Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels: a matched case-control study.

BACKGROUND: The antiviral effect of pegylated interferon (Peg-IFN) plus ribavirin combination therapy in chronic hepatitis C (CHC) patients with normal alanine aminotransferase (ALT) levels (N-ALT) has been reported to be equivalent to that for patients with elevated ALT levels (E-ALT). However, the actual antiviral effect in N-ALT patients remains obscure because efficacy can be overestimated in patients with an advantageous background. METHODS: In this study, 386 patients were extracted, for a matched case-control study, from 1320 CHC patients treated with Peg-IFN alpha-2b plus ribavirin combination therapy; 193 N-ALT patients [116 with hepatitis C virus genotype 1 (HCV-1), 77 with HCV genotype 2 (HCV-2)] were matched with 193 E-ALT patients by a propensity score method using the variables of age, sex, IFN treatment history, body mass index, and platelet counts. RESULTS: On multivariate analysis for sustained virological response (SVR) in N-ALT patients, younger age, low HCV RNA level at baseline, and HCV-2 were significant factors. The matched case-control study showed that the SVR rates of N-ALT patients were equivalent to those of E-ALT patients; at 49 and 40% in the HCV-1 group (P = 0.146), and 78 and 81% in the HCV-2 group (P = 0.691). However, in N-ALT patients with non-SVR, approximately 40% showed ALT elevation at 24 weeks post-treatment. CONCLUSION: Our findings indicate that the antiviral effect of Peg-IFN plus ribavirin therapy in N-ALT patients is comparable to that for E-ALT patients irrespective of their advantageous background; however, the application of this therapy for N-ALT patients, especially for those with HCV-1, should be considered carefully.

Two types of drug-resistant hepatitis B viral strains emerging alternately and their susceptibility to combination therapy with entecavir and adefovir.

The most serious problem of nucleoside/nucleotide analogue therapy for hepatitis B virus (HBV) infection is the emergence of drug-resistant mutant virus. Here, we describe a patient with chronic hepatitis B infection with a complex drug-resistant mutant virus during sequential therapy with lamivudine (3TC), entecavir (ETV) and adefovir dipivoxil (ADV). The patient was a 52-year-old male with positive hepatitis B e antigen and high HBV DNA (>7.6 log(10) copies/ml). Initial 3TC monotherapy offered little benefit and 3TC resistance was established by the virus with rtA181T and not rtM204V/I. HBV DNA was reduced slightly by replacement with ETV monotherapy and was followed by virological breakthrough. At that time, rtA181T was undetectable and the virus with rtM204V and rtL180M became predominant. ETV resistance was established by an additional rtS202G mutation. Efficacy of subsequent combination therapy with ADV and 3TC was limited because of reappearance of the virus with rtA181T, which might confer cross-resistance to 3TC and ADV. Final combination therapy with ETV and ADV reduced HBV DNA to 3.7 log(10) copies/ml for 5 months, which was the most effective therapy for this patient. Thus, two kinds of mutant viruses (rtM204V-related and rtA181T-related) appeared alternately in this patient. Combination therapy with ETV and ADV might have been effective because these drugs share therapeutic roles, that is, ETV affects the rtA181T-related virus and ADV affects the rtM204V-related virus. This is the first report suggesting clinical significance of combination therapy with ETV and ADV for controlling replication of the complex drug-resistant mutant HBV.

Lamivudine-to-entecavir switching treatment in type B chronic hepatitis patients without evidence of lamivudine resistance.

PURPOSE: A considerable number of chronic hepatitis B (CH-B) patients remain under continuous lamivudine treatment, although switching treatment to entecavir could be beneficial. We investigated the antiviral efficacy of switching treatment to entecavir in CH-B patients without apparent evidence of lamivudine resistance during the preceding lamivudine treatment. METHODS: Forty-four CH-B patients, who underwent lamivudine treatment for more than 6 months and showed no evidence of lamivudine resistance, switched to entecavir. Serial changes in hepatitis B virus (HBV) DNA were correlated with the patients' baseline HBV DNA at the commencement of entecavir administration. The entecavir-resistant substitution was examined by PCR-direct sequencing. The median follow-up period of entecavir treatment was 20 (10-23) months. RESULTS: All 31 patients with baseline HBV DNA <2.6 logcopies/ml maintained HBV DNA-negative status during entecavir treatment. Of seven patients having HBV DNA of 2.6-<4.0 logcopies/ml, all achieved undetectable HBV DNA at the end of follow-up. As for six patients having HBV DNA >or=4.0 logcopies/ml, three patients achieved undetectable HBV DNA, whereas virological breakthrough was observed in one patient at month 15. An entecavir-resistant virus having rtM204V, rtL180M and rtS202G substitutions was detected in this patient. CONCLUSIONS: The lamivudine-to-entecavir switching treatment may be generally recommendable in CH-B patients without evidence of lamivudine resistance during the preceding lamivudine treatment. However, great care should be taken with respect to the emergence of entecavir-resistance, especially in patients who do not respond well to the preceding lamivudine treatment.

Factors contributing to antiviral effect of adefovir dipivoxil therapy added to ongoing lamivudine treatment in patients with lamivudine-resistant chronic hepatitis B.

PURPOSE: The antiviral effect of adefovir dipivoxil (ADV) added to ongoing lamivudine (LAM) treatment for LAM-resistant chronic hepatitis B (CHB) differs among patients. We investigated clinical factors affecting the response to ADV therapy in LAM-resistant CHB. METHODS: The subjects were 75 LAM-resistant CHB patients treated with ADV in addition to LAM. Virological response (VR) was defined as HBV DNA clearance (<2.6 logcopies/ml) at 12 months after the start of ADV therapy. Clinical factors contributing to VR were examined by univariate and multivariate analyses. RESULTS: Lower HBV DNA at baseline and negative hepatitis B e antigen (HBeAg) were significant factors affecting VR in univariate analysis. In multivariate analysis, lower HBV DNA at baseline (P = 0.005), negative HBeAg (P = 0.009), and higher ALT (P = 0.036) were significant independent factors contributing to VR. In HBeAg-positive patients, HBV DNA clearance was more frequently observed during ADV therapy in patients with baseline HBV DNA < or = 7.0 logcopies/ml than in those with baseline HBV DNA >7.0 logcopies/ml. By contrast, the link of lower HBV DNA at baseline to better therapeutic response was not evident in HBeAg-negative patients. CONCLUSION: In ADV therapy added to ongoing LAM treatment for LAM-resistant CHB, lower baseline HBV DNA and negative HBeAg contributed to a better antiviral effect. Addition of ADV should be done promptly before marked increase in HBV DNA, especially in CHB patients showing LAM resistance positive for HBeAg.

Effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis.

AIM: The objective of this study was to elucidate the long-term effects of interferon (IFN)alpha-2b plus ribavirin combination therapy and to clarify whether this therapy can reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. METHODS: A total of 403 patients infected with hepatitis C virus (HCV) were enrolled in a multicenter trial. All patients were treated with a combination of IFN-alpha-2b plus ribavirin therapy. We examined the incidence of HCC after combination therapy and analyzed the risk factors for liver carcinogenesis. RESULTS: A sustained virological response (SVR) was achieved by 139 (34%) of the patients. The cumulative rate of incidence of HCC was significantly lower in SVR patients than in non-SVR patients (P = 0.03), while there was no difference in the cumulative incidence of HCC between the transient response (TR) group and the no response (NR) group. Cox's regression analysis indicated the following risk factors as independently significant in relation to the development of HCC: age being > 60 years (P = 0.006), advanced histological staging (P = 0.033), non-SVR to IFN therapy (P = 0.044). The cumulative incidence rate of HCC was significantly lower in patients who had average serum alanine aminotransferase (ALT) levels of < 40 IU/L than in those who showed average serum ALT levels of >== 40 IU/L after the combination therapy (P = 0.021). CONCLUSIONS: These results suggest that the attainment of SVR or continuous normalization of ALT levels after IFN therapy can affect patients apart from HCC development.

Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.

AIM: Lamivudine (LAM) has been widely used to treat chronic hepatitis B (CHB) patients, but the emergence of a LAM-resistant virus greatly limits its therapeutic efficacy. In this study, we tried to identify factors affecting the emergence of a LAM-resistant virus in CHB patients treated with LAM. METHODS: The subjects were 190 CHB patients in continuous LAM therapy (139 males, mean age 50 years, 87 HBeAg-positive). The mean duration of follow-up was 39 months (range 12-104). The initial viral response (IVR) was defined as HBV DNA < 4.0 logcopies/mL, and the initial biochemical response (IBR) as normalization of alanine aminotransferase (ALT) (<40 IU/L) at 6 months. RESULTS: IVR was positive in 86% of the patients. The cumulative emergence rates of LAM-resistant virus were 10% at 1 year, 30% at 2 years and 46% at 3 years. In univariate analysis, factors contributing to the emergence of LAM-resistant virus were baseline HBV DNA > 6.5 logcopies/mL (P = 0.0044), HBeAg-positivity (P = 0.0062), IBR (P = 0.01) and IVR (P < 0.0001). The cumulative emergence rates of LAM-resistant virus in IVR-positive and -negative patients were 4% and 41% at 1 year, and 41% and 79% at 3 years. In multivariate analysis, only IVR was an independent factor affecting the emergence of LAM-resistant virus (P < 0.0001). CONCLUSION: IVR is a useful factor for predicting the emergence of LAM-resistant virus in CHB patients treated with LAM. For IVR-negative patients, therapeutic options other than LAM monotherapy should be used because of the high incidence of the emergence of LAM-resistant virus.

Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C.

AIM: Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin-induced anemia. METHODS: One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) alpha-2b and ribavirin. The mean age was 50.6 years and 55% were IFN naïve. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment ("2 by 2" standard) was adopted as the predictive factor for the progression of anemia. RESULTS: By applying the "2 by 2" standard, with DeltaHb >/= 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForDeltaHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb /= 2 g/dL group, with none in the DeltaHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb

Early decline of hemoglobin correlates with progression of ribavirin-induced hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C.

BACKGROUND: The aim of this study was to examine the factors correlated with the progression of ribavirin-induced hemolytic anemia in patients with chronic hepatitis C treated by interferon and ribavirin combination therapy. METHODS: This study was conducted on 505 patients by the Osaka Liver Disease Study Group. A decline of hemoglobin (Hb) concentration by 2 g/dl at the end of 2 weeks from the start of the treatment ("2 by 2" standard) was adopted as a predictive factor for progression to severe anemia. The ribavirin apparent clearance (CL/F) was also examined. RESULTS: Of 482 patients whose Hb value was more than 12 g/dl before the treatment, 68 patients (14%) had to discontinue ribavirin owing to severe anemia. Patients in the "2 by 2"-positive group (Hb decline over 2 g/dl) and the group with lower CL/F were significantly more likely to discontinue ribavirin owing to severe anemia. Discontinuation was more common among patients aged 60 years or older than for those under 60 years old (21% vs. 9%, P < 0.001). Among patients aged 60 years or older, only the "2 by 2" standard was significantly associated with the discontinuance of ribavirin owing to severe anemia in a multivariate analysis (odds ratio, 4.18; P < 0.001). CONCLUSIONS: The "2 by 2" standard of Hb decline can be used to identify patients likely to develop severe anemia. The early reduction of ribavirin can help prevent progression to severe anemia, thus allowing ribavirin therapy to be completed even in older patients.

Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy?

UNLABELLED: The aim of this study was to investigate the efficacy and safety of combination therapy of interferon and ribavirin for aged patients with chronic hepatitis C. METHODS: This study was conducted at Osaka University Hospital and institutions participating in the Osaka Liver Disease Study Group on 329 patients with chronic hepatitis C receiving interferon and ribavirin combination therapy (group A, under 60 year old, n=199; group B, 60-64 year old, n=64; group C, over 65 year old (mean age, 67.8+/-2.2 year old, n=66)). Of the 293 patients who were tested for HCV serotype and HCV viral loads, 215 had HCV-RNA with serotype 1 and high viral loads (1H) and the other 78 had HCV-RNA with serotype 2 or low viral loads (non-1H). RESULTS: In per-protocol analysis, the overall SVR rate of 1H patients was 28% (51/184). Among the 1H patients, the SVR rate was significantly lower in group C (16%) and group B (17%) than in group A (34%) (p<0.05). The overall SVR rate of non-1H patients was 85% (57/67). No significant difference was found in the SVR rate among group C (79%), group B (100%), and group A (84%). On the other hand, the discontinuance of both drugs due to side effects was 29% (19/66) in group C, 20% (13/64) in group B, and 11% (21/199) in group A, with the discontinuance rates being higher in the older group (p=0.002). CONCLUSIONS: In aged chronic hepatitis C patients, interferon and ribavirin combination therapy can be recommended for the non-1H patients who showed a high SVR rate of approximately 65%, but not for the 1H patients.