Analytical and clinical sensitivity of the Procleix Ultrio HIV-1/HCV/HBV assay in samples with a low viral load.

BACKGROUND AND OBJECTIVES: The Procleix Ultrio human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV)/hepatitis B virus (HBV) (Ultrio) assay simultaneously detects HIV-1 RNA, HCV RNA and HBV DNA in individual blood donations. The main objective of the study was to assess the analytical and clinical sensitivity of the multiplex and discriminatory probe assays in samples with a low viral load. MATERIAL AND METHODS: The VQC HIV RNA genotype B, HCV RNA genotype 1 and HBV DNA genotype A standard dilutions were tested in 26 repeats. The probability of detection by Ultrio was compared with previously obtained data of the Procleix Duplex HIV-1/HCV assay on the same reference panels. A selection of 121 anti-HIV-1, 138 anti-HCV and 190 HBsAg positive samples from patients receiving antiviral therapy were tested. The majority of patient samples had a viral load below the detection limit of the diagnostic nucleic acid test assays, which made them suitable to evaluate the performance of the multiplex and discriminatory assays on yield cases with a similar low viral load. RESULTS: The 95% and 50% detection end-points of the Ultrio assay along with the corresponding 95% confidence intervals are 53.7 (32.9-117.2) and 8.6 (6.2-12.1) geq/ml for HIV-1 RNA, 30.3 (19.0-62.4) and 5.2 (3.7-7.2) geq/ml for HCV RNA and 393.7 (147.9-6978) and 54.5 (22.4-143.8) geq/ml for HBV DNA. The analytical sensitivity of Ultrio expressed as a potency factor relative to previously obtained Duplex results on the same HIV-1 RNA and HCV-RNA standard dilutions was 1.09 (0.20-6.10) and 1.11 (0.21-5.89), respectively. The assay detected all 22 HIV-1 infected patients with viral load > 50 copies/ml, and 41 of 99 patients (41%) with viral load < 50 copies/ml, of which 23 (56%) were detected by the discriminatory assay. All 47 patients with HCV RNA load > 521 IU/ml and 10/91 polymerase chain reaction-negative patients with viral load < 50 IU/ml tested positive in Ultrio assay of which five were missed in the discriminatory test. The assay detected 53/55 HBV infected patients (96%) with viral load > 250 copies/ml and 108/135 patients (80%) with viral load < 250 copies/ml of which 17 (16%) were missed by the discriminatory test. CONCLUSIONS: The new Procleix Ultrio assay is as sensitive as the Procleix Duplex assay for HIV-1 and HCV detection meeting the requirements of universal guidelines. The ability of the assay to detect HBV DNA in low viral load samples could be useful for screening blood. Inevitable negative results of discriminatory probe assays caused by stochastic sample variation will reduce the chance of recognizing low viraemic blood donors detected by individual donation nucleic acid test.

Molecular epidemiology of hepatitis C virus (HCV) in Greece: temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.

This study aimed to estimate the overall HCV genotype distribution and to reconstruct the HCV genotype-specific incidence in Greece during the recent decades. It also focused at the identification of genotype 4 subtype variability in Greek isolates. A total of 1686 chronically infected HCV patients with detectable serum HCV RNA by RT-PCR, belonging to different risk groups were studied. Amplified products from the 5'-noncoding region were typed using a commercially available assay based on the reverse hybridization principle. The HCV genotype-specific incidence was estimated using a previously described back calculation method. HCV genotype 1 was the most prevalent (46.9%) followed by genotype 3 (28.1%), 4 (13.2%), 2 (6.9%) and 5 (0.4%). A high prevalence of genotype 1 (66.3%) in haemophilia patients was recorded whereas HCV genotype 3 was found mainly among patients infected by I.V. drug use (58.2%). Data on the temporal patterns of HCV genotype-specific incidence in Greece revealed a moderate increase (1.3-1.6 times) for genotypes 1 and 4, and a decrease (1.5 times) for genotype 2 from 1970 to 1990, whereas there was a sharp (13-fold) increase for genotype 3. The molecular characterization of 41 genotype 4 HCV isolates belonging to various risk groups revealed that, subtype 4a was the most frequently detected (78%). Phylogenetic comparison of the Greek 4a isolates with all HCV-4a isolates reported worldwide so far revealed a topology which does not discriminate Greek isolates from the others. HCV-4 does not represent a recent introduction in Greece.

Future trends of HCV-related cirrhosis and hepatocellular carcinoma under the currently available treatments.

SUMMARY: The epidemic of hepatitis C virus (HCV) infection is a major public health issue. We conducted a comprehensive analysis to estimate future HCV-related morbidity and mortality, using a model which is the first to take into account currently available treatments. We reconstructed the incident infections per year in the past that progressed to chronic hepatitis C (CHC) in Greece. Then, the natural history of the disease was simulated in subcohorts of newly infected subjects in the presence or absence of treatment using yearly estimates of the number of treated patients obtained from national databases. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, hepatocellular carcinoma (HCC) and mortality were obtained up to 2030. The current proportion of naïve CHC patients receiving treatment in Greece is 1.2% per year. Treatment of 1.2-10% of naïve CHC patients per year would reduce the cumulative number of incident cirrhosis and HCC cases from 2002 to 2030 by 10.8-39.4% and 12.8-39.8%, respectively and decrease the number of prevalent cirrhosis and HCC cases in 2030 by approximately 17-48% compared with the number estimated under the assumption of no treatment. Approximately 17 cirrhosis cases or six HCC cases or 10 premature deaths would be prevented for every 100 treated patients. However, the prevalent cirrhotic/HCC cases because of HCV and HCV-related deaths would not plateau until 2030. Despite the introduction of effective treatment, HCV-related morbidity and mortality will likely increase during the next 20-30 years in Greece. Intensive primary prevention efforts coupled with increased access to the currently available treatments are necessary to control the chronic consequences of HCV epidemic.

Reconstructing and predicting the hepatitis C virus epidemic in Greece: increasing trends of cirrhosis and hepatocellular carcinoma despite the decline in incidence of HCV infection.

In this study, a comprehensive methodology for modelling the hepatitis C virus (HCV) epidemic is proposed to predict the future disease burden and assess whether the recent decline in the incidence of HCV may affect the future occurrence of cirrhosis and hepatocellular carcinoma (HCC) cases. Using the prevalence of HCV, the distribution of chronic hepatitis C (CHC) patients within the various transmission groups and their infection-onset times, it was possible to reconstruct the incident infections per year in the past that progressed to CHC in Greece. The natural history of the disease was simulated in subcohorts of newly infected subjects using transition probabilities derived either empirically between fibrosis stages 0-4 or from literature review. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, HCC and mortality in Greece were obtained up to 2030. HCV incidence peaked in the late 1980s at five new infections/10,000 person-years. Under the assumption of 20-100% decline in HCV incidence after 1990, the cumulative number of incident cirrhosis and HCC cases from 2002-2030 was projected to be lower by 9.6-48.2% and 5.9-29.5%, respectively, than that estimated under the assumption of no decline. However, the prevalent cirrhotic/HCC cases and HCV-related deaths are predicted to decline in the next 30 years only under the assumption of complete elimination of new HCV infections after 1990. Despite the progress in the reduction of HCV transmission, primary prevention does not seem adequate to reverse the rise in the incidence of cirrhosis and HCC.

A randomized trial to assess the efficacy of interferon-alpha daily in combination with ribavirin in the treatment of naïve patients with chronic hepatitis C.

A randomized trial was conducted to assess the efficacy of interferon-alpha (IFN) daily in combination with ribavirin in 301 naïve patients with chronic hepatitis C (CHC). Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n = 147). Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P = 0.87). The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD (P = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW (P = 0.038). Low baseline viral load (P = 0.017) and genotype non-1 (P = 0.036) were associated with higher SVR rates. Combination of IFN/ribavirin for 48 weeks is more effective when IFN is administered daily for the first 24 weeks in naïve patients with CHC.

A randomized trial to assess the efficacy of interferon alpha in combination with ribavirin in the treatment of interferon alpha nonresponders with chronic hepatitis C: superior efficacy of high daily dosage of interferon alpha in genotype 1.

A randomized trial was conducted to assess the efficacy of daily (QD) or thrice weekly (TIW) administration of interferon-alpha (IFN) in high doses in combination with ribavirin (1.0-1.2 g/day) in patients with chronic hepatitis C (CHC) who were nonresponders to previous IFN monotherapy. Interferon was administered as 10 MU IFN (QD or TIW) for 4 weeks, followed by 5 MU IFN (QD or TIW) for 20 weeks, and then by 3 MU IFN (QD or TIW) for 24 weeks. Sustained virological response (SVR) was evaluated in 142 patients who received at least one dose of medication. One-fourth of the patients achieved SVR, 26% of those treated with IFN QD and 25% of those treated with IFN TIW (P = 0.85). For genotype 1 patients, SVR rates were 32.4 and 15.8% for IFN QD and IFN TIW, respectively, whereas for genotype non-1 patients the corresponding SVR rates were 20.6 and 36.4%, respectively (test of homogeneity: P = 0.031). This finding was further confirmed by multivariate logistic regression analysis where a statistically significant interaction (P = 0.012) was found between treatment and HCV genotype indicating that the IFN QD regimen was superior to IFN TIW among genotype 1 patients whereas, among genotype non-1 patients, the two treatments were similar (odds ratio of SVR in IFN QD vs IFN TIW: 3.33 among genotype 1 patients, 95% CI: 1.00-11.14). In conclusion, re-treatment of patients not responding to previous IFN monotherapy with a combination of high daily dose of IFN with ribavirin may be beneficial for genotype 1 infected patients.

Prevalence and genotypic distribution of TT virus in Athens, Greece.

The prevalence of TT virus (TTV) infection in various population groups from Athens, Greece, was assessed by the polymerase chain reaction (PCR) using two primer sets from distinct regions of the genome: the conventional set derived from the open reading frame-1 (ORF-1) and the new, highly sensitive set targeting the region that includes the TATA signal localized upstream of ORF-2. Based on both primer sets, TTV DNA was detected in 42/50 (84.0%) healthy individuals, 42/50 (84.0%) chronic hepatitis C patients, 31/39 (79.5%) acute non-A-E hepatitis patients (group I), 14/16 (87.5%) renal failure patients with acute non-A-E hepatitis (group II), 47/50 (94.0%) intravenous drug users (IVDU), 36/50 (72.0%) hemophiliacs, and 21/31 (67.7%) hemodialysis patients. The presence of TTV was not associated with any particular risk group, and no differences were observed in relation to demographic, biochemical and virological characteristics between TTV DNA-positive and -negative patients. TTV did not seem to have a profound effect on the course of chronic C or acute non-A-E hepatitis either. Phylogenetic analysis revealed that TTV strains circulating in the greater metropolitan area of Athens belong not only to the G1 and G2 genotypes that are encountered worldwide, but also to G3 and to G5 that are found mainly in Europe and Asia, respectively. Further studies will shed light on the role of this highly prevalent virus.

Molecular epidemiology of GB virus C/hepatitis G virus in Athens, Greece.

The relevance of GB virus C/hepatitis G virus (GBV-C/HGV) infections in liver pathology remains unclear. To investigate the epidemiology of GBV-C/HGV in Athens, Greece, sera from 512 subjects were screened for present and past markers of GBV-C/HGV infection using a reverse transcription-polymerase chain reaction (RT-PCR) and a serological assay, respectively. GBV-C/HGV RNA was detected in 18/56 (32.1%), 12/42 (28.6%), and 16/55 (29.1%) patients with acute hepatitis B, C, or non-A-E, and in 5/58 (8.6%) and 18/68 (26.5%) patients with chronic hepatitis B or C, respectively, as well as in 50/133 (37.6%) hemodialysis patients and 10/100 (10%) healthy individuals. The data indicated that GBV-C/HGV seroprevalence is age-dependent; thus, GBV-C/HGV RNA and anti-E2 positivity were shown to be associated with younger age [odds ratio 0.98, 95% confidence interval (CI) 0. 97-1.00, P = 0.017] and older age (odds ratio 1.03, 95% CI 1.01-1.05, P = 0.002), respectively. No significant associations were identified between GBV-C/HGV RNA status and alanine aminotransferase (ALT) levels in either hepatitis or hemodialysis patients. Nevertheless, GBV-C/HGV RNA-positive acute non-A-E hepatitis patients were more likely to manifest a more severe clinical form of acute hepatitis (P = 0.024). Phylogenetic analysis of partial 5'-untranslated region sequences isolated from 18 viremic individuals showed that most GBV-C/HGV strains circulating in the greater metropolitan area of Athens belong to the 2a subgroup. A genetically diverse type 2 sequence that may represent a novel subtype within group 2 was also characterized.

Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.

This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P <.001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (>/=2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B.

Novel hepatitis E virus (HEV) isolates from Europe: evidence for additional genotypes of HEV.

Hepatitis E infection is associated with areas in which hepatitis E virus (HEV) infection is endemic. Acute infections in industrialized nations are usually linked to travel to endemic areas. Recently, an acute hepatitis infection in a patient from the United States (US), with no recent foreign travel history, was linked to a novel strain of HEV. Although a few additional cases have been reported from patients who have not traveled to endemic areas, the source of these infections has not been determined. The objective of this study was to identify additional HEV isolates from patients with acute infection who had no recent history of travel to areas where HEV is considered endemic, and to determine the genetic relationship between these and other HEV isolates. Viral RNA was isolated from serum and polymerase chain reaction (PCR) was performed using consensus primers based on a number of HEV isolates. HEV sequence in open reading frame (ORF) 1 and ORF2 was identified in three patients from nonendemic areas, one from Italy and two from Greece. Comparative and phylogenetic analyses were performed. The Greek and Italian isolates were significantly divergent from two isolates from the US and isolates identified previously from HEV-endemic regions. The Italian isolate was distinct from the two Greek isolates. In addition, the two Greek isolates were significantly divergent from each other. Phylogenetic analysis indicated that the Italian and two Greek isolates represent three new genotypes of HEV, distinct from the Burmese, Mexican, and US genotypes.

Treatment of patients with chronic hepatitis C and normal ALT levels.

A certain group of patients with chronic hepatitis C have normal serum alanine aminotransferase (ALT) levels, despite the replication of hepatitis C virus (HCV) in infected liver cells and detection of HCV RNA in serum. These patients are usually asymptomatic and are discovered fortuitously, generally after a volunteer blood donation. A standard definition for this group of patients is obviously needed, which should include the presence of anti-HCV, detectable serum HCV RNA by polymerase chain reaction and persistently normal ALT levels. These patients have minimal or mild necroinflammatory lesions in liver tissue specimens and cirrhosis is rare. The natural course of the disease in this epidemiologic setting is unknown, but the progression is probably good. Alpha-interferon has been administered in small pilot studies and three controlled studies. Overall, the end of treatment response was 35% and the sustained virologic response 15%. These response rates are similar to those reported in patients with elevated ALT levels. More important, serum ALT levels became abnormal during therapy in 47% of the patients and levels remained elevated in some patients after therapy. Prospective studies on the long-term natural history of HCV infection in this setting are needed and well designed randomized controlled trials are necessary to determine whether these patients would benefit from IFN or a combination treatment with ribavirin regimen. Currently, there is no rationale to treat these patients.

Factors associated with severity and disease progression in chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C appears to have a highly variable natural course with 20% of patients developing cirrhosis within 20 years, while the majority of them run a relatively mild course. We studied the relationships of epidemiological, biochemical and virological features with histological severity (grade) and liver disease progression (stage). METHODOLOGY: Liver histology, serum HCV RNA level and HCV genotype were determined in a well-defined cohort of 152 consecutive (100 males, 52 females) patients with chronic hepatitis C. RESULTS: Patients with minimal or mild chronic hepatitis were significantly younger than those with moderate or severe chronic hepatitis (mean age: 41.1 vs 49.5 years respectively, p=0.003). On the other hand, patients with no or mild fibrosis compared to those with moderate or severe fibrosis and to those with cirrhosis were significantly more frequently males (73%, 64% and 43%, p=0.01), parenteral drug users (36%, 11% and 11%, p=0.01) and infected with other than 1b genotype (86%, 52% and 33%, p<0.0001), significantly younger (mean age: 37, 48 and 58 years, p<0.0001) and had significantly lower HCV RNA levels (geometric mean: 6.9, 19.2 and 17.5 x 10(5) eq/ml, p=0.007). Multivariate analysis showed that stage was significantly related only to patient age (p<0.0001), HCV genotype (p=0.0025) and HCV RNA level (p=0.044). CONCLUSIONS: In chronic hepatitis C, histological severity seems to be associated only with patient age, while progression of the disease is mainly associated with patient age, HCV genotype and viremia level.

Significance of IgM anti-HCV core level in chronic hepatitis C.

AIM: To investigate the significance of IgM antibody to hepatitis C virus (HCV) core antigen (IgM anti-HCV core) in chronic hepatitis C. METHODS: In a group of 112 patients with histologically proven chronic hepatitis C positive for HCV RNA, IgM anti-HCV core level was studied by a sensitive semi-quantitative enzyme immunoassay. Quantitation of serum HCV RNA was done by a second generation bDNA assay and determination of HCV genotype by RT-PCR and reverse hybridization. RESULTS: IgM anti-HCV core was detected in 72 (64.3%) of the 112 patients. ALT levels were significantly higher in IgM anti-HCV core positive than negative patients. No other significant difference was observed in any of the patients' characteristics between IgM anti-HCV core positive and negative groups. On the contrary, IgM anti-HCV core level was found to be significantly higher in females than in males, in patients with moderate or severe chronic hepatitis, in patients with high HCV RNA levels and in patients infected with HCV genotype 1b. Moreover, IgM anti-HCV core level was significantly correlated with age and ALT level. Multiple regression analysis showed that IgM anti-HCV core level was significantly related only to the HCV genotype (p=0.001), histological grade (p=0.017) and ALT level (p=0.038). CONCLUSIONS: Our data support the hypothesis that IgM anti-HCV core level is associated mainly with HCV genotype and secondly with liver disease necroinflammatory activity. These associations may have implications in the pathogenesis of chronic hepatitis C.

Differential diagnosis of acute HBsAg positive hepatitis using IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay.

BACKGROUND/AIMS: We determined the diagnostic significance of IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay (IMx CORE-M) in acute HBsAg positive hepatitis. METHODS: We studied prospectively for at least 6 months 100 patients with acute self-limited hepatitis B (group A) and 40 patients with acute hepatitis superimposed on histologically confirmed chronic hepatitis B (group B). On admission, all patients in group A were positive and those in group B were negative for IgM anti-HBc by a commercially available enzyme immunoassay. RESULTS: Based on the assay criteria, the rates of IMx CORE-M (> 1.2) positive serum samples on admission, 4, 12 and 24 weeks later were: in group A: 100%, 95%, 72%, 44% and in group B: 20%, 27.5%, 17.5%, and 15%, respectively. Misclassification was observed in 20-27.5% of the acute on chronic hepatitis B cases. However, the mean IMx CORE-M index value was found to be significantly higher in group A during the whole follow-up. In particular, on admission the mean IMx CORE-M index value was 2.504 +/- 0.435 (range: 1.508-3.482) in group A and 0.747 +/- 0.346 (range: 0.062-1.384) in group B (p < 0.001). Discriminant function analysis showed that the cutoff level between the two groups for IMxCORE-M index on admission was 1.5. Four to 12 weeks from admission, in the group with acute on chronic hepatitis B cases, 13 patients with HDV and/or HCV superinfection had significantly lower IMx-CORE M index values compared with 27 patients with acute hepatitis due to exacerbation of chronic hepatitis B. CONCLUSIONS: IMx CORE-M appears to be an accurate diagnostic test to differentiate acute from acute on chronic HBsAg positive hepatitis, but the cut-off level seems to be higher (1.5 instead of 1.2).

Recombinant interferon-alpha therapy for acute hepatitis B: a randomized, double-blind, placebo-controlled trial.

In spite of the availability of hepatitis B vaccine, acute hepatitis B continues to be a worldwide problem for which no specific therapy is available. We investigated the safety and the effectiveness of recombinant interferon-alpha2b (rIFN-alpha2b) in the treatment of acute hepatitis B by determining overall severity and duration of symptoms, time required to clear viral antigens and hepatitis B virus (HBV) DNA, and titre of antibodies to hepatitis B surface antigen (HBsAb), 24 weeks after the onset of therapy. One hundred patients were randomly assigned to treatment with either 3 million units (MU) (n = 34) or 10 MU (n = 33) rIFN-alpha2b or to placebo (n = 33), three times weekly for 3 weeks. Follow-up was for 24 weeks. A significantly shorter duration of the symptoms and signs of acute hepatitis was observed in patients who received 3 MU rIFN-alpha2b compared with those who received 10 MU rIFN-alpha2b or placebo. Twenty-one weeks post-therapy, patients treated with 10 MU rIFN-alpha2b showed a significantly higher geometric mean HBsAb titre than those treated with placebo (85.1 vs 35.5 IU l-1, P < 0.05). rIFN-alpha2b administration was well tolerated even in jaundiced patients. No serious side-effects were observed necessitating reduction in dose or discontinuation of the drug. The effect of rIFN-alpha2b on transition of HBV infection to chronicity could not be evaluated in this trial because such an unfavourable course was not seen in any of the treated or the control patients. In conclusion, rIFN-alpha2b was safe in acute hepatitis B, and at low dose was found to ameliorate symptoms and to shorten significantly the duration of illness.

Patterns of progression: unpredictability and risk of decompensated cirrhosis.

Hepatitis C virus (HCV) infection appears to have a slow but progressive evolution to chronic hepatitis and cirrhosis in a significant percentage of patients. Chronic hepatitis develops in 60-80% of patients. Worldwide prospective studies have shown that a further 20-30% of patients with chronic active hepatitis will develop cirrhosis regardless of the possible source of HCV infection. The percentage of cirrhotics is generally believed to increase progressively as the length of follow-up increases. In patients with chronic HCV, there also is high risk for the development of hepatocellular carcinoma. Factors influencing the rate of progression from chronic hepatitis to cirrhosis appear to include age at time of exposure, duration of infection, degree of liver damage at initial biopsy, immunological status, and possibly HCV genotype. The mean intervals between the time of initial infection and the diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma have been estimated to be 10, 20, and 30 years, respectively. The progression of disease is variable and is not always orderly and sequential. Patients can progress from chronic persistent hepatitis or chronic active hepatitis directly to hepatocellular carcinoma without first developing cirrhosis, especially those with genotype 1b. In addition, cirrhosis does not appear to lead to clinically apparent hepatic failure in all patients. Because of the variability in the clinical presentation and clinical progression of chronic HCV, long-term follow-up studies may be necessary to fully assess the sequelae of chronic HCV infection. Most patients with chronic HCV have abnormal liver histology but can present as otherwise healthy individuals. In contrast, patients with chronic HCV who have normal hepatic chemistries can have substantial hepatocellular damage. Consequently, treatment at diagnosis offers the greatest likelihood of eliminating the virus and preventing progression to more severe liver disease.

Comparative efficacy of a high or low dose of interferon alpha 2b in chronic hepatitis C: a randomized controlled trial.

OBJECTIVES: Our objective was to determine the relative efficacy of 6 months of treatment with 10 MU versus 3 MU of interferon-alpha 2b (IFN-alpha), three times weekly, in chronic hepatitis C (HCV) in a randomized trial. METHODS: Ten megaunits of IFN-alpha were given to 28 patients (group A), and 3 MU were given to 30 patients (group B). After treatment ended, follow-up was continued for 26 wk. RESULTS: Overall, the sustained response rate was higher in group A than in group B (16/26 or 61.5% vs. 12/28 or 42.9%, p = 0.17), but the difference did not reach statistical significance. However, it was higher in group A than in group B among patients with minimal or mild chronic hepatitis (15/20 or 75% vs. 9/24 or 37.5%, p = 0.013) and among those with mild or moderate fibrosis (15/17 or 88.2% vs. 11/19 or 57.9%, p = 0.042). IFN-alpha treatment significantly reduced histological activity index (HAI) scoring and all its parameters, except fibrosis, but the decrease was similar in the two groups. Sex, age, stage, and HCV genotype were statistically significant predictors of sustained response in univariate analysis. However, multiple logistic regression analysis revealed that advanced histological stage (severe fibrosis and cirrhosis) was the only significant prognostic factor of poor sustained response (RR = 31.0, 95% CI 2-460, p = 0.01), whereas the presence of genotype 1 had marginal statistical significance (RR = 5.0, 95% CI 0.9-28, p = 0.07). CONCLUSIONS: 1) A larger dose of IFN-alpha does not improve the sustained response rate; however, it may be of benefit in early stages of chronic hepatitis C. 2) Pretreatment, histological stage, and possibly HCV genotype appear to be the main prognostic factors of sustained response.