Successful anti-viral treatment improves survival of patients with advanced liver disease due to chronic hepatitis C.

BACKGROUND: Long-term outcome of chronic hepatitis C patients with successful viral eradication seems to be promising. AIM: To evaluate mortality, incidence of hepatocellular carcinoma (HCC), liver failure and liver transplantation in sustained virological responders (SVR) and non-SVR patients with different stages of fibrosis. METHODS: Seven hundred and fourteen patients with a follow-up of 7.2 (1-21.1) years (age: 51.4 ± 12.0 years, 276 female, IFN-monotherapy: n = 19, IFN/RBV: n = 122, peg-IFN/RBV: n = 573, SVR: 551, non-SVR: 163) were studied. Two hundred and ten of 540 patients with a liver biopsy prior to treatment had advanced stages of fibrosis (Metavir F3/F4). RESULTS: Forty-eight patients died during follow-up, 15 with SVR and 33 without (P < 0.001). Five- and 10-year mortality rates were 1.8% (10/551) and 2.7% (15/551) in the SVR group and 8.6% (14/163) and 19.1% (31/163) in the non-SVR patients (P < 0.001). In 29 patients, decompensation of liver disease [SVR: 9 (1.6%) vs. non-SVR: 20 (12.3%); P < 0.001] occurred and in 29 patients, HCC developed during follow-up [SVR: 10 (1.8%) vs. non-SVR: 19 (11.7%); P < 0.001]. Non-SVR was an independent predictor for developing (i) HCC [HR: 2.36 (95% CI: 1.07-5.23; P = 0.034], (ii) liver-related complications [HR: 2.62; (95% CI: 1.18-5.81; P = 0.018] and (iii) mortality (HR: 3.46; 95% CI: 1.91-6.29; P < 0.001). For patients with early stages of fibrosis (F0-F2), a survival benefit of SVR patients could not be demonstrated. CONCLUSIONS: Successful anti-viral therapy decreases mortality, incidence of hepatocellular carcinoma and liver failure in patients with advanced fibrosis. However, hepatocellular carcinoma development or liver failure are not prevented completely, and further follow-up of patients is advisable.

Polymorphisms of interferon-λ4 and IL28B - effects on treatment response to interferon/ribavirin in patients with chronic hepatitis C.

BACKGROUND: The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin (PEG/RBV) therapy in patients with chronic hepatitis C (CHC). Recently, a dinucleotide frame shift variant in ss469415590 (TT or ΔG) was described, which generates the novel interferon lambda 4 protein (IFNL4). IFNL4 ss469415590 (ΔG) allele carriers have an impaired clearance of HCV infection and response to IFN-α therapy. In this study, we compared the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC. AIM: To compare the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC. METHODS: A total of 754 PEG/RBV patients treated (male/female = 484/270; Caucasians: 98.8%; mean age: 42.8 [CI 95%: 42.0-43.6] y; genotype (GT)1: n = 435, GT2: n = 23, GT3: n = 185, GT4: n = 114) were investigated. Liver fibrosis was assessed by liver biopsy in 456 patients. Single nucleotide polymorphisms (SNPs) in ss469415590, rs12979860 and rs8099917 were analysed by RT-PCR system. RESULTS: Of the patients, 12.9% (n = 97) had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% (n = 387) were heterozygous (TT/ΔG) and 35.8% (n = 270) had TT/TT. IFNL4 polymorphism was independently associated with SVR in GT1 (OR: 2.539, CI 95%: 1.629-3.021, P < 0.001) and GT4 (OR: 12.573, CI 95%: 3.427-46.133, P < 0.001), but not in GT3 (OR: 1.514, CI 95%: 0.933-2.458, P = 0.093). IFNL4 correlated strongly with rs12979860 (ρ = 0.988, P < 0.001), but only moderately with rs8099917 (ρ = 0.598, P < 0.001). CONCLUSIONS: These findings underscore the role of IFNL4 for treatment response in patients with CHC genotypes 1 and 4. However, due to its strong correlation with rs12979860 in IL28B, there is no benefit in additional testing for IFNL4 for treatment prediction in Caucasian patients. By contrast, IFNL4 improves prediction of response to interferon-based therapies, if SNP rs8099917 is used.

Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral.

BACKGROUND: The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking. AIM: To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals. METHODS: Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7-64) months. RESULTS: One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5-49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24-6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance. CONCLUSION: Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up.

The risk of infections in HIV-HCV coinfected patients during antiviral therapy with pegIFN+RBV.

OBJECTIVES: Antiviral treatment with pegIFN/RBV decreases ANC and CD4+ cell count. An association between neutropenia, a low CD4+ cell count and infections has not been demonstrated so far in HIV-HCV coinfected patients. METHODS: The incidence, type, and severity of infections were recorded in 85 HIV-HCV coinfected and 164 monoinfected patients receiving pegIFN/RBV for 48 weeks. ANC and CD4+ cell count were assessed every 4 weeks during therapy. RESULTS: The incidence of infections was significantly higher in HIV-HCV than HCV-Mono (38% vs. 15%; p = 0.001). Types of infections: pneumonia (n = 16/n = 24), bacteraemia/sepsis (n = 5/n = 2), skin infections (n = 15/n = 12), urinary tract infections (n = 4/n = 1), OIs (n = 10/n = 1). The incidence of neutropenia grade 1, 2 3 or 4 was similar in HIV-HCV and HCV-Mono, respectively. The incidence of infections was not associated with neutropenia (HCV-Mono: p = 0.584; HIV-HCV: p = 0.23) or with CD4+ cell counts <200/µL (HIV-HCV: p = 0.29). OIs occurred more often in HIV-HCV patients with CD4+ cell count <200/µL (p = 0.024). CONCLUSIONS: Up to 38% and 15% of HIV-HCV coinfected and HCV-monoinfected patients develop infections during pegIFN+RBV therapy but without any correlation to neutropenia. Antibacterial prophylaxis/treatment should be considered early in HIV-HCV coinfected patients developing CD4+ cell counts <200/µL during antiviral therapy as these patients have an increased risk of OIs.

Prevalence and clinical significance of GB virus type C/hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy.

Coinfection with GBV-C/HGV in patients with chronic hepatitis C (CHC) may influence clinical course and response rates of antiviral therapy. Aim of the study was to investigate the prevalence of GBV-C/HGV/HCV coinfection and its influence on outcome of interferon/ribavirin combination therapy. Three hundred and four patients with CHC [m/f = 211/93, age: 42 (18-65)] were investigated. HGV RNA detection was performed by polymerase chain reaction prior to and 6 months after the end of antiviral therapy. HGV/HCV coinfection could be identified in 37/304 (12.2%) patients with intravenous drug abuse as the most common source of infection (N = 21, (56.8%)). The predominant HCV genotype in coinfected individuals was HCV-3a (HCV-3a: 51.4%, HCV-1: 37.8%, HCV-4: 10.8%). HGV coinfection was more prevalent in patients infected with HCV-3 compared to HCV-1 or HCV-4 [19/45 (42.2%) vs. 14/185 (7.6%) vs. 4/52 (7.7%), P < 0.01]. Patients with HGV/HCV coinfection were younger [35 (18-56) vs. 43 (19-65), years; P < 0.01], and advanced fibrosis (F3-F4) was less frequent (22.2% vs. 42.9%, P < 0.05). A sustained virological response was achieved more frequently in HGV/HCV coinfected patients [26/37 (70.3%)] than in monoinfected patients [120/267 (44.9%), P < 0.01]. HGV RNA was undetectable in 65.7% of the coinfected patients at the end of follow-up. Intravenous drug abuse seems to be a major risk factor for HGV coinfection in patients with chronic hepatitis C. Coinfection with HGV does not worsen the clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy. Interferon/ribavirin combination therapy also clears HGV infection in a high proportion of cases.

Hepatocellular carcinoma in long-term sustained virological responders following antiviral combination therapy for chronic hepatitis C.

Antiviral treatment results in a sustained virologic response (SVR) in 50-75% of patients with chronic hepatitis C. Long-term follow up studies have observed ongoing SVR in the overwhelming majority of them. Thus chronic hepatitis C is considered 'cured' if an SVR is achieved. Consequently, it is expected that in sustained virologic responders long-term complications of hepatatic C virus (HCV) related chronic liver disease including hepatocellular carcinoma are eliminated or have a decreased incidence. We report on five patients (three from Austria, two from USA) who developed hepatocellular carcinoma during follow up (3-6 years) after achieving SVR. During follow up and at diagnosis all were HCV-RNA neg. None of the patients had other liver diseases. One patient presented with bilateral adrenal metastasis, the remaining four with large hepatic tumours. Three patients were noncirrhotic at the start of treatment at the time of tumour diagnosis. Successful antiviral treatment in HCV patients does not prevent development of hepatocellular carcinoma even in non-cirrhotic livers. Long-term follow up of patients with SVR is mandatory and should include surveillance for hepatocellular carcinoma.

Efficacy and safety of antiviral therapy in patients with Crohn's disease and chronic hepatitis C.

BACKGROUND: Efficacy and safety of antiviral combination therapy in patients with Crohn's disease (CD) and chronic hepatitis C (CHC) is presently not established and consequently CHC is rarely treated in CD patients. AIM: To analyse the efficacy and tolerability of antiviral interferon/ribavirin therapy in patients with CHC and CD. METHODS: Eleven HCV-infected CD patients received either 3 x 1.5 microg/kg/week interferon-alpha-2b or 180 microg/week peginterferon-alpha-2a (PEGASYS; Roche, Basel, Switzerland) as monotherapy (n = 1) or in combination with 800-1200 mg/day ribavirin (COPEGUS; Roche) (n = 10) for 24-54 weeks according to HCV-genotype and initial response respectively. Eight patients were under CD-specific therapy. RESULTS: Five (46%) patients (HCV-1: a = 3; HCV-2: n = 0; HCV-3: n = 1; unknown: n = 1) achieved a sustained virological response, three (27%) patients relapsed, three (27%) were nonresponders (all GT 1b). At baseline, the Harvey--Bradshaw Index was 0 (0-8) [median (range)], increased on antiviral therapy to 4 (1-15) (P = 0.005) and decreased to baseline level 0 (0-6) after 6-month follow-up. CONCLUSIONS: This preliminary experience demonstrates that treatment of CHC in patients with CD is comparable to the treatment of CHC in those without CD. However, gastrointestinal symptoms may be temporarily exacerbated and haemopoietic growth factors may be required.