Showing posts with label 2017-10th Paris Hepatitis Conference. Show all posts
Showing posts with label 2017-10th Paris Hepatitis Conference. Show all posts

Thursday, January 5, 2017

The impact of antiviral therapy for hepatitis C on the quality of life: a perspective

Special Issue: Liver International
Proceedings of the 10th Paris Hepatitis Conference. International Conference on the Management of Patients with Viral Hepatitis undefined

Volume 37, Issue S1
January 2017
Pages 7–12

The impact of antiviral therapy for hepatitis C on the quality of life: a perspective (pages 7–12)Geoffrey Dusheiko
Version of Record online: 3 JAN 2017 | DOI: 10.1111/liv.13292

Abstract
Instruments to assess the impact of hepatitis C virus infection on health and measurements of reported outcomes in patients (health-related quality of life [HRQOL]) are not frequently used to assign priority for treatment. Several systematic reviews have been performed that provide a comprehensive analysis to help understand patient reported outcomes (PROs) with direct acting antiviral treatment. Clinical trials with direct acting antivirals (DAAs) provide an important opportunity to assess PROs without interferon or ribavirin. Significant improvement in quality of life parameters have been noted with DAA therapy. The results show improvement in HRQOL indices when interferon-free and particularly interferon and ribavirin-free treatments are compared to interferon and ribavirin treatment. Improvements in HRQOL indices are an encouraging aspect of the cure of chronic hepatitis C. It is unclear whether these measurable HRQOL improvements can be translated into a net benefit improvement in work productivity and a social dimension that is significant enough to convince payers of the added value of early and more widespread treatment.

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Key points
Several systematic reviews of patient reported outcomes provide a comprehensive analysis suggesting improved patient reported outcomes with direct acting antiviral treatment.
Direct acting antiviral treatment regimens overcome the disadvantage of interferon (and ribavirin) containing regimens as well as reducing the duration of treatment. Significant improvement in quality of life parameters have been noted with DAA therapy.
Improvements in health-related quality of life indices are an encouraging aspect of an SVR.
However, instruments to assess the current impact of HCV infection on health, and measurements of patient reported outcomes (health-related quality of life) are less frequently used to determine priority for treatment than is stage of disease.

1 Introduction
New direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) have improved sustained virological response (SVR) rates, and can be used with fewer adverse events. Regulatory submissions often require patient reported outcomes (PROs) to support efficacy data and claims of benefit to patients as well as improved cost-effectiveness.[1] Several systematic reviews of PROs have been performed. These provide a comprehensive analysis to understand PROs with DAA treatment.[2-8] This summary provides a brief perspective based on recent reviews, which provide an excellent overview of the subject and results derived from major trials.

Hepatitis C virus causes a substantial burden of disease in many countries. It is believed that one in five patients will develop cirrhosis and continued disease progression, including hepatocellular carcinoma. Before the introduction of DAAs, pegylated interferon (PEG IFN) and ribavirin were the mainstay of treatment. However, this regimen involves parental injections and results in numerous side effects without the desired efficacy in many patients, in particular those with advanced liver disease and unfavourable host factors. Treatment with interferon and ribavirin is often given for up to 48 weeks. The introduction of interferon-free DAA regimens has been a major breakthrough. Several interferon-free regimens including sofosbuvir and ribavirin, sofosbuvir and simeprevir, sofosbuvir and ledipasvir, sofosbuvir and daclatasvir, (daclatasvir and asunaprevir in some countries) ombitasvir, paritaprevir/ritonavir and dasabuvir, grazoprevir and elbasvir, or sofosbuvir plus velpatasvir, are licenced or in widespread use. Others are under development. All are highly effective and can be given for a shorter duration than PEG IFN and ribavirin.

2 Natural history and treatment decisions
Hepatitis C has a complex and heterogeneous natural history and the prognosis can be difficult to assess. The natural history of hepatitis C has been well categorized. In particular, there is a high risk of chronic hepatitis C following acute hepatitis C infection. After 30 years it is thought that approximately 30% of individuals will have minimal liver disease and 40% will have some degree of hepatic fibrosis including 30% with cirrhosis with a risk of hepatocellular carcinoma in those individuals with advanced fibrosis or cirrhosis.[9]

Published data show a marked variability in the natural history of disease. The progression even varies in patients with cirrhosis so that the disease may remain inactive for a period. However, once cirrhosis has developed there is a 1%-5% annual risk of hepatocellular carcinoma, a 3%-6% annual risk of hepatic decompensation and the risk of death in the year after an episode of decompensation is between 15%-20%. The onset of an event signalling hepatic decompensation such as the development of encephalopathy, ascites or variceal bleeding is a poor sign. A number of risk factors have been identified to characterize more rapid disease progression.

Budget impact and affordability have often driven reimbursement decisions. The stage of fibrosis has been the most important factor where structured pricing is utilized to determine the need to treat, because the risk of disease progression has been linked to fibrosis. Earlier studies with PEG IFN and now with DAA therapy, have shown that patients with cirrhosis who achieve an SVR have a significant decrease in the risk of developing decompensation or hepatocellular carcinoma. Achieving an SVR may reduce, but does not eliminate, the risk of hepatocellular carcinoma in patients who already have cirrhosis.[10-15] The predicted cumulative rates of progression to cirrhosis are influenced by the setting in which patients are studied.

3 Hepatitis C and extrahepatic morbidity and mortality
A body of evidence suggests that chronic HCV infection increases mortality from both hepatic and extrahepatic disease. A higher mortality rate has been observed in anti-hepatitis C positive individuals with detectable HCV RNA than in those with undetectable HCV RNA. All-cause mortality may be increased in HCV RNA positive individuals, with death related to not only hepatic disease but extrahepatic disease, in particular circulatory disease, nephritis, nephrotic syndrome and several cancers including oesophageal, prostate and thyroid cancer.[14, 16-25] The syndrome of mixed cryoglobulinaemia and vasculitis is associated with skin purpura and neuropathy as well as organ damage including membranoproliferative glomerular nephritis and central nervous system vasculitis vasculitis.[26-29]

In a community-based long-term perspective study (Reveal-HCV) (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer) of hepatitis C positive and negative individuals, the risk of dying from all causes, hepatic diseases and extrahepatic diseases, was significantly higher in anti-HCV seropositive persons with detectable HCV RNA than in anti-HCV seronegative or anti-HCV seropositive patients without detectable HCV RNA.[22] Petta et al. have suggested that hepatitis C virus infection may be a risk factor associated with the presence of carotid plaques and cardiovascular mortality in genotype 1 HCV infection.[30, 31]

4 Health-related quality of life and hepatitis C
Instruments to assess the impact of HCV infection on health and measurement of PROs (health-related quality of life [HRQOL]) are less frequently used to determine priority for treatment than staging of the liver disease. In addition to the impact of the severity of fibrosis on health, these individualized, personalized assessments of the impact of disease may also be pertinent when evaluating appropriate payment for treatment.

Patient reported outcomes are defined as direct reports obtained from patients on their health in the absence of any intervention, amendment or even interpretation of this assessment by clinicians. These reports have provided some understanding of the effects of various treatments and interventions on patient-perceived quality of life with the goal of improving treatment and interventions. They can be considered to be surrogate estimates of the patient's experience of his/her disease and most important his/her treatment.[7, 32-43] Thus, HRQOL instruments allow patients to be questioned about the perceived effect these treatments have on their health and quality of life. They can also be used to calculate quality adjusted life years. The results derived from these measures can be used by health economists to calculate quality adjusted life years (QALYs) to compare treatments in cost-effectiveness models. Regulatory submissions may require PROs data.

Fatigue, depression and cognitive impairment are thought to be associated with chronic hepatitis C and to impair HRQOL. Evaluation of hepatitis C requires not only assessment of liver function and exclusion of other liver diseases but also lifestyle and HRQOL testing, especially in clinical trials.[7, 32-43]

5 Improvement of patient reported outcomes and extrahepatic manifestations with interferon induced SVR
Early on, an SVR was shown to be associated with an improved HRQOL.[44] Patients with an SVR had a statistically significant improvement in their physical and mental scores compared to baseline. Decreased fatigue was observed in hepatitis C positive patients with and SVR to PEG IFN and ribavirin. “Harder” end points have also been determined after a cure of hepatitis C. Arase et al. showed that an SVR reduced the incidence of onset of type II diabetes in chronic hepatitis C or haemorrhagic stroke.[45, 46] Interestingly, there might be an important change in cerebral magnetic resonance spectrometry (MRS) signals in patients with hepatitis C: The MRS signal in basal ganglia and myo-inositol/creatinine ratio was altered in responders after treatment with PEG IFN and ribavirin. Patients with an SVR also demonstrated improvement in verbal learning and visuospatial memory.[47]

It has been suggested that patients who received PEG IFN and ribavirin (and who were matched with untreated controls by propensity scores) had a lower incidence of end-stage renal disease, ischaemic stroke and acute coronary syndrome after receiving antiviral treatment.[48, 49] Single photon emission computed tomography images in hepatitis C patients vary according to virological response. Maruyuma et al. detected myocardial perfusion defects in 87% of patients with chronic hepatitis C that improved after SVR with IFN therapy.[50]

6 Data derived from clinical trials of DAAs
The HCV treatment landscape has markedly altered since 2014 with the introduction of protease, NS5b and NS5a inhibitors. Both clinical trials and real-world data have shown remarkable SVR rates for DAA therapies in treatment-naive and experienced patients with or without cirrhosis across all genotypes. These treatments are well tolerated and lack the toxicity associated with IFN and even with ribavirin, so that simple, safe, highly effective and in some instances ribavirin-free regimens are available. Unfortunately, the addition of ribavirin may be necessary to improve response prevent relapse with some regimens and in treatment-experienced patients with cirrhosis, in particular those with baseline resistance associated substitutions. The need for ribavirin is gradually diminishing as more potent dual and triple regimens become available.

Overall PRO results have suggested that treatment with PEG IFN and ribavirin-free regimens have resulted in improved PROs, but treatment with PEG IFN and ribavirin have tended to worsen during treatment over time, often culminating in a marked nadir at the end of treatment. In addition, ribavirin may also worsen PROs. PEG IFN and ribavirin-free regimens have improved scores for both physical and mental components during treatment. Statistically significant decreases have been observed. DAA regimens overcome the disadvantage of interferon containing compared to interferon-free regimens and treatment is shorter. The typical instruments to determine PROs have included the short form-36 (SF-36), EuroQol five dimensions questionnaire (EQ-5D), short form 6D (SF-6D) Chronic Liver Disease Questionairre-HCV (CLDQ-HCV), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Work Productivity and Activity Impairment Questionnaire scores (WP AI). A full discussion of the patient reported instruments that have been used in chronic hepatitis C is tabled in the systematic review of PROs in hepatitis C by Younossi and Henry.[3] In general, an SVR is associated with an improvement in PRO scores. Fatigue is markedly worsened by PEG IFN and ribavirin, while this side-effect is less severe with interferon-free regimens.

Thus, during treatment health status and health utilities have been shown to improve, especially if ribavirin is not included. Treatment-naive and experienced HCV genotype 1 patients treated with sofosbuvir and ledipasvir with or without ribavirin in the ION trials, showed improvement in the SF-36, FACIT-F, CLD Q-HCV and WP AI scores which measures factors such as bodily pain and physical, emotional and social function, fatigue, work productivity, work activity and work absenteeism. Differences were noted in mean baseline HRQOL and work productivity in patients with and without fibrosis.[1, 5, 37, 51-58]

The overall view that emerges is that treatment with IFN reduces HRQOL, worsening towards the end of treatment, but that HRQOL indices improve after treatment is completed. These indices sometimes exceed baseline levels, especially in patients who achieve an SVR. This may be interpreted as an improvement in the quality of life as a result of clearance of the virus. The results tend to be in agreement and predictable, and also show the greatest improvement in HRQOL indices when interferon-free and particularly IFN and ribavirin-free treatments are compared to IFN and ribavirin treatment.

Other indices may be required such as the Schornberg index, for example, based on age, gender, medical comorbidities and functional status then adjusted for liver disease, and in which a higher baseline may predict mortality in patients with and without cirrhosis.[59]

7 Conclusions and questions
Clinical trials with DAAs have provided an important opportunity to assess PROs without IFN and in some cases without ribavirin, to exclude the confounding effects of these treatments that reduce on-treatment quality of life measurements. Very detailed and comprehensive analyses have been compiled before, during and after treatment. Although the main goal of current treatment is to prevent disease progression, new DAA treatments will also relieve symptoms and improve the well-being of patients with HCV infection, reduce the social stigma associated with the disease, prevent transmission and decrease the burden of hepatitis C in society. Clearance of hepatitis C may have indirect health effects that are not being measured at present. Because of the costs of current therapy, DAA treatment largely targets patients with advanced fibrosis to provide short-term, easily measured outcomes.

Improvements in HRQOL indices are an encouraging aspect of an SVR and show a positive benefit of treatment. Measuring the impact of HCV on health using PRO tools could be used to develop a reformed reimbursement policy that is based on tests of health perception and HRQOL with a rationale of treating patients independently of their stage of hepatic fibrosis. Patients would be treated for the current impact of the disease. Many questions remain: How can this approach be used in times of budgetary restraints? What are the potential biases and weakness of the data? Could HRQOL data be affected in those with a known diagnosis for treatment gain? What are the most appropriate tools? Can the extensive quantitative data be used to obtain reliable statistical analyses across different regimens and in different populations, for example, injecting drug users vs post-liver transplant patients? Does the heterogeneity of studies invalidate the information? How can this information be standardized? Is there a consistency among trials allowing interpretation? Is this clinically important information? Which of the components of these tools is most valuable in evaluating changes in hepatitis C scores that have prognostic value?

The degree of liver disease is a key variable to a reduced quality of life. Prior IFN-based treatment can increase impairment. Are these differences important to help improve access to care and determine the number of patients to be treated? Are the benefits obtained by reducing viraemia rather than by reducing inflammation and to a degree, fibrosis and inflammatory responses in other sites, including the brain? Most important can these findings guide payers and be used to develop recommendations? Can these HRQOL findings be translated into a model showing improved work productivity including measurable outcomes of productivity in the work place and a social dimension that will convince payers of the added value of treatment? SVR is the primary outcome of studies rather than PRO: do these variables add value to high cost drugs?

These studies must be rigorously performed to avoid the risk of bias, and a placebo group is usually necessary. Frequent follow-up clinical visits, the timing of evaluations and other confounding factors including the mode of disease acquisition or concomitant IV drug use could affect the results. Nevertheless, there is convincing evidence of a pattern in patients with persistent HCV infection suggesting that HRQL can be improved by successful antiviral treatment.

Economic health data are now considered to be critical to examine the benefit of interventions in chronic diseases. The healthcare costs of chronic hepatitis C are considerable and could be improved by treating early stage disease, but the results based on patient reported improvements are still frequently insufficient to persuade payers of the value of early treatment.
Conflicts of Interest

Professor Dusheiko currently acts as an advisor to Gilead Sciences, Bristol-Myers Squibb, Janssen and Merck. He has received speaking honoraria from Gilead Sciences, AbbVie, Bristol-Myers Squibb, Merck and Janssen in the past 2 years. He has received grant support from Gilead Sciences, AbbVie, Glaxo Smith Kline, Bristol-Myers Squibb, Janssen and Merck. He has acted as an advisor to the National Institute of Clinical Excellence. He currently serves on the safety monitoring boards for Regulus and Transgene.