Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells.

Aim: Previous studies have revealed that functional impairment of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, might be associated with the persistence of hepatitis C virus (HCV) infection. However, the involvement of innate immune cells, which predominate in the liver, in therapeutic HCV clearance is still unclear. Methods: To clarify the role of intrahepatic innate immune cells in the clinical outcome of patients with chronic hepatitis C (CHC) treated with interferon-alpha plus ribavirin (IFN/RBV), we prospectively investigated the status of NK and NKT cells in paired liver biopsy and peripheral blood (PB) samples obtained from 21 CHC patients before and immediately after IFN/RBV treatment by flow cytometry. Normal liver and PB samples were obtained from 10 healthy donors for living donor liver transplantation. Results: Before treatment, intrahepatic NK and NKT cells constituted a significantly lower proportion in CHC patients than in healthy individuals (P < 0.05). After IFN/RBV treatment, the proportions and absolute numbers of CD3(-)CD161(+) NK and CD3(+)CD56(+) NKT cells in the liver, but not in PB, were significantly increased in sustained responders (SR) as compared with poor responders (P < 0.05). The proportion of CD3(+)CD161(+) NKT cells was also increased in the liver of SR after the treatment. Moreover, there was a striking increase of activated CD152(+) cells among CD3(+)CD56(+) NKT cells in the liver of SR (P = 0.041). Conclusion: These findings demonstrate that sustained response to IFN/RBV treatment for patients with CHC is closely associated with increased dynamism of NK and NKT cells in the liver.     

Diabetes mellitus reduces the therapeutic effectiveness of interferon-α2b plus ribavirin therapy in patients with chronic hepatitis C

Aim: Patients with chronic hepatitis C (CHC) often have diabetes mellitus (DM). However, it is unknown whether DM affects patient response to interferon (IFN) plus ribavirin therapy. Therefore, the aim of this study was to examine the influence of DM on the outcome of IFN-alpha2b plus ribavirin therapy. Methods: In a cohort of 110 patients with CHC, the outcome of 6 months of IFN-alpha2b plus ribavirin therapy was evaluated by comparing the patients with and without DM. Results: There were 46 sustained-responders; 64 patients did not become sustained responders. Higher age (P = 0.015), lower platelet counts (P = 0.036), hepatitis C virus (HCV) serotype 1 (P = 0.001), advanced liver fibrosis (P = 0.004), and the presence of DM (P = 0.007) were significantly associated with not becoming a sustained-responder. Seventeen CHC (15%) patients had DM. Sex ratio, age, body mass index, alanine aminotransferase levels, HCV-RNA titer, and HCV serotypes did not significantly differ between the patients with and without DM, while fasting plasma glucose, hemoglobin A1c and liver histological staging were significantly different. On multiple logistic regression analysis, HCV serotype 1 (odds ratio 8.743, 95% confidence interval 2.215-34.517; P = 0.002) and the presence of DM (odds ratio 8.657, 95% confidence interval 1.462-51.276; P = 0.014) were independently associated with not becoming a sustained-responder. Conclusions: The findings indicate that DM reduces the response to IFN-alpha2b plus ribavirin therapy in CHC patients.     

Re-treatment of interferon-resistant patients with chronic hepatitis C with interferon-α

Summary. Non-responders to 6-months treatment with recombinant interferon (rIFN)-α, 3 MU thrice weekly (primary non-responders) were treated for 6 further months with the same therapy or with a double dose of rIFN-α or with a different type of IFN (L-IFN). 112 primary non-responders were randomly enrolled into four groups of 28 patients each over a period of 4 years and were followed up for 6 months: group A continued the same dose of rIFN-α, group B was treated with the same rIFN-α but received a double dose (6 MU thrice weekly), group C received L-IFN, 3 MU thrice weekly, and group D stopped IFN therapy and did not receive any treatment. Patients were examined at monthly intervals and response was defined as a complete normalization of alanine amino transferase (ALT). The four groups were homogeneous as to age, sex, duration of the disease, probable source of infection, histological diagnosis, ALT and γ glutamyl transferase (γGT) levels. No patient discontinued therapy for side-effects. Further treatment with rIFN-α 3MU thrice weekly (group A) induced normalization of ALT levels in four patients (14%); treatment with double-dosed rIFN-α (group B) induced normalization of liver enzymes in six cases (21%); a different type of interferon (L-IFN) (group C) achieved normalization of serum ALT in five patients (18%). None of 28 primary non-responders who did not receive any treatment (group D) showed normalization of ALT levels. None of the patients was anti-HCV negative at the end of the study and no statistically significant difference was noted between responders and non-responders to the second course of IFN therapy as to age, sex, duration of the disease, ALT and γGT levels at the end of the trial. Overall at the end of the study the primary non-responders with normal levels of ALT were 15/112 (13%), with a therapeutic advantage of 7%. No statistically significant difference in the response rate was found among patients who continued IFN therapy, but prolongation of rIFN-α treatment at double dosage seems to be the best therapeutic regimen.     

Case Report: Agranulocytosis induced by interferon-α therapy for chronic hepatitis C

A 60-year-old woman presented with chronic active hepatitis C whose HCV-RNA genotype was II according to Okamoto's classification and serum HCV-RNA concentration was 10⁴ copies/mL. Agranulocytosis was induced 13 days from the commencement of interferon (IFN)-α 2b (6 MU/day) therapy, so the IFN therapy was immediately discontinued. The agranulocytosis improved rapidly with the administration of a granulocyte colony stimulating factor (G-CSF). The possibility that IFN was associated with maturational arrest of myeloid progenitor cells was considered. During the course of 3 years of follow-up, her liver function has remained normal and serum HCV-RNA remains negative.     

慢性乙型肝炎患者外周血NK细胞和T淋巴细胞计数变化及其临床意义

目的观察慢性乙型肝炎患者外周血NK细胞和T淋巴细胞数量的变化。方法在56例乙型肝炎肝衰竭、49例HBeAg阳性慢性乙型肝炎和41例乙型肝炎病毒携带者使用流式细胞仪检测外周血CD3+T细胞、CD3+CD4+T细胞、CD3+CD8+T细胞和NK(CD3-CD16+CD56+)细胞占淋巴细胞的比率(%)。结果肝衰竭患者CD3+T细胞和CD3-CD16+CD56+NK细胞计数比慢性乙型肝炎患者和乙型肝炎病毒携带者显著性降低(P0.05);慢性乙型肝炎患者CD3-CD16+CD56+NK细胞计数比乙型肝炎病毒携带者显著性升高(P0.05)。结论乙型肝炎肝衰竭患者外周血T细胞和NK细胞数量减少,而HBeAg阳性慢性乙型肝炎患者外周血T细胞数量增多。     

Clinical predictors of response to recombinant interferon-α treatment in patients with chronic non-A, non-B hepatitis (hepatitis C)

SUMMARY. Chronic non-A, non-B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon-α (IFN) treatment at a dose of 3 × 10⁶ units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH-C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty-three adult patients who had participated in a large multi-centre treatment trial were included in the study group: 84 had been treated with 3 × 10⁶ units of recombinant IFN-α-2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 × 10⁶ units rIFN in the same dosage schedule. Forty-one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m^-2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two-tailed, P < 0.15). By multivariate analysis, however, only the 3 × 10⁶ dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 × 10⁶ units of rIFN, seven variables [body weight, surface area, dose m^-2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12–16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.     

Serum levels of anti-hepatitis C virus IgM core antibodies may predict the response to interferon-α therapy in chronic hepatitis C

SUMMARY. We measured the optical densities (OD) of serum anti-hepatitis C virus IgM core antibodies in 40 HCV-positive patients (24 males and 16 females) with histologically proven chronic active hepatitis but without cirrhosis. All patients were treated with i.m. injections of 3 MU thrice weekly of interferon-α (IFN-α) for 6 months and followed-up monthly. Optical densities were evaluated in thawed sera before beginning treatment and 6 months after completion, and in fresh sera obtained at the end of an 8–12-month follow-up period. Patients were grouped into three categories according to the OD obtained: <0.3 (negative test): 0.3-0.6 (intermediate positivity): >0.6 (high positivity). According to the response to treatment during the follow-up period, patients were further divided into three classes: sustained responders: relapsers or partial responders: non-responders. In each patient, the OD values were similar in the three determinations before, after therapy and at the end of the follow-up period. All patients with an intermediate positive test for anti-HCV IgM core antibodies were relapsers or partial responders, and all patients with high OD values were non-responders. Conversely, 71% of the patients with a negative test were sustained responders. We conclude that this cheap and easily performed test may be useful in predicting the response to IFN therapy.     

High-dose natural interferon-α therapy for chronic hepatitis C with a high viral load: Predictors of efficacy

BACKGROUND: The effectiveness of interferon against hepatitis C has been found to be greatly affected by viral factors. However, few controlled interferon trials have involved seemingly intractable cases of chronic hepatitis C. METHODS: In 44 patients with high hepatitis C virus RNA levels (> or = 10(5) copies/mL), we carried out a prospective, controlled study of two natural interferon-alpha regimens, seeking predictors of therapeutic efficacy. Total natural interferon-alpha doses over 6 months in two groups were 780 and 840 million units, respectively. RESULTS: High therapeutic efficacy was achieved with no significant outcome difference between the regimens. The virus eradication rate was 35% and the rate of sustained biochemical response was 45% for both regimens. Multivariate logistic regression analysis identified viral genotype as the only significant predictor of success in viral eradication. CONCLUSIONS: Hepatitis C virus genotype 2 showed high sensitivity to interferon-alpha and this therapy can be recommended even for patients with a high viral load of this genotype. In contrast, with genotype 1b, cure was extremely difficult in cases with 10(7) or more copies/mL with a single 6-month course of interferon-alpha.     

直接抗病毒药物治愈的慢性丙型肝炎患者NK细胞的免疫学特点分析

目的探讨直接抗病毒药物(direct-acting antivirals, DAAs)治愈的慢性丙型肝炎(chronic hepatitis C, CHC)患者NK细胞的免疫学变化。方法入组13例经达拉他韦(daclatasvir, DCV)和阿舒瑞韦(asunaprevir, ASV)治疗24周的初治型HCV 1b型CHC患者,同时入组13例健康者为健康对照(healthy controls, HC)组。采用流式细胞术分析患者治疗前,治疗第24周,治疗结束后随访第12周、24周的外周血NK细胞表型和功能特点。结果 13例CHC患者经DCV/ASV抗病毒治疗均获得持续病毒学应答即临床治愈;与HC组相比,CHC患者抗病毒治疗前外周血NK细胞表达HLA-DR、NKP46、CD38的水平显著增高(P均<0.05),分泌CD107a和TNF-α的水平增高(P均<0.05),但产生IFN-γ的能力降低(P <0.05)。抗病毒治疗后,CHC患者外周血NK细胞活化程度降低,分泌IFN-γ的能力明显增强(P均<0.05)。结论经DAAs治愈的CHC患者外周血NK细胞的表型和功能显著改善。     

Predictors of sustained response, relapse and no response in patients with chronic hepatitis C treated with interferon-α

Summary. Three main patterns of response are seen when interferon-α (IFN-α) is used for the treatment of chronic hepatitis C: 1 sustained response with alanine-aminotransferase (ALT) normalization that is maintained after cessation of therapy, with or without clearance of serum hepatitis C virus (HCV) RNA; 2 transient response with ALT normalization during therapy followed by relapse after its withdrawal, and 3 no response with no or only partial reduction in ALT levels. In order to define variables that could predict each of these three types of response we studied 321 cases of chronic hepatitis C treated with IFN-α in two consecutive trials conducted in our Unit. By univariate analysis, age < 45 years (P < 0.01), known disease duration < 60 months (P < 0.01), normal gamma-glutamyltranspeptidase (γGT) levels (P < 0.01) and infection by HCV genotype 2 or HCV genotype 3 (P < 0.01) were found to be statistically associated with sustained response while age > 45 years (P < 0.01), body weight (P= 0.05), cirrhosis (P < 0.01) and elevated γGT levels (P < 0.01) were associated with no response. By multivariate analysis sustained response was predicted by HCV genotype 2 (P < 0.01) and HCV genotype 3 (P < 0.01), known disease duration (P < 0.01), patient's age (P < 0.05) and associated with the use of a more aggressive treatment schedule (P < 0.05). Transient response with relapse was predicted by known duration of disease (P < 0.05), HCV genotype 1 (P < 0.05) and female sex (P < 0.05). No response was statistically associated with elevated γGT levels (P < 0.01), higher body weight (P < 0.05) and with the less aggressive regimen of 3 MU of natural IFN-α given three times weekly for 6 months (P < 0.05). These results indicate that the HCV genotype as well as the schedule of treatment greatly affect the pattern of response to IFN in chronic hepatitis C and allow us to define criteria to predict which type of response is more likely in individual patients.     

Randomized, placebo-controlled, double-blind trial with interferon-α with and without amantadine sulphate in primary interferon-α nonresponders with chronic hepatitis C

In primary interferon-α (IFN-α) nonresponders with chronic hepatitis C, retreatment with IFN-α has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-α alone or in combination with amantadine sulphate in nonresponders to previous IFN-α monotherapy. Fifty-five IFN-α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-α 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate ( n =26) or a matched placebo ( n =29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-α dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-α/amantadine sulphate, one patient; IFN-α/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-α and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue ( P  < 0.05) and vigor ( P  < 0.05) in patients receiving combined IFN-α/amantadine sulphate treatment compared with those treated with IFN-α alone. IFN-α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-α and amantadine sulphate does not increase the low sustained virological response rates of IFN-α therapy in primary IFN-α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.     

Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C

BACKGROUND AND AIMS: Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy. METHODS: We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks. RESULTS: CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 +/- 5.34 vs 4.41 +/- 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake (P = 0.0213, r = 0.290), transaminase level (P = 0.0126, r = 0.247), platelet count (P = 0.0002, r = -0.369), histological grading (P = 0.0121, r = 0.248) and staging (P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 +/- 5.76 vs 4.39 +/- 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin (P = 0.0277). CONCLUSIONS: Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment.     

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.     

Late onset autoimmune thrombocytopenia associated with pegylated interferon-alpha-2b plus ribavirin treatment for chronic hepatitis C

Interferon-induced, immune-mediated, thrombocytopenia is a rare event. In this report the case is described of development of severe, reversible, autoimmune thrombocytopenia in a patient with chronic hepatitis C virus infection, 6 months after the discontinuation of pegylated interferon-alpha-2b plus ribavirin treatment. Physicians must be aware that autoimmune thrombocytopenia can occur even after the end of treatment, as a late onset complication, especially when using the pegylated forms of interferons, which have longer half-lives and prolonged activity.     

Changes in natural killer T cells subsets during therapy in type C hepatitis and hepatocellular carcinoma.

Natural killer T (NKT) cells share features of both classical T cells and NK cells. NKT are heterogenous populations, and recognize glycolipids associated with CD1d molecule. We investigated Th1/Th2 cytokine production as well as frequency and phenotype of circulating NKT cells in 14 healthy subjects and in patients during therapy with type C chronic hepatitis (CH; 14 cases) and hepatocellular carcinoma (HCC; 13 cases). Peripheral blood mononuclear cells (PBMC) were obtained before and 2 weeks later interferon (IFN)/ribavirin and radiofrequency ablation therapy for CH and HCC, respectively. PBMC were cultured for 10 days with alpha-galactosylceramide (alpha-GalCer) and interleukin-2 (IL-2). Frequencies and IFN-gamma/IL-4 production of NKT cells were analyzed using flow cytometry. Intrahepatic lymphocytes were analyzed in seven CH patients with liver biopsy specimen. Prevalence of circulating Valpha24+CD3+ T cells was 0.9+/-0.9% of PBMC for controls and increased to 8.5+/-8.9% (p<0.001) in response to alpha-GalCel. Similar frequency and expansion were noted in CH. The frequency increased during therapy. The prevalence in HCC tended to be high compared to controls and response to alpha-GalCel was well. Although frequency of Valpha24+Vbeta11+CD3+ T cells was low in all groups, the distribution pattern was similar to Valpha24+Vbeta11-CD3+ T cells. Prevalence of CD56+CD3+ T cells was low independent of therapy in CH (2-3%) compared to 5.0+/-4.0% of controls, although response to alpha-GalCel was not impaired. IFN-gamma production of Valpha24+CD3+ T cells did not differ among groups, but became greater after treatment in contrast to lowered IL-4 production. Frequencies of NKT populations were higher in liver than in peripheral blood. Our study suggests that CD1d-reactive T cells have distinct distribution in different populations and therapy for patients alters cytokine response of NKT cells.     

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.     

Effect of combination therapy with ribavirin and high-dose interferon-α2b for 24 weeks in chronic hepatitis C

Background and Aim: The aim of the present study was to determine whether a 24‐week course of combination therapy with ribavirin and high‐dose interferon‐α2b (IFN‐α2b) could provide an acceptable treatment efficacy in chronic hepatitis C (CHC). Methods: Seventy‐six patients with CHC whose serum hepatitis C virus (HCV) RNA levels were more than 100 kIU/mL on quantitative polymerase chain reaction (PCR) assay were included. The patients were assigned to two different dose groups of IFN‐α2b: group A (n = 39) received 6 MU and group B (n = 37) received 10 MU. Each group received the dose daily for 14 days then three times per week for a total of 24 weeks. In addition, HCV genotype 1b patients in group A and group B were classified into group C (n = 20) and D (n = 29), respectively. All patients received 600 or 800 mg ribavirin per day. Results: Sustained response rates in group A were significantly higher than those in group B (66.7%vs 35.1%, intent‐to‐treat, P = 0.0060). However, sustained response rates in group C were not different from those in group D (45.0%vs 20.7%, intent‐to‐treat, P = 0.0696). The proportion of patients who discontinued the treatment or reduced drug dosage because of adverse events was significantly higher in group B than in group A (27.0%vs 7.69%, P = 0.0224). Conclusion: A 24‐week course of combination therapy with ribavirin and 6 MU IFN‐α2b had an acceptable efficacy with fewer adverse events than that with ribavirin and 10 MU IFN‐α2b in CHC.     

High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon

BACKGROUND: Recently, the combination treatment of recombinant alpha-interferon plus ribavirin has been proposed for chronic hepatitis C patients unresponsive to previous therapy with recombinant alpha-interferon alone. AIM: To determine the effectiveness of the combination therapy for the re-treatment of chronic hepatitis C patients unresponsive to previous interferon therapy. Immediate and long-term follow-up data are reported. PATIENTS AND METHODS: A series of 100 patients with chronic hepatitis C not responding to recombinant alpha-interferon 3 MU tiw, were randomly assigned to two groups of 50 patients each: Group A, treated with recombinant alpha-interferon therapy for an additional six months but at a double dosage (6 MU tiw) in association with ribavirin. Group B, same treatment as group A but without ribavirin. All patients responsive to therapy were then followed-up for at least 12 months. At the end of the treatment and at the end of the follow-up period, we distinguished between complete responses (return to normal of alanine aminotransferase with undetectable serum HCV-RNA] and biochemical responses (return to normal of alanine aminotransferase still with detectable viraemia). RESULTS: Side-effects were observed only in patients treated with recombinant alpha-interferon plus ribavirin: 12% discontinued the therapy due to haemolytic anaemia. In group A, the percentages of end-of-treatment complete response, end-of-treatment biochemical response, sustained complete response, and sustained biochemical response, were 38%, 20%, 8%, and 14%, respectively, whilst in group B, these percentages were 12%, 16%, 6%, and 16%, respectively. CONCLUSION: The results indicate that in patients with chronic hepatitis C unresponsive to previous recombinant alpha-interferon therapy, re-treatment with higher recombinant alpha-interferon doses, either alone or in combination with ribavirin, lead to mild long-term benefit. However, the satisfactory end of treatment complete response in group A suggests that a significant percentage of patients are sensitive to the combination therapy; and that a more aggressive therapeutic protocol in this selected subset of patients could result in a larger number of long-lasting responses leading, in turn, to a more favourable cost-effect ratio.