Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63‐year‐old man with HCV‐related liver cirrhosis, who failed to respond to IFN‐β plus RBV after LT. Treatment was switched to PEG IFN‐α‐2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)‐28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL‐28 SNP (rs8099917). Completion of 12‐week triple therapy was followed by PEG IFN‐α‐2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70‐year‐old woman with HCV‐related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN‐α‐2b plus RBV after LT, and was subsequently switched to PEG IFN‐α‐2b/RBV/TVR. Genotype analysis showed TG genotype of IL‐28 SNP for the donor, and TT genotype of IL‐28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN‐α‐2b plus RBV after LT.     

Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection

Ribavirin amplifies the interferon‐alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)‐IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy on viral kinetics, on‐treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty‐eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG‐IFN2a (PEG‐IFN2a arm) for 6 weeks prior to 12 weeks of PEG‐IFN2a/ribavirin combination therapy within a double‐blind, placebo‐controlled trial. Then, standard PEG‐IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG‐IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log₁₀ IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG‐IFN2a‐induced first‐ or second‐phase viral decline (P values >0.100) nor on‐treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG‐IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG‐IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy did neither increase the first‐ or second‐phase viral decline nor on‐treatment response or SVR.     

ITPA genetic variants influence efficacy of PEG‐IFN/RBV therapy in older patients infected with HCV genotype 1 and favourable IL28B type

Inosine triphosphatase (ITPA) genetic variants are strongly associated with ribavirin (RBV)‐induced anaemia during pegylated interferon (PEG‐IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG‐IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥3 g/dL reduction or <10 g/dL of haemoglobin (Hb) up to week 12, was more frequent in patients with CC at rs1127354 [65% (145/224), 33% (73/224)] than in those with CA/AA [25% (21/85), 6% (8/85)] (P < 0.0001). ITPA genotype, pretreatment Hb level and age were independent predictive factors for severe anaemia: Hb < 10 g/dL. In IL28B favourable type, the sustained virologic response rate was higher in ≥60‐year‐old patients with CA/AA than in those with CC [71% (22/31) vs 40% (26/65), P = 0.005], although there was no significant difference in treatment efficacy according to ITPA genetic variants in the <60‐year‐old patients. The proportion of patients administered ≥80% of the dosage of RBV was significantly higher in the patients with CA/AA than in those with CC (P = 0.025), resulting in a lower relapse rate. In conclusion, ITPA genetic variants were associated with severe RBV‐induced anaemia and could influence the efficacy of PEG‐IFN plus RBV treatment among elderly patients with IL28B favourable type.     

Sustained virological response of patients with hepatitis C virus genotype 2 depends on pegylated interferon compliance

Aim: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10–20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV. Methods: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN‐α‐2b (1.5 µg/kg) and a weekly weight‐adjusted dose of RBV (600, 800 and 1000 mg per <60, 60–80 and >80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined. Results: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, =0.021, =0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, =0.018, respectively) as factors involved in the SVR, but not mean RBV dose. Conclusion: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients.     

Valuable antiviral therapeutic options for the treatment of chronic hepatitis C patients with thrombocytopenia

Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG‐IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty‐one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10⁹/L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA‐IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA‐IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA‐IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA‐IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG‐IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA‐IR adds valuable therapeutic information.     

Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C

We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG‐IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty‐eight patients with genotype 1b high viral loads were treated with PEG‐IFN/RBV/TVR. Peg‐IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.     

Grazoprevir plus peginterferon and ribavirin in treatment‐naive patients with hepatitis C virus genotype 1 infection: a randomized trial

Grazoprevir (MK‐5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25–100 mg/day in combination with peginterferon and ribavirin (PEG‐IFN/RBV). In this randomized, dose‐ranging, multicentre trial, treatment‐naive adults with chronic HCV genotype 1 infection received once‐daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG‐IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG‐IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty‐seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100‐mg arm and 22 days in the 25‐ and 50‐mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25‐, 50‐ and 100‐mg arms, respectively (per‐protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25‐ and 100‐mg arms). Conclusion: These data support further study of the grazoprevir 100‐mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).     

Pegylated Interferon and Ribavirin Failures: Is Retreatment an Option?

Currently, there are limited therapeutic options available for chronic hepatitis C (HCV) patients who fail treatment with peginterferon α (PEG IFN) + ribavirin (RBV). An option is retreatment with a second course PEG-IFN + RBV. However, the virologic clearance with this option is unknown. Thus, we evaluated the outcome of our cohort of patients with chronic HCV who achieved a sustained viral response when retreated with PEG IFN plus RBV after having no response to an initial course of PEG IFN plus RBV. Nonresponse to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of PEG-IFN + RBV therapy. Twenty patients (12 [60%] men; 8 [40%] women) were treated with PEG IFN α-2b plus RBV and PEG IFN α-2a plus RBV. The mean age of the patients was 50 years, 85% were white, 95% had genotype 1, and 35% had cirrhosis. Prior to the first course of PEG IFN plus RBV, 12 (60%) of 20 patients had no prior treatment for Hepatitis C. After the second course of PEG IFN plus RBV, 2 (10%) of 20 patients achieved a sustained virologic response. These results suggest marginal benefit of retreatment of patients with chronic HCV with another course of PEG IFN plus RBV after they have not responded to an initial course of PEG IFN plus RBV.     

Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study

Summary. The optimal duration of treatment with pegylated interferon (PEG‐IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty‐six treatment naïve patients were treated with PEG‐IFN‐α2a (180 μg/week) plus weight‐based RBV (1000–1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response‐guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log₁₀ IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response‐guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG‐IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response‐guided strategy in a larger number of patients with genotype 6.     

Interleukin-28B single nucleotide polymorphism of donors and recipients can predict viral response to pegylated interferon/ribavirin therapy in patients with recurrent hepatitis C after living donor liver transplantation

Background and Aim: Interleukin‐28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long‐term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living‐donor liver transplantation (LDLT). Methods: Thirty‐five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy. Results: The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG + GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG + GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT : TT (donors' : recipients'), TT : TG + GG, TG + GG : any group were 81%, 50%, and 20%, respectively. The VR rate of TT : TT, TT : TG + GG and TG + GG : any group at 12 weeks were 28%, 0%, and 0%; those at 48 weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors : recipients (TT : TT) as the only independent determinant of SVR (odds ratio 15.0, P = 0.035). Conclusion: Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients.     

HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin

Summary. In patients with hepatitis C virus (HCV)‐related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon α‐2a (PEG‐IFN) alone, but the efficacy and tolerability of the PEG‐IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment‐naïve patients with biopsy proved HCV‐related advanced fibrosis/cirrhosis (Ishak score F4–F6, Child–Pugh score ≤7) were randomized to 48 weeks of PEG‐IFN (180 μg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG‐IFN (180 μg sc weekly) and low‐dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG‐IFN/STD RBV (52%) were higher – albeit not significantly – than that with PEG‐IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count ≥150 × 10⁹/L were independently associated with SVR. The likelihood of SVR was <7% if viraemia had not declined by ≥2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV‐cirrhotics with STD PEG‐IFN/RBV is favourable.     

Safety and efficacy of sofosbuvir‐based direct‐acting antiviral regimens for hepatitis C virus genotypes 1‐4 and 6 in Myanmar: Real‐world experience

This open‐label, clinical experience investigated the safety and efficacy of direct‐acting antiviral (DAA) hepatitis C virus (HCV) therapy in Myanmar; 344 patients completed treatment between June 2015 and May 2016. Patients with HCV genotypes 1‐4 and 6 received one of four treatments: (i) Peg‐interferon (PEG‐IFN)+sofosbuvir (SOF)+ribavirin (RBV) for 12 weeks, (ii) SOF+RBV for 24 weeks, (iii) ledipasvir (LDV)+SOF for 12 weeks or (iv) daclatasvir (DCV)+SOF+RBV for 12 or 24 weeks. Genotype 3 was most common (n=133, 38.7%), followed by genotype 6 (n=122, 35.5%) and genotype 1 (n=86, 25%). Overall, 91% of patients achieved sustained virologic response (SVR); 99% in group 1, (n=148/149), 90% in group 2 (n=95/106), 78% in group 3 (n=65/83) and 100% in group 4 (n=6/6). In group 3, SVR rates were 96.8% in genotype 1 (n=30/31) and 64.1% in genotype 6 (n=25/39). Multivariable regression analysis identified advanced fibrosis (F3‐4) (OR=.16 CI: 0.05‐0.57, P=.005), genotype 6 (OR=.35, CI: 0.16‐0.79, P=.012) and diabetes (OR=.29, CI: 0.12‐0.71, P=.007) as negative independent predictors of response. Adverse events were mild with all‐oral therapy. Conclusion: DAA therapy ±PEG‐IFN achieved high SVR rates. Genotype 6 patients had a low SVR to 12 weeks of LDV and SOF raising the need for other regimens, RBV or longer treatment duration in this population.     

HCV E1E2‐MF59 vaccine in chronic hepatitis C patients treated with PEG‐IFNα2a and Ribavirin: a randomized controlled trial

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV‐specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy‐eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon‐(IFN)/ribavirin‐(RBV)] were randomly assigned to vaccine (V:23), Peg‐IFNα2a‐180‐ug/qw and ribavirin 1000–1200‐mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0‐4‐8‐12‐24‐28‐32‐36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2‐specific‐CD4 + T cells were performed at week 0‐12‐16‐48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV‐RNA levels (P = 0.026) at week 16. HCV E1E2MF59 vaccine in combination with Peg‐IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies.     

Diabetes Mellitus Is Associated with Impaired Response to Antiviral Therapy in Chronic Hepatitis C Infection

Insulin resistance may promote hepatic fibrosis in chronic hepatitis C (HCV) and has emerged as a cofactor in failure to achieve sustained viral response (SVR). Aims (1) To assess the association of diabetes mellitus (DM) in HCV patients to the severity of hepatic fibrosis and to the response to antiviral treatment. (2) To assess the safety of pegylated interferon and ribavirin combination therapy (Peg IFN/RBV) in diabetic HCV patients. Methods HCV diabetics (n = 61) were identified. A 2:1 matching control group was used to identify independent factors of advanced fibrosis and treatment failure. Results Compared to HCV non-diabetics, HCV diabetics were more likely to have steatosis (P < 0.0001) and advanced fibrosis (P = 0.003). Patients’ age, Caucasian ethnicity, obesity, and histologic activity index were independently associated with advanced fibrosis (P < 0.05). Only 23% of HCV diabetics achieved SVR compared to 46% of HCV non-diabetics (P = 0.003). DM, genotype 1, high baseline viral load, and African-American ethnicity were independently associated with less SVR (P < 0.05). Significant adverse events were more common in HCV diabetics compared to HCV non-diabetics (P = 0.001). Side effects did not increase in patients receiving PEG IFN/RBV and insulin sensitizers. Conclusion DM was associated with impaired virologic response to PEG IFN/RBV in HCV patients. Adverse events during therapy were more frequent in diabetic compared to non-diabetic HCV patients.     

Very early prediction of response to HCV treatment with PEG‐IFN‐alfa‐2a and ribavirin in HIV/HCV‐coinfected patients

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV‐coinfected patients. Twenty‐six patients (15 HCV genotype‐1 and 11 genotype‐3) were treated with a 48‐week regimen of peginterferon‐alfa‐2a (PEG‐IFN) (180 μg/week) and weight‐based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3‐ to 12.9‐fold viral rebound until the administration of the second dose of PEG‐IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype‐1 and <0.97 log for genotype‐3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second‐phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first‐phase viral decline at day 2 and second‐phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on‐treatment prognosticators of nonresponse in patients with HCV and HIV.     

Ribavirin suppresses erythroid differentiation and proliferation in chronic hepatitis C patients

Combination therapy with pegylated interferon (pegIFN) plus ribavirin (RBV) is the standard of care for chronic hepatitis C. One of the major treatment‐related side effects is anaemia, attributed to RBV‐induced haemolysis. However, haemolysis biomarkers are not present in all patients supporting the existence of other pathogenetic mechanisms. We studied the role of RBV in inducing haemolysis and its effects on erythropoiesis. In 18 hepatitis C virus (HCV) genotype 2 patients treated with pegIFN‐alpha‐2a (180 mcg/week) plus RBV (800 mg/day) for 24 weeks and in 10 hepatitis B virus (HBV) patients treated with pegIFN‐alpha‐2a (180 mcg/week) for 48 weeks, haemolysis was assessed by serum LDH, haptoglobin and reticulocyte count. Erythropoiesis was evaluated both ex vivo, analysing the clonogenic activity of patients' erythroid progenitors, as well as in vitro adding pegIFN and RBV to liquid cultures obtained from CD34+ cells of healthy volunteers. The majority of patients developed anaemia; the week 4 mean haemoglobin decrease was greater in HCV than in HBV patients (1.7 vs 0.47 g/dL, P = 0.01). Only three HCV patients (17%) and no HBV patients showed signs of haemolysis. The 15 nonhaemolytic HCV patients and all HBV patients showed a delay in erythroid differentiation, with a reduction in colony number and a relative increase in undifferentiated colony percentage. Haemolytic HCV patients had an increase in colony number at week 4 of therapy. In vitro, erythroid cell proliferation and differentiation were inhibited by both pegIFN and RBV. Both pegIFN and RBV have an inhibitory effect on erythroid proliferation and differentiation.     

Open‐label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1‐infected patients who failed placebo plus peginterferon and ribavirin

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1‐infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥800 000 IU/mL (80% vs 58%) and a non‐CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.     

Efficacy and safety of pegylated interferon alpha‐2a therapy for chronic hepatitis C in HIV‐infected patients with haemophilia

Summary. The objective of this study was to evaluate the efficacy and safety of pegylated interferon (PEG‐IFN) alpha‐2a monotherapy in a cohort of Chinese haemophilic patients co‐infected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and undergoing highly active antiretroviral drugs therapy. Twenty‐two (n = 22) patients with CD4 lymphocyte counts over 200 cells μL^?1 were treated with 180 μg of PEG‐IFN alpha‐2a subcutaneously once in a week for 48 weeks. HCV load (HCV RNA), HIV load (HIV RNA) and CD4 lymphocyte counts were measured at baseline and 4, 12, 24, 48 and 72 weeks after initiation of anti‐HCV therapy. Efficacy and safety were analysed according to baseline CD4 status (≥350 cells μL^?1). Significant HCV‐RNA decreases (>1 log₁₀ copies mL^?1) were observed through week 72 after PEG‐INF alpha‐2a monotherapy across both CD4 strata. CD4 status was not associated with treatment outcomes as evaluated using rapid viral response rate (P = 0.655), early viral response rate (P = 0.387), end‐of‐treatment viral response rate (P = 1.000) or sustained viral response rate (SVR, P = 0.674). A sustained virological response was achieved in nine patients (41%), five with genotype 2a (83%) and four with genotype 1b (25%, P = 0.023). SVR was HCV genotype dependent. Eleven patients required a dose reduction in PEG‐IFN alpha‐2a. PEG‐IFN alpha‐2a monotherapy could be considered as a safe and effective option for the treatment of HCV infection in HIV patients with haemophilia, particularly in resource‐limited settings. While higher CD4 lymphocyte counts resulted in greater HCV‐RNA reduction, HCV genotype was a predictor for sustained virological response.     

Virologic response and haematologic toxicity of boceprevir‐ and telaprevir‐containing regimens in actual clinical settings

Effectiveness, safety and tolerability of boceprevir (BOC) and telaprevir (TPV) in actual clinical settings remain unknown. We determined rates of sustained virologic response (SVR) and haematologic adverse effects among persons treated with BOC‐ or TPV‐containing regimens, compared with pegylated interferon/ribavirin (PEG/RBV). Using an established cohort of hepatitis C virus (HCV)‐infected persons, Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), we identified those treated with a BOC‐ or TPV‐containing regimen and HCV genotype 1‐infected controls treated with PEG/RBV. We excluded those with HIV coinfection and missing HCV RNA values to determine SVR. Primary endpoints were SVR (undetectable HCV RNA ≥12 weeks after treatment completion) and haematologic toxicity (grade 3/4 anaemia, neutropenia and thrombocytopenia). We evaluated 2288 persons on BOC‐, 409 on TPV‐containing regimen and 6308 on PEG/RBV. Among these groups, respectively, 31%, 43% and 9% were treatment‐experienced; 17%, 37% and 14% had baseline cirrhosis; 63%, 54% and 48% were genotype 1a. SVR rates among noncirrhotics were as follows: treatment naïve: 65% (BOC), 67% (TPV) and 31% (PEG/RBV); treatment experienced: 57% (BOC), 54% (TPV) and 13% (PEG/RBV); (P‐value not significant for BOC vs TPV; P < 0.0001 for BOC or TPV vs PEG/RBV). Haematologic toxicities among BOC‐, TPV‐ and PEG/RBV‐treated groups were as follows: grade 3/4 anaemia 7%, 11% and 3%; grade 4 thrombocytopenia 2.2%, 5.4% and 1.7%; grade 4 neutropenia 8.2%, 5.6% and 3.4%. SVR rates are higher and closer to those reported in pivotal clinical trials among BOC‐ and TPV‐treated persons compared with PEG/RBV‐treated persons. Haematologic adverse events are frequent, but severe toxicity is uncommon.