Cirrhosis Regression in Hepatitis C Patients With Sustained Virological Response After Antiviral Therapy

Liver International

A Meta-analysis

Ehsaan Akhtar, Vignan Manne, Sammy Saab

Liver International. 2015;35(1):30-36.

Abstract and Introduction

Abstract

Background & Aims Chronic hepatitis C may be associated with cirrhosis, liver failure and hepatocellular carcinoma. Studies have demonstrated improved clinical outcome in patients who achieved a sustained viral response (SVR).

Methods A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared with patients without a SVR. Six studies totalling 443 patients were included. Dichotomous outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI).

Results Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 [Confidence Interval (CI) 1.45–4.97, P < 0.01] in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favour of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow-up between biopsies. The relative risk for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36-month was 4.33 (CI 1.1–17.0, P = 0.04) as compared to a relative risk of 1.79 (CI 1.26–2.29, P < 0.01) in studies with a mean or median time between the follow-up biopsy of less than 36-month.

Conclusions Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression.

Introduction

Hepatitis C is one of the leading causes of cirrhosis in the United States.^[1] Estimates of the number of Americans infected with hepatitis C range from 3 to 7 million people.^[2,3] The public burden is increasingly realized as the percentage of patients with hepatitis C today with cirrhosis is between 15% and 20%.^[4] Patients with cirrhosis are at risk of liver failure and hepatocellular carcinoma. Indeed, HCV is currently the most common indication for transplantation in the United States.^[5]

The end point of successful antiviral therapy is achieving Sustained Virological Response (SVR).^[6] Sustained virological response has been associated with arrest of disease progression; and improvements in quality of life and reduction of liver-related complications and hepatocellular carcinoma risk.^[7–9] A number of studies have also documented improvement in liver histology after sustained virological response.^[10–17] Histological improvement has been noted even in the context of cirrhosis.^[14] While a large meta-analysis has previously demonstrated reduction of cirrhosis-related complications in patients achieving SVR,^[18] no previous meta-analysis has examined the likelihood of cirrhosis regression in patients who achieved a SVR.

Cirrhosis has been regarded as the final common pathway of liver disease.^[19] Multiple studies have successfully challenged the premise that cirrhosis is irreversible particularly when the liver disease culprit is eliminated.^[20–23] In this meta-analysis, we sought to better understand the relationship between SVR and cirrhosis regression in patients with HCV treated with antiviral therapy.

Methods

Objective

To perform a systematic review of the literature and meta-analysis to determine whether cirrhosis is reversible in hepatitis C patients with sustained virological response to antiviral therapy.

Selection of Studies

Trials that met the following criteria were included: (a) prospective or retrospective cohort studies as well as randomized, controlled, open or blinded trials pertinent to the subject matter and published as an article or abstract, (b) studies that reported follow-up data on patients greater than or equal to 6 months, (c) studies including subjects with serological confirmation of chronic HCV infection, (d) SVR defined as no detectable levels of HCV RNA by PCR at least 24 weeks after antiviral treatment, (e) studies that included paired liver biopsies and data regarding histological preparation of biopsies, such as biopsy length, time between biopsies, presence of central pathologist and a validated method of staging cirrhosis, (f) studies that included at least 10 patients. Articles excluded were (a) studies looking specifically at causes of cirrhosis other than Hepatitis C, including Wilson's disease, PSC, PBC, haemochromatosis, alpha-1 antitrypsin and alcoholic cirrhosis, (b) studies including patients with immunosuppression secondary to chronic steroid use, HIV, or any other aetiology, (c) studies in which data could not be extracted for a subset of cirrhotic patients with and without SVR.

Search Strategy

A comprehensive search of the MEDLINE database and the Cochrane Database of Systematic Reviews was performed to find studies published in the English language up to October 2013 that investigated cirrhosis regression in Hepatitis C end-stage liver patients treated with antiviral therapy. We used combinations of the keywords Hepatitis C, antiviral agents, liver cirrhosis, SVR, viral suppression, histology,revers*, regression and improvement. We also manually searched manuscript references to identify additional studies that may have been missed with a MEDLINE-assisted strategy. Medical science liaisons for the appropriate antiviral therapies were contacted to assess for additional studies to review.

Data Extraction

Studies were subjected to inclusion and exclusion criteria. Two reviewers (EA and VM) independently and in duplicate assessed the eligibility and quality of trials. A formal scoring system to rate the study quality of each individual study was not used. Reviewers noted patient liver biopsy length, duration between biopsies, fibrosis scoring system, baseline biopsy score, antiviral therapy, length of treatment and regression of cirrhosis. Three of the six studies examined cohorts of patients with any amount of liver fibrosis on histology.^[26–28] In these studies, only data regarding cirrhotic patients were extracted from the text. Efforts were made to contact the authors for demographic and clinical characteristics of cirrhotic patients. Collaboration was established with one author. Regression of fibrosis was defined individually for each scoring modality and is noted in the results section below.

Statistical Analysis

We used the statistical package RevMan (Review Manager, Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,v2012). RevMan software was developed by the Cochrane Collaboration to facilitate development of systematic reviews and meta-analyses. The Mantel–Haenszel procedure for binary data was used to determine clinical significance of effect. Sensitivity analysis was two-tailed and set at P ≤ 0.05. A random-effects model was employed because of the anticipated variability between trials in terms of patient populations, interventions and concomitant interventions. Heterogeneity between trials was assessed by the chi-squared test with significance set at P ≤ 0.10. The approximate proportion of total variability in point estimates attributed to heterogeneity was calculated by use of the I ² statistic.^[25]

Results

Number of Studies

A total of 172 relevant articles were identified using the search criteria detailed above. Twenty-one manuscripts were reviewed in full. After applying the inclusion criteria, six studies^{[12,14,24,26–28]} were used in the final analysis (Fig. 1). The six studies included a total of 443 cirrhotic patients. The median number of patients across each study was 62.5 (range 15–153).^{[12,14,24,26–28]}

Figure 1. Study selection – Algorithm depicting the literature search flow chart and why studies were included or excluded.

Diagnosis of Cirrhosis

Cirrhosis was diagnosed by liver biopsy in all studies. Biopsies were evaluated by Metavir score in five studies.^{[12,14,24,27,28]} The remaining study used the Ishak scoring method to evaluate cirrhosis. A Metavir score of F4 or an Ishak fibrosis score of ≥5 was used to define cirrhosis. All studies reported results for paired biopsies. One biopsy was taken prior to antiviral therapy and one biopsy was taken after antiviral therapy. Biopsy length was reported in five of the six studies.^{[12,14,24,26,27]} The time between each biopsy was listed for all studies (Table 1). A central pathologist was used for diagnosis in two of the six studies.^[26,27] These data were not reported in one study.^[14] The remaining studies used 2–3 independent reviewers.^[24,27,28]

Antiviral Therapy

All studies used interferon-based regimens. Five of the six studies treated patients using interferon or pegylated interferon with or without the addition of ribavirin.^{[12,14,24,26,27]} In Shiratori et al., patients were treated solely with interferon.^[28] Duration of therapy across studies varied from 8 to 48 weeks. Specific details regarding antiviral therapy and treatment duration for each study are noted in the table (Table 1). Many of the studies were retrospective analyses of prior randomized controlled trials comparing antiviral dosages and length of therapy (Table 1).^{[12,14,27,28]} The median number of patients achieving sustained virological response across studies was 34% (range 24–44%).^{[12,14,24,26–28]}

Regression of Cirrhosis

Regression of cirrhosis was defined as reduction in Metavir stage to ≤F3 or Ishak fibrosis score to ≤4. Median regression of cirrhosis in patients with SVR across studies was 55% (range 24–83%). Overall, a total of 73 patients with SVR had regression of cirrhosis of a total of 137 patients with SVR (53%). Of note, regression of cirrhosis in patients who did not achieve SVR was also observed. Median regression of cirrhosis in these patients was 19.5% (range 2–44). Risk ratios were calculated to compare regression of cirrhosis in patients with SVR against regression of cirrhosis in patients without SVR. Relative risk for regression of cirrhosis across all studies was 2.69 (95% CI 1.45–4.97, P < 0.01) (Fig. 2).

Figure 2.

Meta-analysis overall result – Cirrhosis regression in patients with and without a sustained viral response.

Subgroup Analysis

A number of subgroup analyses were also performed. The relative risk ratio for studies that studied only cirrhotic or advanced fibrosis patients was 6.15 (95% CI: 3.18–11.91, P < 0.01).^[12,14,24] The relative risk ratio for studies utilizing a central pathologist to review liver biopsy slides as compared with studies without a central pathologist was 1.60 (95% CI: 1.20–2.13, P < 0.01)^[26,27] and 3.97 (95% CI: 1.51–10.45, P = 0.005)^{[12,14,24,28]} respectively. Studies in which the mean biopsy length or median biopsy length of liver samples was less than 15 mm had a relative risk ratio of 1.91 (95% CI: 1.18–3.09, P = 0.008),^[24,26,28] whereas studies that had mean biopsy length or median biopsy length greater than 15 mm had a relative risk ratio of 4.38 (95% CI: 0.95–20.25, P = 0.06)^[12,14,27] for regression of cirrhosis. Subgroup analyses were also performed comparing studies in which the mean time between liver biopsies or median time between liver biopsies was less than 36-month or greater than 36-month. The relative risk ratio for cirrhosis regression in these studies was 1.79 (95% CI: 1.26–2.29, P < 0.01) (Fig. 3)^[24,26,27] and 4.33 (95% CI: 1.1–17.0, P < 0.05) (Fig. 4)^[12,14,28] respectively.

Figure 3.

Follow-up biopsy time mean or median <36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had mean or median time of <36-month.

Figure 4.

Follow-up biopsy time mean or median >36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had a mean or median time of >36-month.

Discussion

Overall, there was considerable variability in the amount of cirrhosis regression across studies (Median 55%, range: 24–83%). When the data were pooled and analysed, we obtained a relative risk of 2.96 indicating that achieving sustained virological response (SVR) led to an almost three-fold increase in chance of cirrhosis regression than not achieving SVR. Half the trials in this analysis studied not just regression of cirrhosis but also improvement in histological score for non-cirrhotics.^[26–28] When our analysis was performed only in manuscripts that specifically studied antiviral therapy in patients with severe fibrosis or cirrhosis, a greater likelihood of cirrhosis regression was noted – 6.15.

The severity of liver disease is a well-known predictor of antiviral response, even with newer direct-acting agents.^[29] Potentially, regression may be less likely in patients with more advanced or established cirrhosis. Differences in patient selection may help explain the greater likelihood of cirrhosis regression in studies focusing on patients with advanced liver disease. For instance, it is possible that more stringent entry criteria were utilized in studies focused specifically on patients with severe fibrosis or cirrhosis. We were unable to cumulatively analyse steatosis, comorbidities, alcohol among studies to determine their association with cirrhosis regression.

An important finding in our analysis is that the likelihood of cirrhosis regression may increase over time after SVR is achieved. This is highlighted by the fact that the risk ratio for regression is 4.13 when the follow-up biopsy is taken ≥36-month as compared to a risk ratio of 1.79. These results are consistent with studies identifying SVR as a statistically significant predictor of histological response to antiviral therapy.^[30,13] Individual studies have demonstrated reduced liver-related morbidity and mortality in patients with advanced hepatic fibrosis or cirrhosis and SVR.^[31,32] These results were further supported by a recent meta-analysis demonstrating a significant risk reduction in hepatic decompensation, hepatocellular carcinoma and liver-related mortality in patients with SVR.^[18] The histological outcomes observed in this meta-analysis may provide an explanation for the clinical outcomes observed in previous studies.

A noteworthy finding in our analysis is that cirrhosis regression was seen even among treated patients who did not achieve a SVR.^{[12,14,24,26–28]} There are several potential explanations for this. First, the 'Non-SVR' comparative group in our analysis did receive interferon.^{[12,14,24,26–28]} Poynard et al. noted identified factors other than SVR that were associated with decreased fibrosis after treatment, including age <40, lower BMI, and mild or no activity of the virus in a multivariate analysis.^[27] In addition, it is possible that other factors promoting cirrhosis such as alcohol consumption may have improved in the 'Non-SVR' group. Indeed, 25% of the patients in the study by Shiratori et al. reported alcohol prior to the study initation.^[28] But, the majority of the patients had completely stopped drinking at study completion.

Optimal liver biopsy length has been a subject of intense controversy because of the risk of sampling variation and interpretation.^[34] Biopsy sampling variation can limit the interpretation of results. Studies have shown that this sampling variation can lead to ≥1 stage change in fibrosis score when biopsies are taken from different lobes of the liver or even when taken through the same skin puncture site.^[35–38] Within our analysis, we found that the cirrhosis regression was better documented when a minimal biopsy length was utilized in the analysis. Although there was a trend, the difference was not statistically significant. To reduce further discrepancies, AASLD has issued a Class IC recommendation that liver biopsy length be at least 2–3 cm.^[34] Analysis by an experienced pathologist or consensus reading between pathologists has been associated with increased agreement.^[39] Interestingly, studies that used more than one pathologist had a higher regression of cirrhosis benefit as compared with those studies using a central pathologist (RR 3.96 vs. 1.71).

There are a number of limitations to this study. Heterogeneity between studies is an important limitation of this meta-analysis. Possible factors accounting for the heterogeneity may include relatively small study size, antiviral therapy, patient population, prevalence in confounding factors or duration of follow-up. It is not possible to extrapolate our results to patients with decompensated liver disease. All studies limited clinical trial entry to patients with compensated cirrhosis. This may be secondary to the risk of hepatic decompensation and worsening cytopenias with interferon-based therapy. Now with the introduction of non-interferon-based therapy for hepatitis C, the pool of patients with advanced liver disease who are eligible for treatment will expand.^[40,41] A third limitation is the utilization of only two literature databases – Cochrane and Medline. We may have missed studies not found in those indices. However, we searched through the references of all identified manuscripts to be as complete as possible. Our results may also be subject to publication bias in that authors were more likely to publish if there was a cirrhosis regression than not.

With the emergence of new therapies and better therapies for hepatitis C upcoming, further study into whether these new therapies may lead to different cirrhosis regression rates must be evaluated.^[41] Patients with advanced liver disease are more likely to undergo therapy with non-interferon based therapy. For instance, moderate thrombocytopenia is not necessarily an absolute contraindication with the newer therapies.^[40–42] We believe that with the advent of the newer therapies, previously interferon ineligible patients may be candidates for antiviral therapy but the rate of cirrhosis regression remains to be seen when treating patients with more advanced liver disease.

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Source

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C

Dig Liver Dis. 2014 Mar 10. pii: S1590-8658(14)00207-2. doi: 10.1016/j.dld.2014.01.157. [Epub ahead of print]

Ponziani FR¹, Viganò R², Iemmolo RM³, Donato MF⁴, Rendina M⁵, Toniutto P⁶, Pasulo L⁷, Morelli MC⁸, Burra P⁹, Miglioresi L¹⁰, Merli M¹¹, Di Paolo D¹², Fagiuoli S⁷, Gasbarrini A¹³, Pompili M¹³; on behalf of AISF RECOLT-C Group, Belli L, Gerunda GE, Marino M,Montalti R, Di Benedetto F, De Ruvo N, Rigamonti C, Colombo M, Rossi G, Di Leo A, Lupo L, Memeo V, Bringiotti R, Zappimbulso M,Bitetto D, Vero V, Colpani M, Fornasiere E, Pinna AD, Morelli MC, Bertuzzo V, De Martin E, Senzolo M, Ettorre GM, Visco-Comandini U,Antonucci G, Angelico M, Tisone G, Giannelli V, Giusto M.

Abstract

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival.

AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis Crecurrence.

METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis Crecurrence were retrospectively evaluated.

RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008).

CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: HCV antiviral treatment, Hepatitis C recurrence, Liver transplantation, Sustained viral response

PMID: 24635906 [PubMed - as supplied by publisher]

Source

Achieving SVR reduces hep C treatment costs

Provided by Clinical Advisor

Jennifer Southall
February 17, 2014

Achieving SVR reduces hep C treatment costs

Patients with hepatitis C virus genotype-1 infection who had no detectable levels of the virus on blood tests, also known as sustained virological response, experienced a 13-fold reduction in treatment costs vs. those who did not achieve a response five years after treatment, according to researchers.

“We have shown important cost reductions arising from sustained virological response [SVR], which previous studies have either assumed or only observed on small numbers of patients,” William L. Irving, of the University of Nottingham in the United Kingdom and colleagues reported in the Journal of Viral Hepatitis.

For the study, researchers assessed health resource usage and costs associated with treatment outcomes in193 patients who received at least two months of treatment with pegylated interferon and ribavirin therapy for HCV genotype-1 infection.

Unit costs were derived from the National Health Service Payment by Results database and the British National Formulary. Average follow-up was 3.5 years for those who achieved SVR and 4.9 years for non-SVR patients.

There were no patients with SVR that experienced progression of liver disease state. Conversely, 7.4% of patients without SVR progressed from chronic hepatitis to cirrhosis, and 4.9% progressed from cirrhosis to decompensated liver disease.

During the five-year post-treatment observation period, researchers observed a 13-fold increase in costs among patients that failed to achieve SVR. This increased to 56-fold among those who were retreated.

“Achievement of a [SVR] has significant effects on health service usage and costs,” the researchers concluded. “This work provides real-life data for future cost-effectiveness analyses related to the treatment of chronic HCV infection.”

References

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Source

DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4

Liver Int. 2014 Jan 19. doi: 10.1111/liv.12471. [Epub ahead of print]

Everson G, Cooper C, Hézode C, Shiffman ML, Yoshida E, Beltran-Jaramillo T, Andreone P, Bruno S, Ferenci P, Zeuzem S, Brunda M, Le Pogam S,Nájera I, Zhou J, Navarro MT, Voulgari A, Shulman NS, Yetzer ES.

Abstract

BACKGROUND & AIMS: Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection.

METHODS: Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up).

RESULTS: SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R.

CONCLUSIONS: The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

KEYWORDS: danoprevir, hepatitis C virus, response-guided therapy, ritonavir-boosting, sustained virological response

PMID: 24517252 [PubMed - as supplied by publisher]

Source

Correlates of HIV sustained viral suppression in HIV/HCV coinfected patients: possible role of the hepatitis C virus sustained viral response

AIDS. 2014 Feb 4. [Epub ahead of print]

Bani-Sadr F, Loko MA, Pambrun E, Winnock M, Carrieri P, Gilbert C, Duvivier C, Bouchaud O, Gervais A, Dabis F, Salmon D; for the ANRS CO 13 HEPAVIH Study Group.

Abstract

The impact of hepatitis C virus (HCV)-related characteristics such as genotype, viral load or liver fibrosis on the chances of achieving sustained HIV suppression in coinfected patients is not fully documented. We examined the relationship between both HIV/HCV-related and sociobehavioural characteristics and HIV sustained viral suppression (SVS) in 897 patients included in the ANRS CO13 HEPAVIH cohort. The main outcome variable was HIV SVS, defined as at least two consecutive undetectable HIV viral loads. Among the 897 HIV/HCV-coinfected patients, 419 (47%) had received HCV therapy at least once, and 103 patients (25%) had experienced an HCV sustained virologic response (SVR). In multivariate analysis, older age [odds ratio (OR) 1.23 for each period of 5 years of age, 95% confidence interval (CI) 1.02-1.49; P = 0.03], a higher level of school education (OR 1.92, 95% CI 1.04-3.56; P = 0.04), good adherence to HIV therapy (OR 2.05, 95% CI 1.23-3.43; P = 0.006) and HCV SVR (OR 1.81, 95% CI 1.01-3.26; P = 0.04) remained significantly associated with HIV SVS. In contrast, triple nucleoside reverse transcriptase inhibitor (NRTI) regimens were associated with failure to achieve HIV SVS (OR 0.50, 95% CI 0.27-0.94; P = 0.03). Our results show that HCV SVR is associated with a higher likelihood of achieving HIV SVS. With the advent of direct-acting anti-HCV drugs, a marked increase in the rate of virologic response is observed in coinfected patients. So, further research is needed to determine whether suppression of HCV replication could be associated with a higher efficacy of antiretroviral therapy.

PMID: 24499953 [PubMed - as supplied by publisher]

Source

Patient-important benefits of clearing the hepatitis C virus through treatment: a simulation model

Journal of Hepatology

Article in Press

Hamish Innes, David Goldberg, Geoffrey Dusheiko, Peter Hayes, Peter R. Mills, John F. Dillon, Esther Aspinall, Stephen T. Barclay,Sharon J. Hutchinson

Received 7 August 2013; received in revised form 20 January 2014; accepted 27 January 2014. published online 06 February 2014.
Accepted Manuscript

Abstract

Background & Aims

Given an appreciable risk of adverse-effects, current therapies for chronic hepatitis C virus (HCV) infection pose a dilemma to patients. We explored, via simulation modelling, patient-important benefits of attaining a Sustained Viral Response (SVR).

Methods

We created the HCV Individualised Treatment-decision model (the HIT-model) to simulate, on a per patient basis, the lifetime course of HCV-related liver disease according to two distinct scenarios: (i) SVR attained, and (ii) SVR not attained. Then, for each model subject, the course of liver disease under these alternative scenarios was compared. The benefit of SVR was considered in terms of two patient-important outcomes: (1) The percent-probability that SVR confers additional life-years; and (2) The percent-probability that SVR confers additional healthy life-years, where “healthy” refers to years spent in compensated disease states (i.e. the avoidance of liver failure).

Results

The benefit of SVR varied strikingly. It was lowest for patients aged 60 years with initially mild fibrosis; 1.6% (95% CI: 0.8-2.7) and 2.9% (95% CI: 1.5-4.7) probability of gaining life-years and healthy life-years, respectively. Whereas it was highest for patients with initially compensated cirrhosis aged 30 years; 57.9% (95%CI: 46.0-69.0) and 67.1% (95%CI: 54.1-78.2) probability of gaining life-years and healthy life-years, respectively.

Conclusions

For older patients with less advanced liver fibrosis, SVR is less likely to confer benefit when measured in terms of averting liver failure and premature death. These data have important implications. Foremost, it may inform the contemporary patient dilemma of immediate treatment with existing therapies (that have poor adverse effect profiles) versus awaiting future regimens that promise better tolerability.

Abbreviations: HCV, Hepatitis C Virus, SVR, Sustained Viral Response, HIT model, Hepatitis-C Individual-based Treatment-decision model,HCC, Hepatocellular Carcinoma, NSS, Number need to attain SVR, NNT, Number needed to treat, SA, Sensitivity Analysis

Keywords: Hepatitis C, Chronic Hepatitis C, Patient-centred, Patient-important outcomes, Markov model, Simulation model, Antiviral treatment,Adverse effects, Risk-benefit ratio

Source

Does Eltrombopag Really ENABLE SVR?

Gastroenterology
Volume 146, Issue 2 , Pages 339-342, February 2014

Aviva Leber, Jordan J. Feld

published online 20 December 2013

See “Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy,” by Afdhal NH, Dusheiko GM, Giannini EG, et al, on page 442 -Free.

Patients with hepatitis C (HCV) cirrhosis and thrombocytopenia represent a particularly high-risk group for future liver decompensation, death, and hepatocellular carcinoma.¹ These patients are among those who most desperately require therapy and cannot afford to wait for new treatment developments. However, these are also the patients for whom current therapies pose the highest risk of complications.² Bone marrow suppression is a well-known complication of interferon treatment, with falling blood counts during therapy often leading to dose reductions, dose interruptions, and early cessation of treatment, all of which may lower the likelihood of attaining a sustained virologic response (SVR).³ Cirrhotic patients with significant thrombocytopenia are largely excluded from clinical trials of promising new therapies and therefore must rely on existing interferon-based regimens. Strategies to enhance rates of treatment initiation and completion have the potential to maximize SVR in this difficult-to-treat population.

Eltrombopag is a new oral platelet growth factor that acts as a thrombopoietin (TPO) receptor agonist, resulting in differentiation and proliferation of megakaryocytes. It acts in an additive fashion with endogenous TPO by binding and activating the TPO receptor through an alternate binding site.⁴ Eltrombopag has been studied in patients with immune thrombocytopenia purpura, cirrhosis (from any cause), and in those undergoing interferon-based therapy for HCV. To clarify whether eltrombopag would enhance rates of SVR in patients with HCV and thrombocytopenia, the ENABLE 1 and ENABLE 2 trials (Eltrombopag to initiate and maintain interferon antiviral treatment to benefit subjects with HCV-related liver disease) were carried out in North America and Europe, the results of which are published together in this edition ofGastroenterology.⁵

Before the ENABLE study, McHutchison et al⁶ evaluated the use of eltrombopag in 74 patients with HCV-related cirrhosis and platelet counts between 20,000 and 70,000/μL. Patients were randomized to increasing doses of eltrombopag (30, 50, and 75 mg) for 4 weeks before initiation of interferon and then for 12 weeks during interferon-based therapy. Between 75% and 95% of treated patients achieved the primary endpoint of an increase in platelet count to 100,000/μL during the initiation phase. Higher rates were seen in those treated with higher doses of eltrombopag. Between 36% and 65% of patients treated with eltrombopag maintained a platelet count >50,000/μL and were able to complete 12 weeks of interferon therapy compared with only 6% in the placebo group. Interestingly, no thromboembolic events were seen in this small study.

The ENABLE 1 and ENABLE 2 studies were thus undertaken to assess the effect of eltrombopag on rates of SVR in patients with HCV cirrhosis undergoing interferon-based antiviral therapy. The studies differed only in the pegylated interferon used and the corresponding platelet threshold set for initiation of treatment. Both trials recruited patients with chronic HCV with platelet counts <75,000/μL. Before starting antiviral therapy, all patients received open-label eltrombopag during the study initiation phase. Eltrombopag was initiated at a dose of 25 mg/d and increased gradually to a maximum of 100 mg/d until platelet levels crossed the recommended thresholds for initiating interferon-based therapy according to the peginterferon product label. Only patients who responded to eltrombopag were eligible for randomization in a 2:1 ratio to eltrombopag maintenance treatment during antiviral therapy or placebo (ie, antiviral therapy alone). The primary endpoint of the study was the effect of eltrombopag on the attainment of SVR. Adverse events were recorded as safety endpoints.

The patient population consisted mainly of middle-aged Caucasian men with genotype 1 infection and Child–Pugh A cirrhosis. The median platelet count at trial enrollment was 59,000/μL. Patient characteristics, including interleukin (IL)-28B status, were similar in all groups. During the initiation phase, 96%–97% of patients achieved the required platelet levels to proceed with therapy, with 86% doing so on 25 or 50 mg of eltrombopag. Adverse events were minor and included headache, nausea, and diarrhea. During the antiviral phase of the trial, a significantly higher proportion of eltrombopag-treated patients attained SVR (ENABLE 1, 23% vs 14% [P = .0064]; ENABLE 2, 19% vs 13% [P = .02]) and the treatment effect remained consistent across HCV genotypes. Patients treated with eltrombopag required fewer peginterferon dose reductions and were maintained on full-dose peginterferon for a longer amount of time. Notably, however, portal vein thrombosis (PVT) occurred more frequently in the eltrombopag-treated patients (n = 12 for eltrombopag vs n = 2 for placebo). Rates of thromboembolic complications did not correlate with platelet count or eltrombopag dose. Hepatic decompensation, specifically ascites and hepatic encephalopathy, were also more frequently seen in the eltrombopag-treated group (10% eltrombopag vs 5% placebo).

The ENABLE study was an ambitious effort to improve SVR rates in a very difficult-to-cure population. Although the study nicely confirmed that eltrombopag has potent platelet stimulatory effects, it is difficult to determine whether the improved rates of SVR seen in the trial will translate to better outcomes in general clinical practice. Study investigators were required to lower peginterferon doses according to the product labels rather than clinical judgment. Most seasoned clinicians do not strictly adhere to the thresholds in the label because clinical experience has shown that maximizing medication exposure is important and clinically significant bleeding events with moderate degrees of thrombocytopenia are very rare.⁷, ⁸ The differences in SVR were owing to greater peginterferon exposure in the eltrombopag arms. Had investigators had the freedom to adjust the peginterferon dose, it is likely that patients in the placebo arm would have received more cumulative peginterferon, which may have improved their rates of SVR. The trial design clearly favored the eltrombopag arms. The authors acknowledge this limitation in the discussion; however, it is difficult to overstate the importance of this issue in interpreting the effect of eltrombopag on treatment outcome and the overall significance of the study.

Predicting the risk of bleeding in patients with cirrhosis is complex because end-stage liver disease reduces both procoagulant and anticoagulant factors. In cirrhosis, the cause of thrombocytopenia is multifactorial. In addition to splenic sequestration resulting from portal hypertension, coating of platelets by circulating immunoglobulins may lead to increased platelet destruction by the reticuloendothelial system.⁹ Platelet production may also be impaired owing to reduced levels of endogenous TPO⁴ and HCV-related bone marrow suppression.⁵ However, despite the low platelet counts seen, which can fall significantly further during interferon treatment, data suggest that clinically significant bleeding is uncommon in patients with liver disease–related thrombocytopenia. This may be partially explained by effects on platelet function. In patients with cirrhosis, platelet function may be enhanced due to a decrease in production of ADAMTS13, a plasma metalloprotease that normally limits the effect of von Willebrand factor on platelets.¹⁰ Furthermore, high levels of von Willebrand factor, a common finding in patients with cirrhosis, enhance platelet adhesion to the subendothelium at sites of vascular injury.⁹ Other studies in patients with cirrhosis, have found that platelet counts as low as 60,000/μL are able to generate thrombin levels in the normal range.¹⁰ All of these factors enhance platelet function and may limit bleeding, even with low absolute platelet counts. Roomer et al⁸ recorded bleeding events in a cohort of HCV patients with and without cirrhosis treated with peginterferon and ribavirin. Although epistaxis and gingival bleeding were relatively common in patients with platelet counts of <50,000/μL, only 1 major bleeding event was recorded, which occurred at a platelet level of 65,000/μL.⁸ Hence, a clinically relevant platelet threshold for interferon dose reduction or cessation is not known and accurately predicting the bleeding risk of an individual patient in the office is currently very difficult. However, it is fair to say that the peginterferon product labels are relatively conservative and most clinicians would be comfortable maintaining full-dose peginterferon at platelet counts well below those recommended for dose reduction.

Even if we may be comfortable with lower platelet counts than in the product labels, there is no doubt that clinicians would sleep easier if they did not have to worry about thrombocytopenia during interferon-based therapy—but at what cost? The major concern with eltrombopag in patients with cirrhosis is the potential for an increased risk of thromboembolic complications. This was borne out in the ENABLE study with a higher number of thromboembolic events in the eltrombopag-treated group compared with those who received placebo. This phenomenon has been observed in previous studies¹¹, ¹²and is biologically plausible. Interestingly, a high absolute platelet count or high dose of eltrombopag was not correlated with thromboembolic events, making it difficult to predict who is at highest risk. A post hoc analysis of a previous study¹¹identified a platelet counts of >200,000/μL as a risk factor for thrombotic events. The most common thromboembolic event in the ENABLE study was PVT, which is a well-known complication of advanced cirrhosis. The prevalence of PVT in a large, retrospective, Italian study of 701 patients with cirrhosis was 11%¹³ and PVT occurs more frequently in those with more advanced disease.¹⁴ The effect of PVT on the natural history of cirrhosis is not entirely clear, with studies coming to varying conclusions. A large, retrospective study of 3295 patients awaiting liver transplantation found that the presence of PVT was an independent factor associated with death,¹⁵ whereas a prospective study of 290 patients awaiting liver transplantation did not show a significant effect of PVT on mortality.¹⁶ The effect of PVT post liver transplantation is more evident. In a recent, large, systematic review by Rodriguez-Castro et al,¹⁷ the presence of an occlusive PVT was associated with an increased 30-day and 1-year mortality post liver transplantation. This finding may be particularly relevant in the ENABLE cohort of patients, whose advanced liver disease and poor response to treatment may necessitate a future liver transplant.

Beyond PVT, there was a higher rate of hepatic decompensation among eltrombopag-treated patients. The reasons for this are not entirely clear, because it was not directly correlated with PVT or other obvious thrombotic events. Interferon-based therapy is associated with a risk of decompensation; therefore, it is conceivable that the greater cumulative exposure to interferon pushed some patients to develop hepatic complications. This study confirmed what we already knew; interferon is relatively ineffective and potentially very dangerous in patients with advanced cirrhosis.² We were reminded of this with the introduction of first-generation protease inhibitors, for which thrombocytopenia and low albumin have been recognized as predictors of serious complications, presumably because of greater exposure to interferon in patients who might otherwise have stopped therapy earlier owing to virologic failure.¹⁸ Another intriguing possibility is that decompensation itself may be a thrombotic complication. Recently, Villa et al¹⁹ showed that low-dose enoxaparin treatment in patients with cirrhosis reduced not only PVT but also lowered the rate of hepatic decompensation and improved survival. It has been proposed that the benefits of enoxaparin may relate to prevention of microthrombi in the intrahepatic circulation. Fortunately, the rates of decompensation with eltrombopag were low, but it is conceivable that increased platelet counts may promote microthrombosis, which may be clinically relevant in a very cirrhotic liver.

Eltrombopag has also been evaluated for other treatment indications in cirrhosis. The ELEVATE study (Eltrombopag Evaluated for Its Ability to Overcome Thrombocytopenia and Enable Procedures) assessed the short-term use of eltrombopag in patients with cirrhosis and thrombocytopenia (platelet count <50,000/mm³) who required an invasive procedure.¹¹ The primary endpoint was avoidance of platelet transfusion, and a key secondary endpoint was the occurrence of bleeding. The study demonstrated that patients treated with eltrombopag were significantly less likely to require a platelet transfusion compared with patients receiving placebo (72% vs 19%), but the rate of bleeding was not different between the 2 groups. Thromboembolic events, predominantly PVT, were more common in the treated group (odds ratio, 3.04). The ELEVATE study again confirms the potent physiologic effect of eltrombopag on platelet production but it also demonstrates that the risk of thromboembolic events is present even after short-term use. Although no clear dose or platelet level was associated with thrombosis, if one elects to use eltrombopag, it would seem prudent to use the lowest dose possible to maintain a safe platelet level.

Eltrombopag is a potentially useful tool for treating clinically relevant thrombocytopenia in patients with advanced liver disease. The ENABLE study provides further evidence that eltrombopag is effective at increasing the number of eligible patients for interferon-based therapy, as well as decreasing the number of interferon dose reductions and interruptions. However, owing to the likely difference between the very conservative study protocol and routine clinical practice for platelet count–based initiation and continuation of interferon therapy, the true effect of eltrombopag on SVR rates is uncertain. The widespread use of eltrombopag should further be tempered by the increased rates of thromboembolic events associated with its use. At present, no tools are available to accurately predict the risk of bleeding or thrombosis in an individual cirrhotic patient with thrombocytopenia or to identify in whom the benefit of eltrombopag would likely outweigh the risk. It is important to note that even with eltrombopag, the absolute rates of SVR were very low (19%–23%) and the rates of serious adverse events were high (20%) in this difficult-to-cure population. It would seem, therefore, that eltrombopag should be reserved for a carefully selected subset of patients with severe thrombocytopenia who cannot wait for new therapies and are under the care of clinicians with experience treating patients with advanced cirrhosis. If one opts to use eltrombopag, the minimum effective dose should be used. In this case, rather than a randomized, controlled trial, real-world data will ENABLE us to understand the true effect of eltrombopag on SVR, but hopefully by the time such data emerge, interferon and the need for support with eltrombopag will be a thing of the past.

References 

Source

Management of HCV patients with cirrhosis with direct acting antivirals

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 38–45, February 2014

Review Article

You have free access to this content

Vincenzo Boccaccio, Savino Bruno^*

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12391

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: boceprevir; direct acting antivirals; faldaprevir; HCV-related cirrhosis; hepatitis C virus; simeprevir; sofosbuvir; sustained virological response; telaprevir

Abstract

In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon-based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all-causes of mortality in all categories of patients with HCV-related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg-interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules.

Recently, improvement in the knowledge of the HCV life-cycle, has resulted in the rapid development of many direct-acting antivirals (DAAs). Two first generation DAAs, boceprevir (BOC) and telaprevir (TVR), have been approved, and more than 40 new small molecules are still in development. However, only a few individuals with compensated cirrhosis were included in the phase III studies assessing the safety and efficacy of BOC or TVR in naïve and chronic hepatitis C genotype 1 patients in whom treatment had failed, and patients with either decompensation or end-stage liver disease were excluded. Therefore, the information available in these patients, which have shown significantly lower SVR compared with patients with mild to moderate fibrosis, are not fully reliable. In addition, in real practice, some studies that have not yet been fully published have shown that triple therapy with these two molecules was associated with low SVR and high serious adverse events (SAEs).

Cirrhosis is highly heterogeneous

It is well-known that the prognosis of hepatitis C virus (HCV) infection is mainly linked to the progression of fibrosis [1]. Once cirrhosis has developed, many different clinical features can be recognized, ranging from early (compensated) to more severe (decompensated) cirrhosis and terminal end stage liver disease. Compensated cirrhosis can include patients with very early stage disease who are often diagnosed during an incidental assessment of chronic hepatitis by histology (F3 Metavir or F4 Ishak) or by transient elastography (stiffness ≥ 9.5 < 12.5 kPa). There are frequently no clinical signs of significant portal hypertension (Hepatic Venous Pressure Gradient (HVPG) ≥6 mmHg <10 mmHg), and no varices at endoscopy. In general, these subjects belong to Child-Pugh class A5. However, compensated cirrhosis also includes patients with more severe conditions. Portal hypertension is higher (HVPG ≥10/12 mmHg), esophageal varices may be present on a diagnosis of cirrhosis obtained either by histology or clinically based. Patients can present with thrombo/leukocytopaenia and with low albumin. However, most of these patients can still be classified as Child-Pugh class A (generally A6). Decompensated patients are easier to identify: the MELD score is usually >15 and a number of these patients are on the list for orthotopic liver transplantation (OLT) [2-4].

These heterogenous clinical features strongly influence short and long-term disease outcome [5, 6].

Sustained viral response

Two studies have clearly shown that the regression of cirrhosis and fibrosis are not infrequent in patients with hepatitis C virus (HCV) who achieved sustained virological response (SVR) after antiviral therapy [7, 8]. Moreover, SVR has been shown to be associated with (I) a significant reduction in the development of esophageal varices and (II) a decreased incidence of hepatocellular carcinoma (HCC), liver decompensation and all-causes of mortality in patients with all stages of cirrhosis [9-11].

Unfortunately, it is well-known that the stage of disease is a major independent predictor of SVR using Peg-interferon and ribavirin (PR)[12-14].

Over the past decade, the availability of the HCV replicon has improved knowledge of the HCV life-cycle allowing the development of many direct-acting antivirals (DAAs).

These molecules inhibit all HCV structural proteins (NS3/4A protease, NS5A protein, NS5B polymerase) [15]. Two first generation NS3/4A protease inhibitors (boceprevir (BOC) and telaprevir (TVR)) have recently been approved. Up to now, five large phase III trials have assessed the safety and efficacy of BOC and TVR in untreated patients and in patients with chronic HCV genotype-1 infection in whom standard PR treatment has failed [16-20].

Because of the few patients with cirrhosis included in these phase III studies, available data on the safety and efficacy of both molecules are limited in these patients.

A retrospective, post-hoc analysis of the REALIZE trial showed that the stage of liver fibrosis was a determining factor for treatment success with TVR. SVR rates were 58% and 53% (with and without lead-in respectively) in patients with Metavir F3/4 compared with 75% in F0–F2. However, in previous relapse patients, the SVR rate was 84% regardless of the stage of fibrosis; in previous partial and null responders the SVR rates decreased from 72 to 41% in F0–F2 fibrosis, from 56 to 39% in F3 fibrosis and from 34 to 14% (both TVR12 and lead-in arms combined) in F4 respectively [21].

More detailed results have been obtained with BOC in a retrospective post-hoc analysis in patients with cirrhosis and/or advanced fibrosis who participated in SPRINT-2 and RESPOND-2 [22]. Overall, patients randomized to a BOC-containing regimen had SVR rates ranging from 13% (2/16) to 25% (3/12). Patients with ≥1log₁₀ decline in HCV RNA at week 4 had significantly higher SVR rates than those with <1log₁₀ decline. In both studies, F3 patients who received PR had SVR rates of 40–50%, while those in the BOC/PR48 arm had higher SVR rates [77% (920/26) in SPRINT-2; 87% (20/23) in RESPOND-2] than patients in the BOC/response guided-therapy (RGT) arm [52% (11/21) and 55% (11/20) respectively]. Baseline viral load appeared to influence the SVR in patients who received BOC and with a <1log₁₀HCV RNA decline at week 4. In SPRINT-2, patients who had a viral load >2 000 000 IU/ml had SVR rates of 5% (1/19); the corresponding SVR rate in RESPOND-2 was 7% (1/14). The SVR in both studies combined was 6% (2/33) of patients, 4% (1/26) with HCV genotype 1a and 14% (1/7) with genotype 1b, respectively, corresponding to a negative predictive value (NPV) of 94%. Conversely, SVR rates were 43% (3/7) in the SPRINT-2 and 60% (3/5) in the RESPOND-2 trials in patients with a <1log₁₀ HCV RNA decline at week 4 but baseline viral load ≤2 000 000 IU/ml. Two of the six patients who achieved SVR were genotype 1a (both in SPRINT-2) and four genotype 1b (1 in SPRINT-2; 3 in RESPOND-2). In the BOC/RGT groups of both studies the duration of therapy was based on a pre-established decision that patients with undetectable HCV RNA at week 8 were eligible for shorter therapy. In patients with advanced fibrosis/cirrhosis, treatment week 8 (TW8) was used to define ‘early responders’ (HCV RNA undetectable at week 8) and ‘late responders’ (HCV RNA detectable at week 8). In both studies in patients with advanced fibrosis/cirrhosis, SVR rates in early responders were more than three times higher than in late responders and were comparable to SVR rates in patients without advanced liver disease. SVR rates were also examined according to the historical response to treatment (i.e., prior non-response vs prior relapse) in patients in the RESPOND-2 study. Patients with advanced fibrosis/cirrhosis with a prior non-response had SVR rates of 0% (0/5), 30% (3/10) and 46% (6/13) in the PR48, BOC/RGT and BOC/PR48 arms respectively. The corresponding SVR rates in those with prior relapse were 20% (2/10), 50% (11/22) and 83% (15/18) in the PR48, BOC/RGT and BOC/PR48 arms respectively. An analysis of SVR rates by IL-28 genotype was limited because of the small number of patients. In SPRINT-2, only five patients with cirrhosis had a favourable CC genotype (2 PR, 1 BOC/RGT and 2 BOC/PR48) and each of these patients achieved SVR. The CT genotype was the most common, and SVR rates were 17% (PR48, 1/6), 33% (BOC/RGT, 2/6) and 0% (BOC/PR48, 0/4) respectively. Eight patients had the less favourable TT genotype (1 PR, 3 BOC/RGT and 4 BOC/PR48) and the corresponding SVR rates were 100% (1/1), 0% (0/3) and 50% (2/4). In the RESPOND-2 trial, eight patients with cirrhosis had the CC genotype (0 PR, 4 BOC/RGT and 4 BOC/PR48) and the SVR rate was 75% in each of the BOC arms. SVR rates for patients with cirrhosis with the CT genotype were 0% (PR48, 0/5), 33% (BOC/RGT, 2/6) and 86% (BOC/PR48, 6/7). Ten patients had the less favourable TT genotype (2 PR; 2 BOC/RGT; 6 BOC/PR48) and the corresponding SVR rates were 0% (0/2), 50% (1/2) and 67% (2/6) respectively.

Thus, an SVR was more likely in patients who had >1.0 log₁₀ decline in HCV RNA at week 4, and in patients with undetectable HCV RNA at week 8. As previously reported, the clearest benefit of adding BOC to PEG-IFN was found in patients with previous treatment failure; SVR rates in patients with cirrhosis who received BOC/PR were 35–77%, compared with 0% for PR alone. SVR rates in patients with advanced fibrosis/cirrhosis and >1 log₁₀ decline in HCV RNA after 4 weeks of lead-in were 77–87% after 44 weeks of triple therapy, compared with 50% after 48 weeks of PR alone. Patients with undetectable HCV RNA at week 8 (corresponding to 4 weeks of triple therapy) had SVR rates of 79–80% (BOC/RGT) and 90–93% (BOC/PR48). Thus, early viral kinetics could be used to predict the response to treatment in patients with cirrhosis. Unlike PR therapy, virological failure of protease inhibitor (PI)-based combination therapy may result in the selection of viral variants with resistance to PI (RAVs). This resistance can emerge early during treatment: so it is important to identify which patients have a poor chance of achieving SVR. RAVs were detected in approximately 50% of the patients in the SPRINT-2 and RESPOND-2 trials with advanced fibrosis/cirrhosis, who did not achieve SVR [22].

Very recently and not already fully published, a meta-analysis on cirrhotic patients included in all five phase III BOC clinical trials (SPRINT-2, RESPOND-2, PEGASYS study, EPO study, interim data from PROVIDE) was also performed to (I) combine SPRINT-2/RESPOND-2 results (to create a larger population of patients), to (II) provide predictors of SVR by multiple logistic regression analysis, to (III) evaluate the risk of severe adverse events (SAEs) as suggested by real-life studies, to (IV) develop newer more reliable stopping rules to reduce the cost and risk of therapy, to (V) assess whether short treatment (i.e. 36 weeks) can be applied to a subset of patients.

The meta-analysis showed that over one-half of all F4 patients treated with BOC/PR can achieve SVR (SVR rate by meta-analysis = 55%). In addition, the SVR rates were particularly high (89%) in F4 patients with undetectable HCV-RNA at TW8; these patients accounted for 43% of all patients with cirrhosis who were treated. Eighty-two percent of the patients with detectable HCV-RNA at TW8 (57% of the total population of patients with cirrhosis) achieved more than 3 log₁₀ decline in HCV-RNA resulting in a SVR rate of 35% while 18% had less than 3 log₁₀ decline and did not achieve SVR (SVR 0%). The importance of the virological response at TW8 is shown in Figure 1A.

Figure 1. (A) The importance of TW 8 HCV-RNA decline in patients with cirrhosis (F4 Metavir) during BOC-therapy; (B) Proposed Treatment Algorithm for Cirrhotic (F4) and F3 Patients Treated with BOC/P/R. A potential algorithm for the treatment of F4 and F3 patients was derived from the on-treatment viral responses at weeks 8, 12 and 24. Because no F3 or F4 patients (0/22; 95% CI = 0, 13) with a detectable HCV-RNA and <3 log10 decline in viral load from baseline at Week 8 achieved SVR, stopping therapy in these patients should be considered. Because treatment-naïve F3 and F4 patients with undetectable viral load at treatment week 8 and thereafter achieved similar SVR rates with durations of treatment between 28 and 40 weeks compared with ≥40 weeks, therapy of treatment-naive cirrhotic patients might be stopped after week 28 if the regimen is poorly tolerated [23]. * Consider stopping based on low chance of SVR in F3 and F4 patients with detectable HCV-RNA and <3 log10 decline in HCV-RNA from baseline [SVR = 0/22; 0%; 95% CI (0, 13)].† Consider stopping treatment of treatment-naïve patients after TW28 if undetectable HCV RNA from TW8 through TW24.

A potential algorithm for the treatment of F4 and F3 patients was derived from the on-treatment viral responses at weeks 8, 12 and 24 (Fig. 1B). Because none of the F3 or F4 patients with detectable HCV-RNA and <3 log₁₀ decline in viral load at TW8 achieved SVR, stopping therapy in these patients should be considered. Furthermore, if F3 or F4 patients with detectable HCV-RNA and <3 log₁₀ decline in viral load from baseline to TW8 are not tolerating treatment, stopping therapy should also be considered. Based on the upper limit of a 95% CI, it is possible that up to 13% of F3 or F4 patients with a <3 log₁₀ decline in viral load can still achieve SVR. Because treatment-naïve F3 and F4 patients with an undetectable viral load at TW8 achieved similar SVR rates with between 28 and 40 weeks of treatment (87%) compared with ≥40 weeks (92%), therapy in treatment-naive and experienced patients with cirrhosis could be stopped after week 28 if the regimen is poorly tolerated. In conclusion, predictors of SVR in F3 and F4 patients include male gender, low baseline viral load and on-treatment viral responses at weeks 4 and 8. These factors can help clinicians to identify patients who will probably achieve SVR. The on-treatment response at TW8 was especially helpful in identifying patients with a high likelihood of response and, on the other hand, could be the earliest stopping point because of a very low probability of response. The frequency of SAEs, transfusions, anaemia and thrombocytopaenia (grade 4) were higher in F4 patients treated with BOC/PR than in F0–F2 patients. Overall, tolerance to BOC/PR in patients with cirrhosis was manageable but closer attention should be paid to the management of anaemia [23].

Compassionate Use of Protease Inhibitors in Viral C Cirrhosis (CUPIC) was established prior to the licensing of TVR and BOC in France to provide early access to triple therapy with new drugs to patients with hepatitis C who are considered to be in urgent need of treatment. Early access use of either TVR or BOC was permitted for treatment-experienced patients with compensated cirrhosis, HCV genotype-1 infection. Of the 292 patients treated with TVR, HCV-RNA was undetectable in 161 (55.1%) 236 (80.5%), 230 (78.8%) and 196 (67.1%) at weeks 4, 8, 12, 16 respectively. At week 16, the response rate was significantly higher in relapsers (74.8%) than in partial responders (66.2%) or null responders (45.8%). A virological response was achieved in patients treated with BOC in 2.4% (5 of 205), 37.6% (77 of 205), 54.6% (112 of 205) and 58.0% (118 of 205) of cases, at weeks 4, 8, 12, 16 respectively. At week 16, the response rate was significantly higher in relapse patients (69.0%) than in partial responders (50.0%) and null responders (22.2%).

In the CUPIC study, the safety profile was poor for treatment regimens including both PIs, mainly because of a high number of SAEs and the occurrence of death and severe complications, such as severe infection or hepatic decompensation in 6.4% of patients. These severe complications have not been previously reported in treatment-experienced patients with cirrhosis included in phase III clinical trials. This could be explained at least in part by the different clinical characteristics of patients included in this real-life cohort and those enrolled in phase III clinical trials. In 31.2 and 43.3% of the cases CUPIC patients treated with BOC had at least one exclusion criterion for the REALIZE and RESPOND-2 studies, respectively, while the patients in the TVR group were older, with lower mean haemoglobin (Hb) levels and platelet count compared with the cirrhotic patients enrolled in REALIZE. Thus, many patients treated in CUPIC did not meet inclusion criteria for the TVR or BOC pivotal trials.

In multivariate analysis, two baseline predictors of severe complications were identified: platelet count <100 000/mm³ and serum albumin <35 g/L. The combination of both conditions defined a subgroup of patients at a high risk (44.1%) of severe complications. Authors have therefore suggested that this subset of individuals should not be treated with triple therapy with BOC or TVR [24].

In this observational study, several cases of renal impairment were also observed for the first time. This aspect was recently emphasized by a subanalysis of another real-life survey, the PAN-study, a non-interventional investigation conducted by the Association of German Gastroenterologists in Private Practice, enrolling patients treated with PR with or without TVR or BOC. In this large cohort, about 5% of patients on triple therapy with BOC or TVR developed stage 3 renal insufficiency, some temporarily. However, a substantial proportion of these patients had risk factors for renal impairment at inclusion, such as older age, arterial hypertension or diabetes mellitus. As expected, all these variables were associated with a marked decrease in eGFR to <60 ml/min on univariate analysis. However, it is important to note that treatment with TVR or BOC was found to be independently associated with the development of renal failure on multiple logistic regression analysis. This is reversible in most patients treated with TVR. The improvement of renal function after discontinuation of PIs strongly suggests a causal relationship [25].

SVR data in the CUPIC study are not yet fully known. Partial results presented at the 2013 EASL meeting, showed that overall SVR12 rates were: 79/190 (41%) for BOC, 118/295 (40%) for TVR; in relapsers 43/85 (51%) for BOC, 61/116 (53%) for TVR; in partial responders 32/80 (40%) for BOC, 43/135 (32%) for TVR; in null responders 1/9 (11%) for BOC, 8/28 (29%) for TVR [26].

The Open Label Early Access Program (EAP) for TVR in adult patients with HCV genotype 1 was an international real life study in which 1587 patients, both naïve and treatment-experienced (genotype 1a/1b: 22%/74%) were treated with triple therapy including TVR. Patients enrolled had persistent compensated bridging fibrosis (752) or cirrhosis (835), ≥3.5 g/dl albumin, ≥90 000 platelets, ≥1500 neutrophils, Hb>12 g/dl (women) or >13 g/dl (men). 321 patients (20%) were naïve, 436 (27%) prior null responders, 531 (33%) relapsers, 49 (3%) had a previous viral breakthrough, 47 (3%) were classified as non-responders (unspecified response). The most relevant grade 2–4 AEs that developed during treatment were: anaemia (44%), rash (13%), thrombocytopaenia (8%), pruritus (6%), asthenia (6%), nausea (4%) and anorectal disorders (4%). Seven patients (six with cirrhosis) experienced AEs with a fatal outcome: four died because of severe infections, two of hepatic failure and one of variceal bleeding. No data are available on SVR [27]. Assessment of data from another very large real-life study of BOC (The Italian and Spanish Name Patient Program) is still ongoing.

Figure 2. Differences between clinical trials and real-world studies.

More than 40 new NS3/4A, NS5A, or NS5B inhibitors are under development. Sofosbuvir (formerly GS 7977, an NS5B polymerase nucleotidic inhibitor), faldaprevir and simeprevir (both NS3 protease inhibitors), are in phase III development and almost ready for marketing distribution.

In particular, clinical studies have shown that sofosbuvir (SOF) has a strong and excellent antiviral activity, with broad HCV genotype coverage, a high genetic barrier to resistance, and is safe and well-tolerated. SOF has been tested both in interferon-based and in interferon-free regimens. The NEUTRINO trial enrolled 327 naïve patients with genotypes 1, 4, 5 or 6 HCV infection (17% with cirrhosis), who received SOF+PR for 12 weeks. SVR12 rates were high in all genotypes, including 89% in genotype 1, 96% in genotype 4 and 100% in genotypes 5 and 6. The SVR12 rate in patients with cirrhosis was 80% [28].

In a non-inferiority trial (FISSION), 499 treatment-naïve patients with genotype 2 or 3 were randomly assigned to receive SOF+ribavirin (RBV) for 12 weeks or PR for 24 weeks. There were 20–21% of patients with cirrhosis. The SVR12 rate in patients with cirrhosis and genotype 2 was 91% vs 61%, respectively, while in those with genotype 3 it was 34% vs 30% respectively [28].

The POSITRON trial compared 12 weeks of treatment with SOF and RBV with matching placebo patients with genotype 2 and 3 who were unwilling, intolerant or ineligible for IFN therapy. Approximately 20% of included patients had evidence of compensated cirrhosis at screening. The SVR12 rate was 94% and 21% in patients with genotype 2 and genotype 3 with cirrhosis respectively [29].

The FUSION study included treatment-experienced patients with genotypes 2 and 3, who received SOF and RBV for 12 or 16 weeks. Approximately 33–35% of the patients enrolled had compensated cirrhosis. SVR12 was achieved by 78% vs 60% of cirrhotic patients with genotype 2 (16 vs 12 weeks of treatment) and by 61% vs 19% in genotype 3 [29].

The most promising study is the phase II LONESTAR trial which evaluated 8-and 12-week courses of therapy with the once-daily fixed-dose combination of SOF and ledipasvir with and without RBV. In this study, 40 patients (half with documented compensated cirrhosis) who had previously failed therapy with an HCV specific PI-based regimen were included. 95% of patients in both arms achieved SVR4, one patient with cirrhosis in the SOF and ledipasvir arm relapsed and one patient in the SOF and ledipasvir plus RBV arm was lost to follow-up [30].

Finally, two other ongoing phase III studies are examining all-oral HCV therapy with SOF and ledipasvir. ION-1 and ION-2 are testing 12- and 24-week courses of the fixed-dose combination with and without RBV in treatment-naïve and treatment-experienced genotype 1 HCV patients, including those with compensated cirrhosis. Based on the results of the LONESTAR trial, Gilead has amended ION-2 to shorten the duration of therapy in one of the two fixed-dose combination arms without RBV from 24 to 12 weeks [30].

Simeprevir (SMV) is an NS3/4A PI with potent antiviral activity against multiple genotypes in preclinical studies and with once-a day dosing.

ASPIRE was a phase IIb trial which included treatment-experienced patients with genotype 1 and F3/F4. Patients received PR alone (for 48 weeks) or in combination with SMV for 12, 24 or 48 weeks. SVR24 in F3/F4 patients treated with SMV was 65% in relapsers, 67% in partial-responders and 33% in null responders [31].

Two additional phase III trials, QUEST-1 and QUEST-2, evaluated the safety and efficacy of SMV plus PR in naïve patients with HCV genotype 1 infection. These two trials differed for the percentage of patients with cirrhosis and with genotypes 1a or 1b in this study: in QUEST-1 there were 56–57% of patients with genotype 1a and 12–13% of patients with cirrhosis; in QUEST-2 there were 58% of patients with genotype 1b and 7–11% with cirrhosis. The addition of SMV to PR in treatment-naive patients with HCV genotype 1 infection was associated with a significant improvement in efficacy over PR alone in both trials, with an overall SVR12 of about 80–81% and 50% respectively. In QUEST-1, the SVR12 rate for patients with cirrhosis was 58% in the SMV arm vs 29% in the PR arm. In QUEST-2, the SVR12 rate for patients with cirrhosis was 65% in the SMV arm vs 40% in the PR one. Response to therapy was also more rapid in patients treated with SMV; the rapid virological response (RVR) rate was 80% vs 12% with placebo. SMV was generally well-tolerated and was only associated with transient, mild elevations in bilirubin levels [32, 33].

The COSMOS trial is now evaluating a combination of SMV and SOF with or without RBV in treatment-naïve patients and non-responders, both without cirrhosis (cohort 1) and with cirrhosis (cohort 2). Treatment for 12 weeks with SMV and SOF, with or without RBV, led to SVR4 rates of 96% and 100%, respectively, in cohort 2, including 90 treatment-naïve or previous null responders [34].

Faldaprevir (FDV) is a potent PI that has been developed in combination with interferon or in all-oral therapeutic regimens. The phase III STARTVerso1 trial has suggested that the response rate to PR in naïve patients with genotype 1 (6% of patients with cirrhosis) can be improved by adding FDV. In fact, the overall SVR12 rate was significantly higher in patients receiving triple therapy (79–80%) than in the placebo group (52%). The SVR12 rate in F3 patients treated with FDV was 67% and 56% in F4 [35].

FDV was also administered, in the phase IIb SOUND-C2 trial, in combination with a non-nucleoside polymerase inhibitor (deleobuvir) with or without RBV in naïve genotype 1 patients (9% with cirrhosis). In patients with cirrhosis SVR12 rates ranged from 36 to 76% depending upon the dosage and duration of therapy. Rashes, photosensitivity, nausea, vomiting, diarrhoea and transient hyperbilirubinaemia were the most common AEs [36].

The results of some trials carried out with second generation DAAs in patients with cirrhosis are shown in Figure 3.

Figure 3. Results of some trials carried out with second generation DAA in cirrhotic patients: (A) Lonestar, (B) Quest-1, (C) Quest-2 [30, 32, 33].

Even more promising third generation DAAs are in phase II of development. Very high cure rates can be obtained with these DAAs when combined with PR, in a triple or quadruple therapeutic regimen (add-on strategy) and, at the same time, clinical results are promising when they are administered in all-oral regimens (combining drugs with different viral targets).

In conclusion, despite not conclusive, the available results suggest that patients with early stage compensated cirrhosis should be treated now with first generation PIs. However, these molecules should be cautiously used in patients with signs of more severe portal hypertension. Baseline characteristics can help to select individuals to be treated while newer on-treatment stopping rules, if validated, could optimize/maximize the treatment schedule, reduce costs and avoid AEs.

Future research must define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease or waiting for OLT, as well as HIV-coinfected patients), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration.

Acknowledgement

Conflict of interest: V. Boccaccio does not have any discosure to report. S. Bruno: advisory board MSD; speaker bureau MSD and Roche.

References

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