3 in liver biopsies. Serum samples were deproteinized by zinc sulphate and, after reducing nitrate to nitrite (incubation in the presence of 20 mU nitrate reductase, 5 ml FAD, 0.6 nM NADPH in 50 nm phosphate buffer, pH 7.5 for 1 h at 37æC) total nitrite was measured by a procedure based on the Griess reaction (6,7). The mean serum nitrite/nitrate concentrations in patients and control subjects were 72.1∫6.91 mmol/l and 29.0∫4.6 mmol/l, respectively (Fig. 1). Thus, we concluded that serum nitrite/nitrate concentrations are increased in chronic hepatitis. There is a discrepancy between our results and previously reported studies which concluded that nitric oxide production was reduced or unchanged in chronic hepatitis (8–10). In the study reported by Moriyama et al., normal serum nitrite/nitrate levels were found in chronic hepatitis (8). However, interestingly, these authors found even higher values of nitrite and nitrate levels in patients with hepatocellular carcinoma based on chronic hepatitis than in patients with carcinoma
512
based on liver cirrhosis. A similar finding was also reported by Mihm et al. (10). These authors found that iNOS transcript expression was increased in chronic hepatitis C and, although this increase was not
Fig. 1. Total serum nitrite and nitrate concentrations (mmol/l in patients with chronic hepatitis and controls.