Development of sarcoidosis during interferon alpha 2b and ribavirin combination therapy for chronic hepatitis C--a case report and review of the literature

Sarcoidosis is a chronic granulomatous multisystemic disorder of unknown aetiology. Although interferon gamma has been implicated in the pathogenesis of sarcoidosis, only a few cases of sarcoidosis associated with interferon alpha therapy have been reported. We report a case with chronic hepatitis C (CHC) who developed sarcoidosis after the treatment by interferon alpha and ribavirin. The combination therapy of interferon alpha and ribavirin was given to a 50-year-old female with CHC who had not responded to a previous treatment by interferon alpha. She has been admitted with non-productive cough, dyspnoea and fever 11 months after the initiation of combination therapy. Chest x-ray and thorax computed tomography revealed bilateral hilar masses and nodular infiltrations in the lung parenchyma. Pulmonary function test showed a mild restriction. Biopsy of mediastinal lymphadenopathy revealed noncaseating granuloma. She was diagnosed to have pulmonary sarcoidosis at stage II, and the combination treatment was discontinued. Her symptoms regressed after inhaler steroid treatment. Six months after the diagnosis of sarcoidosis, the patient was asymptomatic and a complete sustained response to hepatitis C was achieved. During the three years of follow-up, both pulmonary sarcoidosis and hepatitis C have not recurred. We suggest that sarcoidosis may develop in chronic hepatitis C patients during interferon alpha and/or ribavirin treatment, and diagnostic tests for this adverse effect should be performed during the follow-ups.     

Response to pegylated interferon alpha-2b and ribavirin in children with chronic hepatitis C

GOALS: The purpose of this communication is to report our observations on the treatment of a diverse group of adolescent patients who were chronically infected with hepatitis C and received pegylated interferon and ribavirin. BACKGROUND: The currently accepted optimal therapy for adults with chronic hepatitis C is weekly injections of pegylated interferon and twice daily oral ribavirin. Information on interferon alone or in combination with ribavirin for chronic hepatitis C in children is limited. There is no published information on pegylated interferon and ribavirin in pediatric patients who previously failed interferon therapy. REPORT: Ten patients 11 to 18 years old received weekly pegylated interferon and twice daily ribavirin for hepatitis C. Treatment continued for 48 weeks, except for 1 patient with hepatitis C virus type 3a who was treated for 24 weeks and 1 patient who did not complete the course of treatment. The period of observation continued from November 2002 to December 2004. Within this group were 3 pediatric patients who had previously failed interferon therapy for hepatitis C. RESULTS: All but 1 patient had a viral response (no detectable virus) at some time during or after the treatment. Three patients achieved sustained viral response (no detectable virus 6 mo after the therapy). One patient who previously failed interferon therapy was among the sustained responders. CONCLUSIONS: In response to treatment with pegylated interferon and ribavirin, children and adolescents with chronic hepatitis C achieve results similar to those seen in adults. Previous antiviral therapy does not preclude positive response to pegylated interferon and ribavirin.     

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.     

Efficacy of combined pegylated interferon and ribavirin therapy in Jewish patients of Israel suffering from chronic hepatitis C

Background and purpose  

The efficacy and safety of pegylated interferon and ribavirin treatment for chronic hepatitis C (CHC) in the Jewish population has not been previously ascertained. The aims of our study were to determine the efficacy of pegylated interferon and ribavirin therapy in an Israeli outpatient practice.     

Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C

BACKGROUND & AIMS: Liver fibrosis is an important prognostic factor in patients with hepatitis C. The effect of pegylated (PEG) interferon alone or its combination with ribavirin on fibrosis has not been established. METHODS: We pooled individual data from 3010 naive patients with pretreatment and posttreatment biopsies from 4 randomized trials. Ten different regimens combining standard interferon, PEG interferon, and ribavirin were compared. The impact of each regimen was estimated by the percentage of patients with at least 1 grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least 1 stage worsening in fibrosis METAVIR score, and by the fibrosis progression rate per year. RESULTS: Necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 73% (optimized PEG 1.5 and ribavirin; P < 0.001). Fibrosis worsening ranges from 23% (interferon 24 weeks) to 8% (optimized PEG 1.5 and ribavirin; P < 0.001). All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis. Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ratio [OR] = 0.12; P < 0.0001), sustained viral response (OR = 0.36; P < 0.0001), age < 40 years (OR = 0.51; P < 0.001), body mass index < 27 kg/m(2) (OR = 0.65; P < 0.001), no or minimal baseline activity (OR = 0.70; P = 0.02), and viral load < 3.5 millions copies per milliliter (OR = 0.79; P = 0.03). CONCLUSIONS: PEG-interferon and ribavirin combination significantly reduces the rate of fibrosis progression in patients with hepatitis C.     

Pyoderma gangrenosum and exacerbation of psoriasis resulting from pegylated interferon alpha and ribavirin treatment of chronic hepatitis C

Interferon therapy is the cornerstone of chronic hepatitis C treatment. Side effects of interferon include possible triggering or exacerbation of immune diseases in consequence of immunomodulatory effects. We describe the unique case, in which pyoderma gangrenosum and exacerbation of psoriasis were developed 8 weeks after pegylated interferon alpha 2a and ribavirin therapy in a 45-year-old woman. The therapy had to be stopped on account of pyoderma gangrenosum and exacerbation of psoriasis in spite of a biochemical response to the therapy for hepatitis C. The evolution was favorable after stopping treatment. Therefore, we propose this would suggest a possible autoimmune mechanism for the development of pyoderma gangrenosum and exacerbation of psoriasis with pegylated interferon therapy. A susceptible patient, who has an autoimmune disease before interferon therapy, had to be informed that interferons may induce de novo or exacerbate existing immune diseases by immunomodulatory actions. To the best of our knowledge, this is the first case report of pyoderma gangrenosum and psoriasis that resulted from pegylated interferon alpha 2a and ribavirin treatment of chronic hepatitis C.     

聚乙二醇干扰素仪-2α／2b联合利巴韦林复治慢性丙型肝炎患者的疗效观察

目的探讨聚乙二醇干扰素α（PEG-IFNα）联合利巴韦林治疗复发慢性丙型肝炎（CHC）患者的应答情况及影响因素。方法 30例经IFN-α或PEG-IFNα标准RGT治疗后复发的CHC患者,均用PEG-IFNα-2a（180μg）或PEG-IFNα-2b（1.5μg/kg）联合利巴韦林（900 mg/d）再治疗,基因1型治疗48周,非基因1型治疗24周,停药随访24周,分析病毒基因型、基线HCV RNA载量、初治药物种类对联合治疗疗效的影响。结果 30例复发患者经联合再治疗后,24例（80%）获得持续病毒学应答（SVR）。18例低病毒载量（HCV RNA≤105拷贝/ml）患者中,17例（94.4%）获得SVR,与高病毒载量组（58.3%）差异有统计学意义（P=0.026）。基因1型组18例,其中14例（77.8%）获得SVR,与非基因1型组（83.3%）差异无统计学意义（P=1.000）。初治应用PEG-IFNα联合利巴韦林抗病毒的患者17例,其中13例（76.5%）经再治疗后获得SVR,与初治应用IFN-α抗病毒组（84.6%）无明显差异（P=0.672）。结论 PEG-IFNα联合利巴韦林治疗复发CHC患者的疗效较好。基线病毒载量高,再治疗效果差;病毒基因型及初治所采用的IFN类型与再治疗的疗效无显著相关性。     

A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C

OBJECTIVES: The efficacy of combination therapy with pegylated interferon (PEG IFN) alpha plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established. METHODS: Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN alpha-2b 1.5 microg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN alpha-2b 1.0 microg/kg per wk plus RBV 1,000-1,200 mg per day (Regimen B, n = 161) for 48 wks. RESULTS: Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18%vs 13%, p= 0.21), in 8% of the combination therapy nonresponders (10%vs 6%, p= 0.35), in 21% of the IFN monotherapy nonresponders (16%vs 27%, p= 0.35), and in 42% of the combination therapy relapsers (50%vs 32%, p= 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels >or=100,000 copies/mL (21%vs 5%, p= 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14%vs 33%, p= 0.01), and African Americans had lower SVR than Caucasians (4%vs 18%, p= 0.01). CONCLUSION: Combination therapy with PEG IFN alpha-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.     

Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin

Thyroid dysfunction is a known complication of interferon treatment in patients with hepatitis C virus (HCV) infection. Other uncommon endocrine complications have been reported during the treatment of viral hepatitis with IFN-alpha, such as hypopituitarism. A 54-year-old female patient with chronic hepatitis C began treatment with pegylated (PEG)-IFN-alpha 2a 180 mug/week plus ribavirin 1,000 mg/day. At week 20 of treatment, her routine laboratory control showed low levels of thyroid-stimulating hormone (TSH) and free serum thyroxine. This was confirmed at week 24, and other laboratory values showed low levels of adrenocorticotrophic hormone (ACTH). A T1-weighted magnetic resonance imaging scan demonstrated high intensity of the anterior pituitary gland and enhancement after intravenous administration of gadolinium. Hypophysitis with hypothalamic-pituitary dysfunction and secondary or central hypothyroidism was diagnosed on the basis of the clinical features, endocrinological assessment, immunological markers and imaging studies. Twenty-four weeks after stopping treatment, HCV RNA was negative by polymerase chain reaction and alanine aminotransferase values were below the upper limits of normal, and ACTH and thyroid values remained within the reference values. This is the first report of central hypothyroidism and hypophysitis during treatment with PEG-IFN-alpha plus ribavirin, and may be included in the potential list of side effects of the combination treatment.     

Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C

Background

This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE).

Methods

Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG-IFN/RBV, 90 were diagnosed with cirrhosis.

Results

Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR.

Conclusions

Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B.     

Efficacy of ribavirin monotherapy following combination therapy with interferon alfa-2b and ribavirin for patients with chronic hepatitis C.

Reappearance of HCV-RNA followed by exacerbation of biochemical parameters after combination therapy consisting of interferon and ribavirin is an obstacle to achieve sustained response and improve long-term prognosis. We hypothesed that ribavirin monotherapy after 6 months of combination therapy may improve sustained viral and biochemical responses, and conducted a prospective, randomized and controlled study. Thirty-eight patients with chronic hepatitis C treated with combination therapy for 6 months and had no detectable serum HCV-RNA were enrolled, and allocated into two arms. Group I (n=19) was continuously administered oral ribavirin for additional 6 months, and group II (n=19) was followed up without any further treatment. At the end of trial, HCV-RNA negativity was 11/19 (58%) in group I, and 6/19 (32%) in group II (p=0.191). Multivariant analysis demonstrated that ribavirin monotherapy was not a predictor for the eradication of HCV-RNA. In cases without sustained viral responses, serum ALT levels at baseline and the end of 48 weeks' trial were 54.6 and 44.4 in group I (p=0.237), and significant reduction with ribavirin monotherapy was not observed. In conclusion, ribavirin monotherapy following combination therapy fails to improve sustained viral response as well as biochemical response.     

芪参二莲汤加聚乙二醇干扰素α-2a联合利巴韦林治疗1b型慢性丙型肝炎疗效观察

目的：观察探讨PEG IFN（聚乙二醇干扰素）α-2a联合利巴韦林的基础上,加用芪参二莲汤治疗慢性丙型病毒性肝炎（CHC）的临床疗效。方法：选取我院2011年5月-2012年1月HCV RNA阳性的1b型CHC患者62例随机分为两组,治疗组30例,采用PEG IFNα-2a联合利巴韦林加芪参二莲汤治疗,对照组32例应用PEG IFNα-2a联合利巴韦林治疗,疗程48周,疗程结束后随访24周。并观察治疗前、后两组患者肝功能、HCV RNA及PBMC变化。结果：治疗组EVR为76.67%,ETVR为86.67%,随访SVR为83.33%;对照组分别为34.37%、50.00%、31.32%。两组病毒学应答比较,治疗组EVR、ETVR、SVR较对照组疗效显著,其差异均具有统计学意义（P〈0.05）。两组患者治疗48周后,ALT、TBil与本组治疗前比较,差异均具有统计学意义（P〈0.05）,其中治疗组ALT与同组治疗前比较,差异具有显著意义（P〈0.01）;两组患者治疗48周后,两组间同时段ALT及TBil比较,治疗组更优于对照组,差异均具有统计学意义（P〈0.05）。两组患者治疗48周后IL-10水平较本组治疗前均有所降低,差异均有统计学意义（P〈0.05）;两组间治疗后48周同时段相比较,治疗组患者改善优于对照组,差异有统计学意义（P〈0.05）,随访24周,两组间比较,差异仍具有统计学意义（P〈0.05）。治疗48后两组患者IL-12水平较本组治疗前比较差异均无统计学意义（P〉0.05）,但随访24周显示,治疗组IL-12水平较同时段对照组比较,差异有统计学意义（P〈0.05）。结论：芪参二莲汤加PEG IFNα-2a联合利巴韦林治疗1b型CHC疗效显著,明显优于单用干扰素联合利巴韦林的临床疗效。不仅可以显著抑制HCV RNA复制,改善肝功能,而且可以减轻不良反应,预后良好稳定,值得临床推广。     

Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin

This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients (P < 0.05). C(max) of PEG-IFN occurred 12-48 h after the initial administration, with t(1/2) and C(min) being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs (P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression.     

A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group

The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 microg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron-induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.     

Cost effectiveness of interferon alpha2b combined with ribavirin for the treatment of chronic hepatitis C.

Treatment of chronic hepatitis C with Interferon (IFN) alpha2b monotherapy results in 10% to 15% sustained virological response (SVR). Combining IFN with ribavirin increases this response. In this analysis, using the Markov model, 6 treatment strategies for chronic hepatitis C (previously untreated) were compared on the basis of incremental cost per additional quality-adjusted life years ($/QALY). Our results showed that the no treatment strategy was associated with a cost of $38,747 and 13.10 QALYs. The strategy using IFN alone for 48 weeks was associated with a cost of $35,642 and 14.05 QALYs. The strategy using IFN monotherapy followed by combination therapy for nonresponders and relapsers was associated with a cost of $34, 561 and 15.53 QALYs. A similar strategy, but limiting combination to relapsers only, was associated with a cost of $34,758 and 14.40 QALYs. The strategy using IFN with ribavirin as the initial therapy for all patients was associated with a cost of $34,792 and 15.31 QALYs. Finally, the strategy using viral genotyping first and then adjusting the duration of combination therapy based on genotype was associated with a cost of $37,263 and 15.89 QALYs. The strategy using genotyping to guide duration of combination therapy was the most cost-effective approach with an incremental cost-effectiveness ratio of $7,500 per QALY. Sensitivity analyses confirmed the robustness of these results. We conclude that combination of IFN and ribavirin with duration of therapy based on the viral genotype, is a cost-effective approach in treating patients with chronic hepatitis C.