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.     

Hepatitis C virus NS3/4A quasispecies diversity in acute hepatitis C infection in HIV‐1 co‐infected patients

The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV‐1)‐positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV‐1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV‐coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV‐coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous‐nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV‐1‐infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV‐coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV‐1‐positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.     

Long‐term outcomes of direct acting antivirals in post‐transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis

Long‐term functional outcomes of sofosbuvir‐based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post‐transplant hepatitis C virus (HCV) recurrence. Seventy‐three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24‐week sofosbuvir with ribavirin±pegylated interferon or interferon‐free sofosbuvir‐based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82‐112) weeks. Twelve of 73 (16.4%) died (10 non‐FCH, 2 FCH) and two underwent re‐LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non‐FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow‐up, MELD and Child‐Turcotte‐Pugh scores improved both in non‐FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short‐treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long‐term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child‐Turcotte‐Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals‐based treatments for severe post‐transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long‐term survival. The setting of severe HCV recurrence may require the identification of “too‐sick‐to‐treat patients” to avoid futile treatments.     

Sofosbuvir‐Daclatasvir is suboptimal in patients with genotype 2 chronic hepatitis C infection: real‐life experience from the HEPATHER ANRS CO22 cohort

Sofosbuvir plus daclatasvir with or without ribavirin has demonstrated a high efficacy and an acceptable safety profile in clinical trials of patients infected with genotype 2 hepatitis Cvirus (HCV); however, there are currently no real‐world data available for this regimen. To evaluate the real‐life safety and efficacy of sofosbuvir/daclatasvir with or without ribavirin in genotype 2 HCV patients in the French cohort ANRS CO22 HEPATHER(NCT01953458). In this ongoing, national, multicentre, prospective, observational study, we observed patients with HCV genotype 2 infection who initiated treatment with sofosbuvir (400 mg/d) plus daclatasvir with or without ribavirin (1‐1.2 g/d). Patients were divided into two treatment groups: sofosbuvir/daclatasvir with or without ribavirin (12 weeks/24 weeks). The primary end point was a sustained virological response at week 12 following the end of therapy. Overall, 88% and 91% of patients achieved a sustained virological response following 12 and 24 weeks of treatment with sofosbuvir/daclatasvir with or without ribavirin, respectively. The most common adverse events were asthenia (29%), headache (15%) and fatigue (20%), and ribavirin addition was associated with a higher rate of adverse events and treatment discontinuation. Sofosbuvir/daclatasvir with or without ribavirin was associated with lower rates of sustained virological response in the real‐life setting compared with the clinical setting and demonstrated suboptimal efficacy for the treatment of patients with genotype 2 chronic HCV.     

Role of hepatitis C virus substitutions and interleukin‐28B polymorphism on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy

Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity‐determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin‐28B (IL‐28B) locus affect the outcome of interferon (IFN)‐based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV‐1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non‐EVR patients. Logistic regression analysis showed that ISDR mutation (≥2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts ≥ 15 × 10⁴/μL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (≥2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy.     

Use of a hepatitis C virus (HCV) RNA‐positive donor in a treated HCV RNA‐negative liver transplant recipient

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA‐positive donor organs are typically not given to patients who have cleared HCV. A 64‐year‐old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24‐week treatment course, the patient underwent deceased‐donor LT and received an organ from an anti‐HCV‐positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV‐infected transplant patients.     

Effectiveness and safety of ombitasvir,paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment‐naïve and treatment‐experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment‐naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow‐up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child‐Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.     

Hepatitis C treatment from “response‐guided” to “resource‐guided” therapy in the transition era from interferon‐containing to interferon‐free regimens

Peginterferon/ribavirin has been the standard‐of‐care for chronic hepatitis C virus (HCV) infections: 48 weeks for genotype 1 or 4 (HCV‐1/4) and 24 weeks for HCV‐2/3. Response‐guided therapy recommended shorter 24‐ and 16‐week regimens for HCV‐1 with lower baseline viral loads (< 400 000–800 000 IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV‐2/3 with RVR, respectively; and extending to 72 and 48 weeks for HCV‐1 slower responders and HCV‐2 non‐RVR patients, respectively, to improve the efficacy. The progress of directly acting antivirals (DAA), moving from interferon‐containing regimens in 2011 to interferon‐free regimens in 2013, has greatly improved the treatment success. Interferon‐containing regimens include boceprevir or telaprevir or simeprevir or daclatasvir plus peginterferon/ribavirin, 24–48 weeks, for HCV‐1 or 4. However, adding these DAA has no benefit for HCV‐1 with lower baseline viral loads/RVR. Instead, 12‐week sofosbuvir plus peginterferon/ribavirin attained sustained virological response rates of > 90% for HCV‐1/3–6. Interferon‐free regimens include two main categories: NS5B nucleotide inhibitor (sofosbuvir)‐based regimens and NS3/4A inhibitor/NS5A inhibitor‐based regimens (daclatasvir/asunaprevir, paritaprevir/r/ombitasvir/dasabuvir and grazoprevir/elbasvir). About 8–24 weeks interferon‐free regimens could achieve sustained virological response rates of 82–99% for corresponding HCV genotypes. Although the newly DAA interferon‐free regimens have high efficacy and safety, the huge budget impact increases the treatment barriers. The current recommendation should, therefore, base on the availability, indication, and cost‐effectiveness in the transition era of DAA. Based on the concept of “resource‐guided therapy,” peginterferon/ribavirin might be applied for easy‐to‐treat interferon‐eligible patients in resource‐constrained areas. Prioritizing patients for interferon‐free regimens according to “time‐degenerative factors” (age and fibrosis) is justified before the regimens becoming available and affordable.     

Role of rapid virological response in prediction of sustained virological response to Peg-IFN plus ribavirin in HCV / HIV co-infected individuals

Summary.  The objective of the study was to evaluate the role of rapid virological response (RVR) in predicting sustained virological response (SVR) rates to hepatitis C virus (HCV) therapy. 65 HIV / HCV co-infected patients commenced HCV treatment per protocol. HIV / HCV patients with a mean CD4 count of 502 were treated for 24–48 weeks depending on genotype. Virological response was assessed at weeks 4 (RVR), 12 [early virological response (EVR)], 24, at end of treatment (EOTR) and 24 weeks post-completion of treatment (SVR). Primary end-point was defined as undetectable HCV RNA at 24 weeks post-treatment completion. Fifty-five per cent of co-infected patients were on highly active anti-retroviral therapy. A majority of patient group were male. 60% of HIV / HCV patients achieved SVR (35% genotype 1 / 4; 77% genotype 2 / 3). 24 HIV / HCV patients achieved undetectable HCV levels compared with baseline by week 4. The positive predictive value (PPV) of RVR at week 4 for subsequent SVR in HIV–HCV co-infected patients was 100%; the negative predictive value (NPV) was 57%. Significant variables associated with SVR were: (i) lower median pre-treatment HCV viral load, (ii) genotype 2 / 3 disease and (iii) achievement of RVR. Independent variables associated with RVR were low pre-treatment HCV viral load and genotype 2 / 3 disease. Achievement of RVR, a negative HCV-PCR, at week 4 of treatment is predictive of SVR in this cohort of patients. This may be used to guide optimal treatment duration in patient groups. More significantly, the data serve to highlight the subgroup of patients who, on achieving RVR, should be actively supported to complete HCV treatment with full dose therapy, especially patients co-infected with G2 / 3 disease for whom 6 months' full dose therapy may be sufficient to obtain a SVR.     

Management of hepatitis C in HIV infected and other immunocompromised individuals.

Host immunity is important in determining the natural history of HCV infection. Patients with ineffective polyclonal HCV specific CD4+ response are persistently infected and loss of HCV-specific CD4+ T cells is associated with relapse of viraemia. Weak HCV-specific CD4+ response early in the course of chronic hepatitis C correlates with higher rates of fibrosis during subsequent course of the disease. In HIV co-infected patients, the HCV load is higher by an average of 0.5-1 log than the mono-infected patients. Based on the evidence from randomized control trials, the therapy for chronic hepatitis C in HIV co-infected patients is pegylated interferon and ribavirin for 48 weeks irrespective of genotype. In patients with CD4 counts < 200 cells/l and/or plasma HIV RNA above 100,000 copies/ml, it is recommended to administer HAART before HCV therapy. The sustained viral response rate achieved in the HCV/HIV co-infected patients is lower than that for mono-infected patients. Pre-treatment HCV RNA level and the genotype are the best predictors of sustained viral response. Treatment may be discontinued at 12 weeks if there is no early viral response as the likelihood of sustained viral response in this sub-group is only 2%. Biochemical response may not be relevant in HIV/HCV co-infected patients as a third of them have normal pretreatment ALT and normalization of ALT does not correlate with virological clearance. Histological response may not also correlate with virological response as up to 43% of subjects without sustained viral response may show histological improvement at the end of 48 weeks treatment. Liver disease due to HCV in patients with end stage renal disease on maintenance dialysis, is a significant cause of morbidity. The value of aminotransferases in patients on haemodialysis is lower than in the non-uraemic population and the level may not rise above the 'normal' range despite active liver disease. HCV RNA may be required to diagnose HCV infection, as anti-HCV may not be detectable, in such patients. Weekly pegylated interferon may be effective in them. In renal allograft recipients, paired biopsies may show rapid progression of liver disease in the absence of fibrosing cholestatic hepatitis. Interferon is contraindicated in this population due to increased risk of graft rejection. Following liver transplantation, recurrence of HCV is universal and histological evidence of recurrent infection may occur as early as 1 to 8 weeks after transplantation. Combination therapy with pegylated interferon and ribavirin may be effective in them.     

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.     

A multicenter survey of re‐treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

Aim: This study aimed to clarify the factors associated the efficacy of re‐treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods: One hundred and forty‐three patients who had previously shown relapse (n = 79), non‐response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re‐treated with PEG IFN plus ribavirin. Results: Twenty‐five patients with intolerance to previous treatment completed re‐treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re‐treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re‐treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin‐28B major genotype responded significantly better and earlier to re‐treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re‐treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re‐treatment for HCV genotype 1 patients. Re‐treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re‐treatment.     

Antiviral treatment withdrawal in viremic HCV‐positive liver transplant patients: impact on viral loads,allograft function and morphology

Abstract: Background: The aim of this study was to evaluate the clinical long‐term consequences of antiviral treatment discontinuation in viremic hepatitis C virus (HCV)‐positive liver transplant recipients. Methods: Twenty‐five HCV‐positive patients after liver transplantation were included in this study. After diagnosing recurrent hepatitis C, a combination therapy with interferon‐α2b and ribavirin for a minimum of 12 months was initiated. Viremia levels and allograft function were monitored continuously. Allograft biopsies were performed yearly, analyzing grading of inflammation and staging of fibrosis. Results: HCV recurrence rate was 100%. Up to 114 months post‐transplantation, sustained virological response rate was 64%. Treatment discontinuation in virological nonresponders led subsequently to a significant increase of viral loads and deterioration of allograft function (P<0.05) within 1 month. In three patients, a fibrosing cholestatic syndrome developed, resulting in one patient death. Antiviral retherapy was maintained for a mean of 33 months, leading to a significant decline of aminotransferases (P<0.05) as well as decreasing serum levels of bilirubin and HCV‐RNA within 6 months. In addition, development of severe allograft fibrosis was prevented despite persistent viral loads. Conclusion: Our study suggests that antiviral treatment withdrawal carries the risk of severe disease progression in persistently viremic HCV‐positive liver transplant patients.     

Incidence of virological failure and emergence of resistance with twice‐daily vs every 8‐h administration of telaprevir in the OPTIMIZE study

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8‐h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV‐infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR‐resistant variants were classified by fold change in inhibitory concentration (IC₅₀). Baseline TVR‐resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR‐resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR‐resistant variants in non‐SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR‐based treatment arms in non‐SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.     

Time to viral suppression is not related to achievement of SVR12 in HCV GT1‐infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin

High rates of sustained virologic response at post‐treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co‐dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1‐infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non‐virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT‐PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA <LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression <LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on‐treatment virologic monitoring may not be necessary with this regimen.     

Efficacy,safety and patient‐reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor‐experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study)

Objectives

Studies evaluating the efficacy and safety of the fixed‐dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV‐1 and hepatitis C virus (HCV) have mainly included treatment‐naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment‐experienced patients with and without cirrhosis.

Methods

We conducted a multicentre, open‐label, double‐arm, nonrandomized study in patients coinfected with HIV‐1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first‐generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed‐dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient‐reported outcomes.

Results

Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty‐five patients [95.6%; 95% confidence interval (CI): 87.6–99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient‐reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14–0.96; P = 0.04]. Mean tenofovir area under the plasma concentration–time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified.

Conclusions

LDV/SOF provided a high SVR rate in PI‐experienced subjects coinfected with HCV genotype 1 and HIV‐1, including patients with cirrhosis.     

Adjuvant epoetin‐β with peginterferon‐α and ribavirin in Japanese ribavirin‐intolerant relapsed patients with chronic hepatitis C genotype 2

Erythropoietin is widely used in the USA and some other Western countries to maintain doses of ribavirin during peginterferon/ribavirin‐based treatment for chronic hepatitis C virus (HCV) infection. However, the impact of erythropoietin on sustained virological response (SVR) is unclear. Here, we report the cases of three Japanese ribavirin‐intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin. Three women aged 50, 64 and 68 years with chronic HCV genotype 2 received retreatment with peginterferon‐α and ribavirin. During their prior therapy, HCV RNA became negative according to real‐time polymerase chain reaction at weeks 4–8 in all three patients; however, the total dose of ribavirin was 18.1–30.6% lower than the planned dose, and HCV RNA relapsed post‐treatment. At present, epoetin‐β 24 000 IU was introduced at weeks 2 or 3 of dual‐combination therapy, resulting in a less than 4.2% reduction in the total dose of ribavirin. HCV RNA became negative at weeks 4–8, and all patients achieved SVR. Until the next‐generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for ribavirin‐intolerant relapsed patients.     

Boceprevir and telaprevir‐based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end‐stage liver disease score

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)‐NS3/NS4A protease inhibitors (PI)] in association with PEG‐IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow‐up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty‐one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non‐response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non‐responders to 59.1% in partial non‐responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end‐stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI‐based triple therapy leads to high rates of virological response even in previously non‐responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.     

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.     

Hyperinsulinaemia reduces the 24‐h virological response to PEG‐interferon therapy in patients with chronic hepatitis C and insulin resistance

Summary. Insulin resistance (IR) reduces response to pegylated‐interferon (PEG‐IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment – insulin resistance (HOMA‐IR) for assessment of IR in non‐diabetic patients, and the ‘acute’ virological response to PEG‐IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG‐IFN/Ribavirin, serum insulin and HOMA‐IR were assessed at baseline, while hepatitis C virus (HCV)‐RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 ± 8.51 U/L and mean HOMA‐IR was 2.65 ± 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus‐RNA decay observed 24 h after the first injection of PEG‐IFN was significantly lower (0.7 ± 0.8 log) in patients with HOMA ≥3 compared with those with HOMA <3 (1.7 ± 0.8, P = 0.001). A highly significant (r = ?0.42) inverse correlation was observed between baseline insulin levels and the 24‐h HCV‐RNA decay. The difference in early viral kinetics between patients with HOMA ≥3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24‐h response to PEG‐IFN. Hyperinsulinaemia reduces the cellular response to Pegylated‐interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti‐viral treatment.