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The treatment of patients infected with hepatitis C virus (HCV) type 1 remains a challenge necessitating innovative strategies to improve treatment outcome. The extension of treatment duration beyond 48 weeks is one possible strategy to address this problem.The efficacy and safety of 48 weeks (group A, N = 230) vs 72 weeks (group B, N = 225) of treatment with pegylated-interferon-alfa-2a (180 microg/wk) plus ribavirin (800 mg/day) were studied in treatment-naive patients with HCV type 1 infection. On-treatment and sustained virologic response (SVR) 24 weeks after stopping treatment was assessed by qualitative reverse-transcription polymerase chain reaction (sensitivity 50 IU/mL).Overall, no significant differences could be observed in the treatment outcome between both groups. End-of-treatment and SVR rates in groups A and B were 71% vs 63% and 53% vs 54%, respectively. Patients with undetectable HCV-RNA levels already at weeks 4 and 12 had excellent SVR rates ranging from 76% to 84% regardless of treatment group, whereas patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 instead of 48 weeks (29% vs 17%, P = .040). A particular benefit from extended treatment duration was seen in patients with low-level viremia (6000 IU/mL) at week 12. The frequency and intensity of adverse events was similar between the 2 groups.Extended treatment duration generally is not recommended in HCV type 1 infection and should be reserved only for patients with slow virologic response defined as HCV-RNA positive at week 12 but negative at week 24.

Background & Aims: Pegylated interferon therapy has not been adequately evaluated in acute hepatitis C virus (HCV) infection. This randomized trial assessed the efficacy, safety, and timing of pegylated interferon alfa-2b for treatment of acute hepatitis C. Methods: One hundred seventy-five patients acutely infected with HCV were screened. Patients whose infection did not spontaneously resolve by week 8 were randomized to once weekly peginterferon alfa-2b monotherapy (1.5 μg/kg per week) started at weeks 8, 12, or 20 for a duration of 12 weeks. The primary endpoint was undetectable HCV RNA 24 weeks after the end of treatment (sustained virologic response [SVR]). All patients were followed for 48 weeks after cessation of therapy. Results: One hundred twenty-nine subjects started treatment at week 8 (group A, n=43), week 12 (group B, n=43), or week 20 (group C, n=43). By using an intent-to-treat analysis, the overall SVR rate was 87%. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Overall, SVR rates were better for patients infected with genotypes 2, 3, and 4 than those infected with genotype 1. Earlier initiation of therapy improved SVR rates for patients infected with genotype 1 with high viral load. Peginterferon alfa-2b was well tolerated. Subjects with SVR maintained undetectable HCV RNA 48 weeks after therapy. Conclusions: Peginterferon alfa-2b monotherapy in acute hepatitis C induces high sustained virologic response rates, prevents chronic evolution, and is well tolerated. Initiation of treatment at week 8 or 12 results in higher sustained virologic rates than initiation at week 20.

Background & Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown. Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-α-2a (180 μg/wk) plus ribavirin 800–1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patients with HCV RNA ≥600 IU/mL at week 4 (group C) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL). Results: Only 11 of 153 patients (7%) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82%, (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively. In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85%, respectively; P = .003). Conclusions: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-α-2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.

Background & Aims: Pegylated interferons (IFNs) with or without ribavirin were shown in several studies to improve sustained virologic response compared with standard IFN α-2 therapy. This study investigated if the greater efficacy of pegylated IFNs might be related to modulation of immunologic responses. Methods: Hepatitis C virus (HCV)-specific CD4+ T-cell responses and cytokine production to various HCV proteins (Elispot assay) in peripheral blood were prospectively assessed in 42 patients receiving IFN α-2a monotherapy, peginterferon (PEG IFN) α-2a monotherapy, or PEG IFN α-2a plus ribavirin and correlated to the outcome of therapy. Results: The sustained virologic response rate was significantly higher in the PEG IFN groups (42% in PEG IFN α-2a monotherapy and 57% in PEG IFN α-2a/ribavirin combination) than in the standard IFN α-2a group (14%). The sustained response was 48% in HCV genotype 1 patients treated with PEG IFN α-2a/ribavirin therapy. Pretreatment HCV-specific CD4+ responses were either weak or absent. PEG IFN alone or combined with ribavirin induced significant increase in the frequency, strength, and breadth of HCV-specific CD4 + T-cell responses with type 1 predominance; whereas interferon α-2a monotherapy was associated with lower, fluctuating, short-lived responses. Sustained responders maintained multispecific HCV-specific CD4 + T-cell responses with enhanced IFN-γ production. Relapsers and partial responders initially displayed significant HCV-specific CD4 + T-cell responses that waned or were lost. Conclusions: The efficacy of PEG IFN α-2a alone or in combination with ribavirin in inducing high rates of sustained virologic response may be owing to the higher efficacy of PEG IFN in induction and maintenance of significant multispecific HCV-specific CD4 + T-helper 1 responses. GASTROENTEROLOGY 2002;123:1070-1083

Background & Aims: Immune responses during the first few months of acute hepatitis C virus (HCV) infection seem crucial for viral control, but the relationship of these responses to natural history is poorly characterized. Methods: This prospective study investigated the HCV-specific CD4 + and cytokine responses in patients with acute HCV hepatitis with or without Schistosoma mansoni coinfection, a parasitic infection with T helper (Th) 2 immune bias. HCV-specific CD4 + proliferative responses and cytokine production in peripheral blood mononuclear cells were correlated with liver biopsy results at 6 months and at the end of follow-up. Results: Whereas 5 of 15 patients with HCV alone recovered from acute HCV, all (17 of 17) patients with S. mansoni coinfection progressed to histologically proven chronic hepatitis. Coinfected patients had either absent or transient weak HCV-specific CD4 + responses with Th0/Th2 cytokine production. The magnitude of the HCV-specific CD4 + response at week 12 was inversely correlated with the fibrosis progression rate in chronically infected patients. Conclusions: Patients with acute hepatitis C and schistosomiasis coinfection cannot clear viremia and show rapid progression once chronic infection is established. This rapid progression is associated with a strong Th2 response in peripheral immune responses, suggesting that early development of vigorous Th1 responses not only facilitates clearance but delays disease progression. GASTROENTEROLOGY 2001;121:646-656

Hepatitis C virus (HCV) results frequently in chronic hepatitis and its sequelae liver cirrhosis and hepatocellular carcinoma. Interferon-α is at present the most effective treatment, resulting in a sustained response in about 20–25% of patients. HCV genotype, titer and quasispecies determine the success of treatment. In this study, fluorescent single strand conformation polymorphism (f-SSCP) was evaluated for the analysis of HCV quasispecies. Two sera from a chronically HCV-infected patient, obtained 6 years apart, were examined. The hypervariable region I (HVRI) of the HCV genome was amplified by reverse transcription and PCR. The PCR products were cloned and sequenced or fluorescein-labeled and subjected to f-SSCP. Both methods demonstrated a single HCV species in the early serum and multiple quasispecies in the late serum. Single clones of the heterogenous virus population were used to optimize conditions for f-SSCP. The most important factors were the gel temperature and virus titer. At the optimal running temperature one base exchange in 218 bases was detectable. Repeat extractions and amplifications gave identical results. Dilution of the serum containing multiple quasispecies resulted in a ‘loss’ of species. Provided the running temperature is optimal and virus titer is sufficient, f-SSCP is shown to be fast and reliable for HCV quasispecies analysis.

A new procedure for sequence-independent PCR amplification of DNA fragments is described. DNA from pUC18 plasmid was used as a test DNA. It was digested with a frequently cutting restriction enzyme (Sau3A), generating sticky ends. The DNA was ligated to a synthetic, non-phosphorylated adaptor and subsequently amplified in a nested PCR using two oligonucleotides with sequences derived from the adaptor. As little as 1 fg of pUC18 DNA could be detected by this procedure. The product was analyzed on a gel and hybridized with a pUC18-specific probe. The sequence-independent nested PCR was repeated with different amounts of pUC18 DNA in the presence of an excess of non-specific DNA. In these experiments, pUC18 DNA fragments were amplified in a concentration-dependent manner. After hybridization with a digoxigenine dUTP-labelled pUC18 DNA probe, 1 fg of pUC18 DNA could still be detected. This method allows rapid screening of blood for low titred and mutated viruses in which primer binding sites are not conserved.

423 TREATMENT WITH PIRFENIDONE PRODUCES AN IMPORTANT REDUCTION IN NECROINFLAMMATION SCORE, FIBROSIS INDEX AND INCREASED GENE EXPRESSION OF CB2 IN PATIENTS WITH LIVER CIRRHOSIS L. Flores Contreras, A. Sandoval-Rodriguez, S. Lucano-Landeros, I. Arellano-Olivera, J. Armendariz-Borunda. Molecular Biology, Institute of Molecular Biology and Gene Therapy, CUCS, Universidad de Guadalajara, O.P.D. Hospital Civil ‘Juan I Menchaca’, Guadalajara, Mexico E-mail: lucia_floresc1@yahoo.com.mx

Background & Aims There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. Methods We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long-term extension studies (4−6 years), as well as in patients with decompensated cirrhosis (2 years). Results eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4−6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60−89 mL/min/1.73 m 2 (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5−6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). Conclusions In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function—particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined.

vs. 32% (p =0.015), and prior ADV 14% vs. 25% (p =0.044). Tenofovir (TFV) PK parameters (AUCt, Cmax, Tmax) in MRI were comparable to historical data in NRF, and there was no correlation between steady-state TFV exposures (AUCt) and BL CrCL. TDF was well tolerated overall; 3 patients (1.1%) discontinued the study early for an AE (2-MRI and 1-NRF). No patients had a confirmed increase in serum creatinine of ≥0.5mg/dL, and 1% (2-NRF) had transient PO4

ETR 4/31 (13%) 20/53 (38%) 84/100 (84%) 184/192 (96%) 4/57 (7%) 155/176 (88%) SVR 2/4 (50%) 13/20 (65%) 51/84 (61%) 143/184 (78%) 1/4 (25%) 100/155 (65%) Relapse 2/4 (50%) 7/20 (35%) 27/84 (32%) 40/184 (22%) 2/4 (50%) 47/155 (30%) CC 0/1 0/3 4/13 (31%) 22/91 (24%) 0/0 15/49 (31%) CT 2/3 (67%) 6/13 (46%) 14/47 (30%) 14/72 (19%) 2/3 (67%) 23/81 (28%) TT 0/0 1/4 (25%) 6/19 (32%) 1/9 (11%) 0/1 6/17 (35%)