Sofosbuvir plus simeprevir for the treatment of HCV genotype 4 patients with advanced fibrosis or compensated cirrhosis is highly efficacious in real life

Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver‐related death. Recently, multiple regimens of different direct‐acting antiviral agents (DAAs) have been registered. Although treatment with sofosbuvir (SOF) and simeprevir (SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real‐life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response (SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon‐based treatment, and one was treatment naive. In this real‐life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment‐experienced patients as recommended in guidelines.     

Impact of direct‐acting antiviral agents on liver function in patients with chronic hepatitis C virus infection

Whilst the benefit of direct‐acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well‐accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon‐based therapy. Liver function was assessed by the albumin‐bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2‐3 years after interferon‐based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon‐based therapy suggests that failure to achieve SVR is associated with long‐term decline in liver function and, in contrast, patients who do achieve SVR can expect long‐term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.     

Safety and efficacy of sofosbuvir‐based direct‐acting antiviral regimens for hepatitis C virus genotype 6 in Southwest China: Real‐world experience of a retrospective study

Optional treatments for patients with chronic hepatitis C virus (HCV) genotype (GT) 6 infection have not been extensively studied. This study aimed to evaluate the safety and efficacy of sofosbuvir (SOF)‐based direct‐acting antiviral agents (DAAs) for HCV GT6. We performed a retrospective study at the West China Hospital of Sichuan University in Southwest China from January 2016 to May 2017. Our study screened 130 treatment‐naïve patients with chronic HCV GT6 and without liver cirrhosis. A total of 60 HCV GT6 patients were ultimately enrolled. All patients received SOF‐based DAAs therapy, including SOF 400 mg plus daclatasvir (DCV) 60 mg daily or SOF 400 mg plus velpatasvir (VEL) 100 mg daily for 12 weeks. The sustained virological response 12 weeks after treatment (SVR12) was 100% (60/60) in treatment‐naïve patients with HCV GT6, including 100% (37/37) of patients receiving SOF plus DCV therapy and 100% (23/23) of patients receiving SOF plus VEL therapy. Measurements of liver stiffness were significantly decreased in patients at week 12 (P = 0.014) and week 24 (P < 0.001) of DAAs treatment compared to baseline values. The serum biomarker aspartate aminotransferase‐to‐platelet ratio index (APRI) and fibrosis‐4 score were also significantly reduced at week 12 and week 24 compared to before treatment (both P < 0.001). SOF‐based therapy was well‐tolerated, and no serious adverse events were reported. In conclusion, SOF plus DCV and SOF plus VEL were safe and achieved a high SVR12 rate for treatment‐naïve patients with HCV GT6 without liver cirrhosis.     

Interferon‐free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review

Treatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct‐acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3‐infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon‐free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV–HCV‐coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult‐to‐treat subgroup in the near future.     

Efficacy of generic oral directly acting agents in patients with hepatitis C virus infection

Novel direct‐acting antivirals (DAAs) are now the standard of care for the management of hepatitis C virus (HCV) infection. Branded DAAs are associated with high sustained virological response at 12 weeks post‐completion of therapy (SVR12), but are costly. We aimed to assess the efficacy of generic oral DAAs in a real‐life clinical scenario. Consecutive patients with known HCV infection who were treated with generic‐oral DAA regimens (May 2015 to January 2017) were included. Demographic details, prior therapy and SVR12 were documented. Four hundred and ninety patients (mean age: 38.9 ± 12.7 years) were treated with generic DAAs in the study time period. Their clinical presentations included chronic hepatitis (CHC) in 339 (69.2%) of cases, compensated cirrhosis in 120 (24.48%) cases and decompensated cirrhosis in 31 (6.32%) cases. Genotype 3 was most common (n = 372, 75.9%) followed by genotype 1 (n = 97, 19.8%). Treatment naïve and treatment‐experienced (defined as having previous treatment with peginterferon and ribavirin) were 432 (88.2%) and 58 (11.8%), respectively. Generic DAA treatment regimens included sofosbuvir in combination with ribavirin (n = 175), daclatasvir alone (n = 149), ribavirin and peginterferon (n = 80), ledipasvir alone (n = 43), daclatasvir and ribavirin (n = 37), and ledipasvir and ribavirin (n = 6). Overall SVR12 was 95.9% (470/490) for all treatment regimens. SVR12 for treatment naïve and experienced patients was 97.0% (419/432) and 87.9% (51/58), respectively, P = .005. High SVR12 was observed with various regimens, irrespective of genotype and underlying liver disease status. There were no differences in SVR12 with 12 or 24 weeks therapy. No major adverse event occurred requiring treatment stoppage. Generic oral DAAs are associated with high SVR rates in patients with HCV infection in a real‐life clinical scenario.     

Relapse of hepatitis C in a pegylated‐interferon‐α‐2b plus ribavirin‐treated sustained virological responder

A 41‐year‐old woman with chronic hepatitis C was treated with pegylated‐interferon (PEG‐IFN)‐α‐2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re‐emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re‐infection and strongly indicated a late relapse of the disease. Therefore, follow‐up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR.     

HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct‐acting antivirals

Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct‐acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV‐RNA and HBV‐DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow‐up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV‐DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti‐HBc positive, 12 anti‐HBc/anti‐HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty‐seven patients (64.4%) were HCV‐RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg‐positive patients treated with NUCs remained HBV‐DNA negative, but three of four untreated patients showed an increase in HBV‐DNA of 2‐3 log without a biochemical flare and achieved HBV‐DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV‐DNA remained not detectable in all 37 anti‐HBc‐positive patients but in three of them (8.1%) HBV‐DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV‐coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre‐emptive therapy with NUCs should be considered in this setting. Anti‐HBc‐positive patients rarely reactivate HBV without clinical or virological outcomes.     

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.     

Direct acting antivirals failure: cause and retreatment options

ABSTRACT

Introduction: Chronic hepatitis C (HCV) infection is a systemic life-threatening condition that can lead to hepatic and extra-hepatic complications. Sustained virological response (SVR) is associated with a regression of most liver and non-liver manifestations, which reduce mortality. The history of HCV infection therapy radically changed in the last decade, with the introduction of the first generation direct acting antivirals (DAAs).

Areas covered: The new regimens, based on the combination of 2 or 3 second-generation DAAs, allow SVR, namely hepatitis C infection cure, in more than 95% of cases. Antiviral treatment is generally well tolerated and its duration (8–16 weeks) varies depending on the stage of liver fibrosis, HCV genotype, prior treatment, baseline viral load, presence of resistance-associated variants (RAV). This review evaluates the cause, the efficacy and safety results in case of DAAs failure.

Expert commentary: Despite the excellent efficacy of DAAs, a minority of patients (4–5%) still fail to eradicate HCV, mainly related to poor adherence but also to relapse or viral breakthrough. The main causes of a failure of DAAs are the presence of advanced liver disease, suboptimal treatment and NS5A mutations. Many questions regarding resistant associated substitutions (RASs) prevalence and clinical relevance in re-treatment remain unanswered.     

DAAs therapy associated with improved hepatic fibrosis in HCV-GT4 patients co-infected with HIV

ABSTRACT

Background: The present work aimed at evaluation of the potential dynamic changes in hepatic fibrosis following treatment of chronic HCV using DAAs in patients coinfected with HIV.

Patients and methods: In total, 50 HCV/HIV coinfected patients [age; 34.68 ± 10.38 years, 82% men] were included. For all included patients, liver stiffness measured using transient elastography as well as serum liver fibrosis scores; [fibrosis‐4 (FIB‐4) score and the aspartate aminotransferase to platelet ratio index (APRI)] were calculated at baseline and at 12 and 24-weeks following 12 weeks therapy of HCV with once daily sofosbuvir 400 mg plus daclatasvir 60 mg.

Results: Most of the included patients (70%, n = 35) were on anti-retroviral therapy. SVR24 was achieved by 93.48% of the patients. There was significant serial improvement in baseline liver stiffness measurement (LSM), FIB-4 and APRI among responders; [LSM: baseline, 7.05 ± 4.84 kPa vs. 5.66 ± 2.63 kPa at SVR24, p < 0.001], [FIB-4: baseline, 1.24 ± 1.08 vs. 0.93 ± 0.64 at SVR24, p 0.001) and (APRI: baseline, 0.725 ± 0.66 vs. 0.36 ± 0.19at SVR24, p 0.001) respectively.

Conclusion: Treatment of HCV patients coinfected with HIV using DAAs is associated with a rapid significant regression in hepatic fibrosis, as evaluated by FibroScan, FIB-4, and APRI scores.     

Safety and efficacy of direct‐acting antivirals for the treatment of chronic hepatitis C in a real‐world population aged 65 years and older

The availability of direct‐acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real‐life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV‐related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child‐Pugh‐Turcotte (CTP)‐B cirrhosis and 95.4% in CTP‐A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real‐world setting, DAAs are safe and effective in elderly patients with HCV‐related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.     

Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%‐8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long‐term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis‐related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow‐up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow‐up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow‐up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942‐2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407‐3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333‐1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.     

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan

Aim: The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)‐based therapy. Methods: Patients with chronic HCV who had previously undergone at least 20 weeks of IFN‐based therapy were enrolled. The patients’ initial LS measurement was taken at the time of enrollment, and a second LS measurement was made after an interval of at least 38 weeks. LS measurement was carried out with FibroScan®, and changes of LS and its associated factors were analyzed. Results: One hundred and forty‐four patients, including 95 sustained virological response (SVR) patients and 49 non‐sustained virological response (NSVR) patients, were enrolled. There was a significant decrease of LS among SVR patients (median, 0.6; P < 0.001). NSVR patients showed an increase of LS (median, 0.8; P = 0.557). For SVR patients, a high initial LS was the predictive factor of a rapid reduction of LS values. However, advanced fibrosis stage before therapy, higher body mass index (BMI) and longer time remission were predictive factors for slow reduction of LS values. Conclusions: LS decreases in sustained responders following IFN‐based therapy in patients with chronic HCV. Advanced fibrosis, higher BMI, longer time for remission and lower initial LS value are predictive factors for a slow improvement of LS in sustained responders.     

HIV‐positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)‐infected men who have sex with men (MSM). New direct‐acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single‐centre cohort of HIV‐positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan^® and Fibrotest^®. Liver‐related and non‐liver‐related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow‐up for all included patients was 38.7 months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon‐based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3 years’ follow‐up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician‐declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient‐years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV‐positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred.     

Reduced healthcare utilization following successful hepatitis C virus treatment in HIV‐co‐infected patients with mild liver disease

New direct‐acting antivirals (DAA) for hepatitis C virus (HCV) infection have achieved high cure rates in many patient groups previously considered difficult‐to‐treat, including those HIV/HCV co‐infected. The high price of these medications is likely to limit access to treatment, at least in the short term. Early treatment priority is likely to be given to those with advanced disease, but a more detailed understanding of the potential benefits in treating those with mild disease is needed. We hypothesized that successful HCV treatment within a co‐infected population with mild liver disease would lead to a reduction in the use and costs of healthcare services in the 5 years following treatment completion. We performed a retrospective cohort study of HIV/HCV‐co‐infected patients without evidence of fibrosis/cirrhosis who received a course of HCV therapy between 2004 and 2013. Detailed analysis of healthcare utilization up to 5 years following treatment for each patient using clinical and electronic records was used to estimate healthcare costs. Sixty‐three patients were investigated, of whom 48 of 63 (76.2%) achieved sustained virological response 12 weeks following completion of therapy (SVR12). Individuals achieving SVR12 incurred lower health utilization costs (£5000 per‐patient) compared to (£10 775 per‐patient) non‐SVR patients in the 5 years after treatment. Healthcare utilization rates and costs in the immediate 5 years following treatment were significantly higher in co‐infected patients with mild disease that failed to achieve SVR12. These data suggest additional value to achieving cure beyond the prevention of complications of disease.     

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

There are few data about the long‐term histological outcome of HIV‐/HCV‐coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow‐up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow‐up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log‐rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33–7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05–1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow‐up after SVR to interferon therapy in HIV‐/HCV‐coinfected patients.     

Predictors of functional benefit of hepatitis C therapy in a ‘real-life’ cohort

AIM To define predictors of functional benefit of direct-acting antivirals(DAAs) in patients with chronic hepatitis C virus(HCV) infection and liver cirrhosis.METHODS We analysed a cohort of 199 patients with chronic HCV genotype 1, 2, 3 and 4 infection involving previously treated and untreated patients with compensated(76%) and decompensated(24%) liver cirrhosis at two tertiary centres in Germany. Patients were included withtreatment initiation between February 2014 and August 2016. All patients received a combination regimen of one or more DAAs for either 12 or 24 wk. Predictors of functional benefit were assessed in a univariable as well as multivariable model by binary logistic regression analysis.RESULTS Viral clearance was achieved in 88%(175/199) of patients. Sustained virological response(SVR) 12 rates were as follows: among 156 patients with genotype 1 infection the SVR 12 rate was 90%(n = 141); among 7 patients with genotype 2 infection the SVR 12 rate was 57%(n = 4); among 30 patients with genotype 3 infection the SVR 12 rate was 87%(n = 26); and among 6 patients with genotype 4 infection the SVR 12 rate was 67%(n = 4). Follow-up MELD scores were available for 179 patients. A MELD score improvement was observed in 37%(65/179) of patients, no change of MELD score in 41%(74/179) of patients, and an aggravation was observed in 22%(40/179) of patients. We analysed predictors of functional benefit from antiviral therapy in our patients beyond viral eradication. We identified the Child-Pugh score, the MELD score, the number of platelets and the levels of albumin and bilirubin as significant factors for functional benefit.CONCLUSION Our data may contribute to the discussion of potential risks and benefits of antiviral therapy with individual patients infected with HCV and with advanced liver disease.     

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.     

SCCA-IC serum levels are predictive of clinical response in HCV chronic hepatitis to antiviral therapy: a multicentric prospective study

Summary. The combination of pegylated interferon (Peg‐IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost‐benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA‐IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA‐IC in 103 patients with HCV chronic infection. Serum HCV‐RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow‐up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA‐IC levels were higher in responders (238 AU, interquartile difference 130–556 AU) and decreased significantly to 125 AU (70–290 AU). The mean baseline value in nonresponders was 149 AU (86.5–306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80–280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA‐IC after 1 month (OR = 4.82; 95% CI 1.39–16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21–0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA‐IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti‐HCV positive patients undergoing antiviral therapy.