Severe liver injury associated with simeprevir plus pegylated interferon/ribavirin therapy in a patient with treatment-naïve genotype 1b hepatitis C virus: a case report

A second-generation direct-acting antiviral agent, simeprevir, now provides a new treatment option for hepatitis C virus (HCV) infection with good safety profile in combination with pegylated interferon and ribavirin. We herein report a rare case of severe liver injury under simeprevir plus pegylated interferon/ribavirin therapy. We initiated this therapy in a 65-year-old male with treatment-naïve genotype 1b HCV. On day 28, the patient’s HCV-RNA was successfully eliminated, and his liver function was fully restored. However, on day 49, the serum alanine aminotransferase level was elevated at 700 IU/L. The HCV-RNA titer was still undetectable and the involvement of other possible viruses was negligible. A liver biopsy performed on day 60 showed an acute hepatitis pattern. The discontinuation of therapy alone successfully improved his liver damage on day 84. No other treatments such as steroids were required. According to the diagnostic criteria for drug-induced liver injury in Japan (DDW-J2004), the liver injury observed in this case can be associated with the administration of simeprevir plus pegylated interferon/ribavirin therapy. In conclusion, simeprevir plus pegylated interferon/ribavirin should be used with caution, as these agents may cause unreported serious adverse events including severe liver injury, despite their clinical safety profile.     

Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naïve patients with chronic hepatitis C genotype 1 infection

BACKGROUND/AIMS: Amantadine may augment virological response rates to interferon-based therapy in chronic hepatitis C patients. Using a novel design, amantadine was studied in na?ve genotype 1 patients treated in combination with peginterferon alfa-2a (40KD)/ribavirin. METHODS: Patients enrolled in this randomized, placebo-controlled multicenter trial were stratified by single-dose interferon sensitivity (stratum I, 24-h HCV-RNA decline >1.4-log10; II, 0.8-1.39-log10; III, <0.8-log10; a reliable means of identifying nonresponders to interferon/ribavirin) and fibrosis grade (F0/1/2 vs. F3/4) at baseline. All patients received peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 1000-1200 mg/day and were randomized to receive amantadine 100 mg twice daily (N = 114) or placebo (N = 95) for 48 weeks. RESULTS: Week-24 virological response rates in strata II and III, the primary outcome, were similar in patients treated with amantadine (63.7%) or placebo (65.7%), as were sustained virological response rates at week 72 (46.5 and 51.6%, respectively). Adverse event profiles were similar and amantadine did not improve health-related quality of life compared with placebo. Interferon sensitivity was the only significant predictor of treatment outcome. CONCLUSIONS: Adding amantadine to peginterferon alfa-2a (40KD)/ribavirin combination therapy does not augment virological response rates in genotype 1 patients. Virological response was almost exclusively determined by interferon sensitivity at baseline.     

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C

BackgroundAim was to select naïve patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon + ribavirin therapy.MethodsIn 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort).ResultsIn the derivation cohort, 257 achieved rapid virological response and 818 did not, with sustained virological response rates of 80.2% and 25.4%, respectively; interleukin-28B polymorphisms, fibrosis staging, gamma-glutamyl transferase, and viral load predicted sustained virological response. Assuming a <30% sustained virological response probability for not recommending Peg-interferon + ribavirin, 100 patients (25.6%) in the validation cohort were predicted a priori to fail this regimen. Assuming a ≥80% sustained virological response probability as a threshold to continue with Peg-interferon + ribavirin, 61 patients were predicted to obtain sustained virological response, and 55 of them (90.2%) eventually did.ConclusionsThis model uses easily determined variables for a personalized estimate of the probability of sustained virological response with Peg-interferon + ribavirin, allowing to identify patients who may benefit from conventional therapy.     

Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: A randomized phase II study

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-na?ve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. Conclusion: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration. (HEPATOLOGY 2012;56:884-893).     

Daclatasvir plus asunaprevir in treatment-na?ve patients with hepatitis C virus genotype 1b infection

AIM To assess daclatasvir plus asunaprevir(d UAL) in treatment-na?ve patients from mainland China, Russia and South Korea with hepatitis C virus(HCV) genotype 1 b infection. METHODS Patients were randomly assigned(3:1) to receive 24 wk of treatment with d UAL(daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period(immediate treatment arm) or following 12 wk of matching placebo(placebodeferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12(SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin(70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in d UAL-treated patients compared with placebo patients during the first 12 wk(doubleblind phase), and during 24 wk of d UAL in both arms combined.RESULTS In total, 207 patients were randomly assigned to immediate(n = 155) or placebo-deferred(n = 52) treatment. Most patients were Asian(86%), female(59%) and aged 65 years(90%). Among them, 13% had cirrhosis, 32% had IL28 B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/m L. Among patients in the immediate treatment arm, SVR12 was achieved by 92%(95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate(70%). SVR12 was largely unaffected by cirrhosis(89%), age ≥ 65 years(92%), male sex(90%), baseline HCV RNA ≥ 6 million(89%) or IL28 B non-CC genotypes(96%), although SVR12 was higher among patients without(96%) than among those with(53%) baseline NS5 A resistanceassociated polymorphisms(at L31 or Y93 H). during the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving d UAL. during 24 wk of d UAL therapy(combined arms), the most common adverse events(≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities(alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued d UAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.CONCLUSION d UAL was well-tolerated during this phase 3 study, and SVR12 with d UAL treatment(92%) exceeded thehistorical SVR rate for peg-interferon plus ribavirin of 70%.     

Treatment of chronic hepatitis C with pegylated interferon plus ribavirin in treatment-naïve ‘real-life’ patients in India

Purpose/Aim

Results of treatment of chronic hepatitis C (CHC) with pegylated interferon plus ribavirin (PEG-RBV) are mainly available from well-designed clinical trials, and only few ‘real-life’ studies which give a true picture of success of therapy are available. Such data in Indian patients is scarce. This prospective study aimed to evaluate the efficacy, safety, and factors associated with sustained virological response (SVR) in Indian CHC patients treated with PEG-RBV in ‘real-life’ setting.

Material and Methods

All treatment-naïve patients with CHC/compensated cirrhosis treated with PEG-RBV between January 2004 and December 2010 were included.

Results

Of 592 patients started on treatment, 524 (88.5 %) completed therapy (mean?±?SD age—42.0?±?12.1 years; 74.3 % males). Genotype 3 (73.6 %) was the commonest, followed by genotype 1 (19.3 %). In intention to treat analysis, SVR rates for ‘all’ patients, genotype 1 and genotype 3 patients were 72.3 % (428/592), 57 % (65/114), and 78.2 % (341/436), respectively (in per-protocol analysis—81.7 %, 69.1 %, and 85.3 %, respectively). Noncirrhotics had better SVR rates compared to cirrhotics treated for the same duration. About 20 % patients had both low viral load and achieved rapid virological response (RVR). Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.

Conclusion

SVR rates in CHC patients treated in ‘real-life’ setting in India were better than those reported in western population. Therapy should be prolonged for patients with cirrhosis, while one-fifth of patients may qualify for abbreviated therapy. Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.     

Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial

BACKGROUND/AIMS: We assessed the effectiveness and safety of an induction dose of peginterferon alfa-2b (PEG-IFN) plus ribavirin for initial treatment of patients with genotype 1 chronic HCV infection in a randomized, controlled, multicenter trial. METHODS: Three hundred and eleven na?ve patients infected with genotype 1 and chronic hepatitis were randomly assigned to 48-week treatment with PEG-IFN once weekly (80-100 micrograms depending on body weight for 8 weeks, followed by 50 micrograms for the next 40 weeks), or standard interferon alfa-2b (IFN) 6 million units on alternate days, both in combination with ribavirin (1000-1200 mg/day). RESULTS: PEG-IFN plus ribavirin significantly increased sustained virological response (SVR) compared with IFN plus ribavirin (41.1 vs. 29.3% respectively, P=0.030). Less patients discontinued PEG-IFN than IFN (19 vs. 31%, P=0.010). By logistic regression, SVR in the PEG-IFN group was independently associated with age <50 years, and mild fibrosis at liver biopsy. CONCLUSIONS: Combination therapy with an induction dose of PEG-IFN was a more effective and better tolerated treatment for na?ve patients with genotype 1 than combination therapy with high dose standard IFN. In patients aged less than 50 years with mild fibrosis this schedule achieves a very high rate of SVR.     

A phase IIIb study of ledipasvir/sofosbuvir fixed-dose combination tablet in treatment-naïve and treatment-experienced Korean patients chronically infected with genotype 1 hepatitis C virus

Background

The standard-of-care regimen for chronic hepatitis C virus (HCV) infection in Korea, pegylated-interferon-alpha plus ribavirin, is poorly tolerated. Ledipasvir/sofosbuvir is a two-drug, fixed-dose combination tablet approved in the USA, European Union, and Japan for chronic genotype 1 HCV infection.

Methods

This single-arm, phase IIIb study (NCT02021656) investigated the efficacy and safety of ledipasvir/sofosbuvir fixed-dose combination tablet for 12 weeks in treatment-naïve and treatment-experienced Korean patients chronically infected with genotype 1 HCV with or without compensated cirrhosis.

Results

The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 99 % (92/93), with rates of 100 % (46/46) and 98 % (46/47) in treatment-naïve and treatment-experienced patients, respectively. There were no on-treatment failures. One patient relapsed after the end of treatment. The most common treatment-emergent adverse events were headache (8 %, 7/93) and fatigue (6 %, 6/93). There were no grade 3 or 4 adverse events, seven grade 3 laboratory abnormalities, and one premature discontinuation of study treatment (due to nonserious mouth ulceration). None of the three reported serious adverse events were related to treatment.

Conclusions

These data suggest that 12 weeks of ledipasvir/sofosbuvir is effective and well tolerated in treatment-naïve and treatment-experienced Korean patients with chronic genotype 1 HCV infection.

     

Serum HBsAg quantification in treatment-naïve Indian patients with chronic hepatitis B

Background and Aims

There is paucity of Indian data regarding serum HBsAg levels (qHBsAg) in treatment-naïve chronic hepatitis B (CHB). This study was done to determine correlation of qHBsAg with hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels and its ability to independently categorize subgroups of CHB.

Methods

We studied 131 treatment-naive CHB patients and initially classified them based on HBeAg status. The HBeAg-positive group was further classified into immune tolerance (IT) and immune clearance (IC) phases based on serum alanine aminotransferase. HBeAg-negative patients were classified into low replicators (LR) and HBeAg-negative chronic hepatitis (ENH) based on DNA levels. HBsAg quantification was performed using the Architect chemiluminescence system.

Results

HBeAg-positive patients had higher DNA (7.89 vs. 2.69 log₁₀?IU/mL) and higher qHBsAg (4.60 vs. 3.85 log₁₀?IU/mL) compared to the HBeAg-negative group. Good correlation between qHBsAg and DNA was seen in HBeAg-positive (ρ?=?0.6, p?<?0.001) but not in HBeAg-negative CHB (ρ?=?0.2). A qHBsAg level greater than 4.39 log₁₀?IU/mL predicted HBeAg-positive state with 81 % sensitivity and 85 % specificity. However, among HBeAg-negative CHB, qHBsAg failed to discriminate between LR and ENH.

Conclusions

A single point estimation of qHBsAg in treatment-naïve patients could predict replicative HBeAg-positive CHB, but was not helpful in defining replicative status in the HBeAg-negative CHB.     

Antiviral therapy for treatment naïve patients with hepatitis C virus

This article focuses on the most recent therapies for patients with hepatitis C virus (HCV) who are naive to therapy. The primary end point for the treatment of naive HCV patients is viral eradication or a sustained virological response, which is defined as the absence of HCV in the serum, as detected by a sensitive polymerase chain reaction test, 24 weeks after stopping antiviral therapy. Recent data suggest that an SVR can be equated with a biochemical,virological, and histological response that is sustained for up to 5 years and is conceptually a cure of HCV in 90% of patients.     

Antiviral therapy for treatment naïve patients with hepatitis C virus

This article focuses on the most recent therapies for patients with hepatitis C virus (HCV) who are na?ve to therapy. The primary end point for the treatment of na?ve HCV patients is viral eradication or a sustained virological response, which is defined as the absence of HCV in the serum, as detected by a sensitive polymerase chain reaction test, 24 weeks after stopping antiviral therapy. Recent data suggest that an SVR can be equated with a biochemical, virological,and histological response that is sustained for up to 5 years and is conceptually a cure of HCV in 90% of patients.     

Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C

AIM: To investigate the possibility of shortening the duration of peginterferon (Peg-IFN) plus ribavirin (RBV) combination therapy by incorporating interferon-β (IFN-β) induction therapy.METHODS: A one treatment arm, cohort prospective study was conducted on seventy one patients. The patients were Japanese adults with genotype 1b chronic hepatitis C, HCV-RNA levels of ≥ 5.0 Log IU/mL or 100 KIU/mL, and platelet counts of ≥ 90 000/μL. The treatment regimen consisted of a 2 wk course of twice-daily administration of IFN-β followed by 24 wk Peg-IFN plus RBV combination therapy. We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it.RESULTS: The patients, including 44% males, were characterized by an median age of 63 years (range: 32-78 years), an median platelet count of 13.9 (range: 9.1-30.6) × 10⁴/μL, 62% IFN-naïve, and median HCV-RNA of 6.1 (range: 5.1-7.2) Log IU/mL. The sustained virologic response (SVR) rates were 34% (Peg-IFN: 1-24 wk, n = 61, 95% confidence interval (CI): 24%-47%) and 55% (Peg-IFN: 20-24 wk, n = 31, 95% CI: 38%-71%, P < 0.001; vs Peg-IFN: 1-19 wk). The SVR rate when the administration was discontinued early was 13% (Peg-IFN: 1-19 wk, n = 30, 95% CI: 5%-30%), and that when the administration was prolonged was 50% (Peg-IFN: 25-48 wk, n = 10, 95% CI: 24%-76%, P < 0.05; vs Peg-IFN: 1-19 wk). In the patients who received 20-24 wk of Peg-IFN plus RBV, only the higher platelet count (≥ 130 000/μL) was significantly correlated with the SVR (odds ratio: 11.680, 95% CI: 2.3064-79.474, P = 0.0024). In 45% (14/31) of the patients with a higher platelet count (≥ 130 000/μL) before therapy, the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-β, and their SVR rate was 93% (13/14) after 20-24 wk administration of Peg-IFN plus RBV.CONCLUSION: These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-β induction regimen.     

Kinetics of hepatitis C virus RNA load during pegylated interferon alpha-2a and ribavirin treatment in naïve genotype 1 patients

Background

Pegylated interferon given for 24 or 48 weeks constitutes the most effective initial therapy for the treatment of chronic hepatitis C. It has been shown that viral load at week 2 appears the best time for predicting response to treatment. The objectives of this study were to assess whether the hepatitis C virus (HCV) RNA viral decline is predictive of sustained virological response (SVR) and to determine the best time for predicting complete response in our cohort of naïve patients treated with pegylated interferon alpha-2a (Peg-IFN alpha-2a) and ribavirin.

Results

Twenty patients treated with Peg-IFN alpha-2a and ribavirin for 48 weeks were studied. Six months after the end of treatment, a SVR (negative HCV RNA measured by PCR six months after the end of therapy) was obtained in 9 patients. Samples were obtained before and at week 2, 4, 8, and 12. At the end of week 2, viral load decreased more than 1.39 log in 8 out of the 9 patients with SVR and in 1 out of the 11 other patients. When we considered the viral load reduction from baseline to each week of treatment, week 2 appeared to be the best point time for predicting SVR, with a sensitivity of 91% (95%CI: 59;99), a specificity of 89% (52;98), a positive predictive value of 91% (59;99) and a negative predictive value of 89% (57;98).

Conclusion

During treatment with Peg-IFN alpha-2a plus ribavirin in genotype 1 patients, when the main objective of the treatment is viral eradication, viral kinetics showed that week 2 appeared to be the best time point for predicting SVR. Our results must be further confirmed on a larger cohort.

     

Efficacy of 5 MU of interferon in combination with ribavirin for naïve patients with chronic hepatitis C virus: a randomized controlled trial

BACKGROUND: In chronic hepatitis C the schedule of interferon (IFN), 3 MU thrice weekly (tiw) plus ribavirin (1000-1200 mg/daily) needs further evaluation, as IFN dosages >3 MU achieve better responses. AIMS: To compare the efficacy of 5 MU tiw of IFN with (96 patients) or without ribavirin (96 patients) for 12 months in na?ve patients, to evaluate the effect of baseline features on the response to therapy, and to determine a reliable point in time during treatment to predict non-response. RESULTS: Sustained virologic response was 20.8% (95% CI 13-29) with IFN monotherapy and 54.2% (95% CI 44-64) with combination (P = 0.0001), the relapse rate 39.4% (95% CI 23-56) and 9% (95% CI 1-16) (P = 0.0007), and the combined rate of sustained biochemical and virologic response 22.7% (95% CI 14-31) and 60.5% (95% CI 50-71) (P = 0.0001), respectively. Patients given combination therapy were more likely to respond regardless of baseline features. Apart from genotype non-1, predictive factors for IFN monotherapy were ineffective in predicting response to combination therapy. Using logistic regression analysis, IFN-ribavirin was the strongest predictor of response (X2 = 21.3; P = 0.0001). Viral persistence at month 3 of therapy was a more accurate predictor than aminotransferase values for non-response to IFN monotherapy but not to combination therapy (positive predictive values of 98 and 82%, respectively). CONCLUSION: In this study, 5 MU of IFN combined with a standard dose of ribavirin has yielded the highest rate of sustained response reported to date. Further dose finding studies are warranted.