Practical use of hepatitis C virus kinetics monitoring in the treatment of chronic hepatitis C

Summary.  Prevention of hepatitis C virus (HCV) infection complications can be achieved by antiviral therapy based on the use of a combination of pegylated interferon (IFN)-α and ribavirin. The steady-state kinetics of HCV infection represents the treatment target. The goal is cure, which is achieved when all infected cells have been cleared from the body. Because of their intrinsic properties, real-time polymerase chain reaction (PCR) methods are rapidly replacing other technologies for routine quantification of HCV-RNA during antiviral therapy. The virological response at week 12 of therapy is currently used to tailor treatment duration in HCV genotype 1 infection only. Recent reports suggest that the virological response at week 4 could be used to tailor treatment duration, whatever the HCV genotype.     

Differential viral kinetics in treated genotype 4 chronic hepatitis C patients according to ethnicity

Summary.  Data concerning the efficacy of PEG-IFNα2a plus ribavirin treatment in treatment-naïve, genotype 4-infected chronic hepatitis C (CHC) patients from Europe are limited. Hence the aim of this study was to investigate the viral kinetics as well as the sustained virological response (SVR) rates and their predictors, in these patients. One hundred and twenty-three patients were retrospectively analysed. Early (EVR) and late virological response (LVR) was confirmed by undetectable (<50 IU/mL) serum HCV-RNA at week 12 and week 24 of treatment, respectively. SVR was confirmed by undetectable serum HCV-RNA at the end of treatment as well as 6 months later. Overall, 43.5% of patients exhibited SVR, 42.6% were nonresponders and 13.9% were relapsers. EVR was observed in 40.74% and LVR in 59.25% of them. The positive predictive values of EVR and LVR were 72.97% and 86.27% whereas their negative predictive values were 64.29% and 92.85%, respectively. EVR independently predicted SVR in Caucasian patients ( P  < 0.001) but not in Egyptian patients ( P  = 0.613), in whom the only independent predictor of SVR was the absence of cirrhosis ( P  = 0.004). LVR seems to be a better predictor of SVR than EVR in the vast majority of genotype 4-infected CHC patients, irrespective of ethnicity and all the other baseline parameters.     

Viral kinetics in the treatment of chronic hepatitis C

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis, and chronic infection can frequently progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment with pegylated interferons (INFs) plus ribavirin has been shown to be more effective than pegylated INFs alone or standard INFs with or without ribavirin. The early response of HCV to treatment with peg-INF has been used to predict treatment outcomes in infected patients, emphasizing the importance of viral kinetics and genotyping in their treatment. Mathematic modelling of viral dynamics has shown the importance of optimal doses of drug, with early virologic response at week 12 predictive of sustained virologic response. Maintaining INF concentration above a therapeutically effective level is necessary to prevent viral rebound and subsequent treatment failure. Once-weekly dosing with peg-INF-alpha2a, which has a longer half-life than other forms of INF, plus daily dosing with ribavirin, has been shown to be effective in reducing viral load.     

Impact of early viral kinetics on pegylated interferon alpha 2b plus ribavirin therapy in Japanese patients with genotype 2 chronic hepatitis C

Summary. The recommended therapy for genotype‐2 chronic hepatitis C is a regimen of pegylated interferon alpha (peginterferon) plus ribavirin. This study was conducted to determine the value of early viral kinetics as a predictive factor for sustained virologic responder (SVR). Peginterferon alpha 2b (1.5 μg/kg/week) plus weight‐based ribavirin (600–1000 mg/day) was administered to 51 patients with chronic HCV genotype 2 for 24 weeks. The HCV‐RNA loads were measured at the baseline, hour 24, and week 1. The rebound index (RI, an index obtained from the viral load of week 1 divided by that of hour 24) was calculated. Compared with the baseline, the viral load at hour 24 for SVR was reduced by more than 1‐log: it continued to decline thereafter, and at week 1 it was significantly lower than at hour 24 (P < 0.05). The viral load for non‐SVR increased again between hour 24 and week 1. The SVR of patients with RI ≤1.0 was 100% (39/39). The SVR conversion for rapid virologic responders was 92% (35/38). The RI (≤1.0) was the only significant independent factor for SVR by multiple logistic regression analysis and is the first predictive factor in 24‐week peginterferon plus ribavirin therapy for patients infected with genotype 2.     

Viral and host factors in the prediction of response to interferon-α therapy in chronic hepatitis C after long-term follow-up

Acute infection with hepatitis C virus (HCV) develops into a chronic hepatitis in about 50–70% of patients. Treatment of these patients with interferon-α (IFN-α) results in a sustained long-term response in only 15–20% but causes numerous unwanted side-effects in a higher percentage of patients. The aim of our study was to define host or viral parameters that would allow identification of responders and non-responders to IFN-α prior to the onset of treatment. We studied a group of 87 patients suffering from chronic hepatitis C who were treated with IFN-α. After long-term follow-up, 18 patients (21%) showed a sustained response to IFN-α therapy (normalization of serum transaminases and loss of viral RNA from serum) for up to 7 years after therapy had ceased. By univariate and multivariate analyses, no host factors were found to be predictive of response to therapy. Neither the degree of inflammation or fibrosis in liver biopsy samples obtained before treatment nor immunogenetic factors (major histocompatibility complex II haplotype and tumour necrosis factor-α promoter polymorphism) were associated with response to therapy. In contrast, viral parameters showed a strong association with response to therapy. HCV genotype 3 was found significantly more frequently in responders (P = 0.034), and mean HCV RNA concentration was lower in responders (3.1 × 10⁴) than in non-responders (2.5 × 10⁵) (P = 0.01). By multivariate analysis, both HCV genotype and HCV RNA concentration were independent predictors of response to therapy. However, exact prediction of response to treatment for an individual patient was not possible on the basis of pretreatment viral RNA concentration or viral genotype. The best association with response to therapy was found to be clearance of HCV RNA from serum 3 months after the start of treatment (32 of 34 partial and sustained responders vs 0 of 53 non-responders; P = 0.001). In conclusion, determination of pretreatment viral factors, but not host factors, was significantly correlated with treatment response but did not give an accurate prediction for patients, whereas clearance of HCV RNA from serum after 3 months of therapy was predictive of response to therapy.     

Fluctuation patterns of HCV-RNA serum level in patients with chronic hepatitis C

The serum level of hepatitis C virus (HCV)-RNA is clinically important as a predictor of the response to interferon (IFN) therapy in patients with chronic hepatitis C. If serum HCV-RNA levels fluctuate during follow-up, and IFN therapy is begun at the time of a low HCV-RNA level, the IFN therapy may be more effective. We evaluated the fluctuation of HCV-RNA serum levels for 2 years in 212 patients with chronic hepatitis C, untreated with IFN who had HCV genotype 1b and an HCV-RNA level of 10 Meq/ml or more at first consultation. The HCV-RNA level was measured monthly for 2 years with an HCV branched DNA probe assay (b DNA probe assay). We classified HCV-RNA patterns into three types by the ratio of maximum HCV-RNA level (a) to minimum HCV-RNA level (b). In pattern 1 (constant type, 151 patients; 71.2%) the a/b ratio was 1–5. In pattern 2 (slight fluctuation type, 46 patients; 21.7%) the a/b ratio was 5–10. In pattern 3 (severe fluctuation type, 15 patients; 7.1%), the a/b ratio was 10 or more. Next, we evaluated the factors associated with the three patterns. Acute exacerbation of chronic hepatitis was regarded as an increase in serum alanine aminotransferase (ALT) level to more than 250 IU/l. The incidence of acute exacerbation for a 2-year follow-up was 13.9% (21/151) in pattern 1, 19.6% (9/46) in pattern 2, and 53.3% (8/15) in pattern 3. Multivariate analysis showed that acute exacerbation was the most important factor in the manifestation pattern 3. In conclusion, we found that: (1) about 70% of patients had a constant HCV-RNA levels for 2 years. (2) A few patients had severe fluctuation of serum HCV-RNA level after acute exacerbation of chronic hepatitis. Received: July 23, 1999 / Accepted: September 24, 1999     

慢性丙型肝炎病毒感染者外周血淋巴细胞增殖反应

目的　观察慢性丙型肝炎患者外周血淋巴细胞对丙型肝炎病毒（ＨＣＶ） 抗原刺激的增殖反应．方法　外周血单个核细胞（ＰＢＭＣ） 与ＨＣＶ 抗原ｃ２２ 、ｃ３３ 、ｃ１００ － ３ 、ＮＳ５ 和植物血凝素（ＰＨＡ） 分别共同孵育,加入胸腺嘧啶核苷（３ ＨＴｄＲ） ,然后收集细胞于液闪仪测定每分钟脉冲数（ｃｐｍ） ．结果　根据对不同ＨＣＶ 抗原的淋巴细胞增殖反应发现,以ｃ２２免疫原性最强,ｃ１００ － ３ 次之：淋巴细胞激活与ＨＣＶ 基因型关系不大;健康对照和慢性乙型肝炎患者对各ＨＣＶ 抗原未能显示有效的淋巴细胞增殖反应;与健康对照比较,慢性丙型肝炎和乙型肝炎患者对ＰＨＡ 刺激的淋巴细胞增殖反应降低．结论　ＨＣＶ 抗原ｃ２２ 免疫原性最强,丙型肝炎患者对ＨＣＶ 抗原的淋巴细胞增殖反应系特异性;慢性丙型肝炎和乙型肝炎患者存在抑制的细胞免疫应答．     

Amantadine's Viral Kinetics in Chronic Hepatitis C Infection

Treatment for hepatitis C virus infection is limited in patients not responding to traditional therapy. Amantadine is effective for influenza infections and has been studied in patients with hepatitis C. Our aim was to determine the efficacy and safety of amantadine and to study the viral kinetics following amantadine therapy. Twelve patients with detectable HCV antibodies received amantadine 100 mg, orally twice daily. Serial HCV RNA and ALT blood samples were drawn and adverse effects were evaluated. Mean HCV RNA levels did not decrease in the first 24 hr of amantadine therapy but did decline significantly by day 3, only to rebound by day 7. All HCV RNA levels remained detectable throughout therapy and were not different from baseline values. Thirty-three percent of the patients obtained normal ALT levels after the first 24 hr of treatment and levels remained within normal range throughout the study period. More than a third of the patients discontinued therapy due to severe adverse effects occurring within one to three months after initiating treatment. In conclusion, although amantadine therapy alone was not effective, it should be considered as an adjunctive form of therapy along with interferon and ribavirin.     

Sustained response to combination therapy in a patient with chronic hepatitis C and thrombocytopenia secondary to alpha-interferon

Recent data suggest that hepatitis C viral (HCV) infection may induce a significant autoimmune reaction to platelets, but the mechanism is unknown. Many patients with chronic hepatitis C, in fact, have high levels of platelet-associated immunoglobulin G (PAIgG) and HCV-RNA is present in the platelets of 100% of those patients with thrombocytopenia and high PAIgG levels. Hepatitis C virus infection has been associated with the development of thrombocytopenic purpura, sometimes triggered during interferon (IFN) therapy. In such cases, the treatment of the underlying disease is a difficult problem to solve. We report the case of a patient with chronic hepatitis C, who developed life-threatening thrombocytopenic purpura after a prolonged course of IFN-alpha2b over a 4-year period. Treatment with anti-immunoglobulin gammaglobulin (Polyglobin; Química Farmaceutica Bayer, Barcelona, Spain) had a transient effect on the platelet count, but prolonged therapy with prednisone was necessary for definitive relief of the haematological complication. Two years later, the patient was treated with combined therapy, including ribavirin (1200 mg/day) and IFN-alpha2b (5 mU, t.i.w.) for 12 months. This therapy induced a sustained response, both biochemical and virological, without haematological complications. This observation suggests that ribavirin may be of benefit in the treatment of immune-mediated thrombocytopenia in patients with chronic hepatitis C, preventing the harmful effect of IFN-alpha but also allowing both drugs to be combined so as to increase the probability of sustained remission of the liver disease.     

Neutralizing antibodies to recombinant alpha-interferon and response to therapy in chronic hepatitis C virus infection

ABSTRACT— Forty-seven patients with chronic hepatitis C were treated with recombinant interferon alpha-2a (rIFNα2a) given subcutaneously in a standard dose of 3 MU thrice weekly for 12 months. Stored baseline sera and monthly samples during treatment were assayed for anti-interferon neutralizing antibodies using the antiviral neutralization bioassay against 5 IU of rIFNα2a. During therapy, 15 of 47 patients (31.9%) developed detectable levels of neutralizing antibodies within 2–8 months after starting treatment. After 12 months of therapy, 26 of 32 antibody-negative patients (81.3%) showed normalization or marked reduction of ALT levels compared to 4 of 15 (26.6%) who developed anti-IFN neutralizing antibodies (p = 0.0009). Four patients demonstrated antiviral response during treatment even in the presence of low levels or late occurrence of neutralizing antibodies. Six of the seven patients who had disease reactivation after an initial response developed high titers of neutralizing antibodies. Our results suggest that reactivation of chronic hepatitis C before completion of therapy seems to be an obvious consequence of anti-IFN neutralizing antibody formation.     

Factors associated with the initiation of alpha-interferon treatment in Medicaid patients diagnosed with hepatitis C

We aimed to determine rates of treatment with alpha-interferon medication in patients diagnosed with hepatitis C virus (HCV), to ascertain the prevalence of selected conditions that could influence initiation of interferon treatment, and to examine the association between the presence of these conditions and interferon treatment. A nested case-control design was used in California Medicaid (Medi-Cal) claims data covering the period from 1 January 1996 to 30 June 2002. Interferon-treated cases and non-treated controls were selected in a 1 : 2 ratio that matched the length of the observation period and year of index HCV diagnosis. Predictor variables examined in bivariate and multivariate analyses included demographics, substance abuse and dependence, psychotropic drug use, selected chronic conditions and medical utilization. The proportion of eligible subjects diagnosed with HCV and treated with interferon ranged from 10.7 to 13.9%. There were 529 treated cases that met the eligibility criteria and 1058 non-treated HCV patients selected as controls. Multivariate factors that increased the likelihood of treatment were a liver biopsy, a diagnosis of mild liver disease, a diagnosis of psoriasis, antidepressant use and classification of race/ethnicity as 'other'. A decreased likelihood of treatment was linked to age > or =65 years, a diagnosis of kidney disease, one to four emergency visits and five or more emergency visits. The proportion of patients receiving interferon treatment in the Medi-Cal-insured population was low compared with published rates in HCV patients in other general medical settings. The diverse factors linked to initiation of HCV therapy raise compelling questions for further research.     

Long-term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon

ABSTRACT: We assessed the long-term outcome in 24 patients with chronic hepatitis C who responded to alpha interferon. All patients were followed up for 12 months, and 16 patients were followed up 41±9 months. During the follow-up period, 18 of the 24 patients (75%) relapsed (serum ALT levels increased again); 16 had an early relapse within the 6 months and two had a late relapse 21 and 36 months after therapy; one cirrhotic patient with relapse died. Serum HCV RNA remained detectable in the two patients before the late relapse and in three of the six patients with sustained biochemical response. Histologic assessment 13 to 31 months after therapy showed a decrease in activity in most patients, even in some of those with relapse, but the decrease in portal inflammation was more marked (p<0.05) in patients with sustained biochemical response. Liver HCV RNA was not detectable in the two sustained responders who were negative for serum HCV RNA. Despite biochemical remission induced by interferon therapy, HCV replication persists in many patients with a potential risk of late relapse. In contrast, some patients have no long-term detectable HCV RNA, suggesting clearance of HCV. Long-term histologic improvement of portal inflammation in most patients confirms the beneficial effect of interferon.     

Long-lasting complete remission of hepatitis C virus (HCV) infection and HCV-associated immunocytoma with alpha-interferon treatment

Several epidemiological data suggest the involvement of hepatitis C virus (HCV) in the pathogenesis of some histotypes of B-cell non-Hodgkin's lymphomas, in particular immunocytoma. We report a patient with HCV-associated immunocytoma, first treated with six courses of fludarabine. A partial response was achieved and subsequent therapy with alpha-interferon resulted in the clearance of the virus and a long-lasting complete clinical and histological remission of the lymphoproliferative disease.     

Interferon plus ribavirin in chronic hepatitis C non-responders to recombinant alpha-interferon

The aim of this study was to evaluate the most appropriate therapeutic protocol for patients with chronic hepatitis C not responding to a previous course of recombinant interferon α-2b (rIFN). Sixty patients were randomly assigned to two groups of 30 subjects each: group A was treated with double dose of the same type of rIFN (6 MU t.i.w. ) plus ribavirin for 6 months; group B was treated with the same rIFN dose and duration as group A, but without ribavirin. An end of treatment complete response (ETCR) was defined as alanine transaminase (ALT) normalization with undetectable serum HCV-RNA at the end of the treatment, while an end of treatment biochemical response (ETBR) as ALT normalization with still detectable viraemia. The two groups were homogeneous. The patients with ETCR or ETBR were than followed-up for at least 1 year. A sustained biochemical response (SBR) was defined as the persistence of normal ALT with still detectable viraemia after a 12-month follow-up, and a sustained complete response (SCR) as the persistence of normal ALT with undetectable viraemia. Side-effects were only observed in patients treated with rIFN plus ribavirin: four cases (13%) discontinued the therapy owing to haemolytic anaemia. Combination therapy induced an ETCR in 11 patients (37%) and an ETBR in six (20%), while a SCR was observed in two subjects (7%) and a SBR in four (13%). The use of a double dose of rIFN alone obtained an ETCR in four cases (13%) and an ETBR in five (17%), with a SCR in two (7%) and a SBR in three (10%). Hence, both combination therapy and single treatment with higher rIFN doses were unable to show statistically significant long-term benefits in patients with chronic hepatitis C resistant to a previous course of rIFN treatment.     

Early viral kinetics on treatment with pegylated interferon-alpha-2a in chronic hepatitis C virus genotype 1 infection

Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-alpha-2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-alpha-2a (days 0 and 1), and before and during weekly 180 microg PEG-IFN-alpha-2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-alpha-2a was greater in virological responders (1.05 log [0.25-1.67]) than in nonresponders (NR) (0.34 [0.14-0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-alpha-2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-alpha-2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-alpha-2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.     

A model to predict long-term sustained response to interferon therapy in chronic hepatitis C

Interferon therapy is used widely for chronic hepatitis C but only a minority of treated patients achieve a long-lasting sustained response. We have developed, by logistic regression, a mathematical model to estimate the probability of sustained response in an individual patient with chronic hepatitis C when treated with interferon-α (IFN-α). The model, which includes age, sex, disease duration, pretreatment serum γ-glutamyl-transpeptidase, alanine aminotransferase and virus genotype, was developed from a database of 307 patients and validated in a new set of 200 patients. It performed well as goodness-of-fit ( P = 0.71 and P = 0.15 in the development and test sample, respectively) and discrimination (area under receiver operating curve = 0.79 in the development and 0.78 in the test sample, respectively). This model may provide decision support in the treatment of chronic hepatitis C with IFN-α.     

Hepatitis C virus genotypes in chronic hepatitis C of children

SUMMARY. Several hepatitis C virus (HCV) genotypes have been recently identified and genotype 1b has been correlated with severe liver disease and a poor response to interferon therapy. HCV infection in children is an interesting model for evaluation of the relationship between HCV genotypes and liver disease, because of its relatively short duration and the infrequent association with confounding cofactors. We have investigated HCV genotypes, using a dot-blot hybridization assay with genotype-specific probes, in 36 Italian children with chronic hepatitis C who were otherwise well and had no other underlying disease. Only four patients were symptomatic; liver histology, obtained in 3 3 patients, showed minimal hepatitis in 17 and mild chronic hepatitis in 16. Infection with HCV genotype Ib was found in 55.5% of patients, with a peak prevalence of 83% in children from southern Italy (P < 0.05 vs other regions). The remaining children were infected with HCV genotype la (16.6%), genotype 2 (11.1%). and mixed (10.9%) or undetermined (2.7%) genotypes. In one patient, HCV viraemia was never detected. There was no statistically significant correlation between genotype and age, sex, source of infection, alanine aminotransferase pattern and histological activity index. These results indicate that genotype 1b is widespread among Italian children with chronic hepatitis C, although with significant geographical variations. It is not associated with a more severe liver disease, therefore suggesting that the greater severity of liver disease recently reported in adults could reflect the cumulative effects of disease duration and of interfering cofactors.     

Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum

Background/Aims: Prediction of response to interferon therapy is important in the management of chronic hepatitis C. Pre-therapy data are valuable but they may be inaccurate in some cases. Our aim was to investigate whether the biochemical and virological events that occur early during interferon therapy in chronic hepatitis C may predict the final result of the treatment.Methods: ALT and serum HCV-RNA were serially measured in 53 HCV-RNA-positive patients who received a standard 6-month course of interferon therapy. Eleven patients with a sustained response, 23 who responded but subsequently relapsed and 19 who did not respond were studied. HCV-RNA was measured with a commercial kit (Amplicor HCV).Results: After 4 weeks of treatment, HCV-RNA became negative in 73% of sustained responders, in 26% of transient responders (p=0.02) and in none of the non-responders. Corresponding figures after 8 weeks of therapy were 82% in sustained responders, 61% in transient responders and 9% in non-responders. The difference between sustained and transient responders at this times was not significant. After 4 weeks of therapy, 82% of sustained responders, 52% of transient responders and none of the non-responders presented normalization of alanine transferase. The difference between sustained and transient responders was not significant. Corresponding figures for normalization of alanine transferase at 8 weeks were 82%, 96% and 0% respectively. At the end of treatment, all sustained responders, 70% of transient responders and none of the non-responders had cleared HCV-RNA from serum.Conclusions: A rapid normalization of alanine transferase induced by interferon therapy is associated with response, but does not differentiate between transient and permanent response. In contrast, clearance of HCV-RNA after 4 weeks of treatment, but not after 8 weeks, is significatively associated with sustained response. Testing for HCV-RNA early during interferon administration may be valuable for further decisions concerning therapy in patients with chronic hepatitis C.