Editorial: direct-acting antivirals significantly improve quality of life in patients with HCV

Aliment Pharmacol Ther.

INVITED EDITORIALS

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection 
Authors S. Sanagapalli, M. Danta

First published: 17 January 2018
DOI: 10.1111/apt.14467

Abstract
Linked Content
This article is linked to Younossi et al and Younossi papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14481.

The effect of direct-acting antiviral chronic Hepatitis C (HCV) therapies on patients’ quality of life has been a topic of minor attention compared with their impressive effects on virological endpoints. Yet, therapeutic benefits on quality of life are important to patients, and knowledge regarding such benefits may be an important tool in improving compliance in real-world scenarios.[1] For this reason, Younossi and colleagues are to be commended for their study, which describes clinically significant improvements in almost all measured physical and mental health-related quality of life outcomes following therapy with sofosbuvir and velpatasvir with or without voxilaprevir.[2] This replicates findings from other direct-acting antiviral regimens, but also confirms our own observations from clinical experience using these drugs.

Comparison with quality of life data from the interferon era may help us to tease out the mechanisms behind these findings. First, impairments in both mental and physical aspects of quality of life have long been described in chronic HCV, with or without cirrhosis, using the SF-36, one of the four instruments used in this study.[3] Second, very similar improvements in quality of life parameters were described 24 weeks after completion of interferon-based therapy, with the benefit confined only to those with sustained virological response.[4] More recent data comparing interferon-containing to interferon-free regimens clearly demonstrates that while both regimens result in equivalent improvements in quality of life (in responders) post therapy, the interferon-containing treatments are associated with significant worsening of quality of life during therapy. In contrast, quality of life seems to be improved early during interferon-free therapy and improves further following completion of successful treatment.[5, 6] Taken cumulatively we can infer that virological clearance plays a key role in improvement of quality of life, but cannot be the only factor, since improvement continues long after the virus has completely cleared from the serum.

What might such other factors be? The authors propose that improvement of liver function may play a role, though this still fails to explain the persistent improvement in benefit in non-cirrhotics post therapy. On the other hand, cerebral inflammation due to chronic HCV may explain some of the findings. Magnetic resonance spectroscopy and positron emission tomography scanning have demonstrated significant metabolic abnormalities in the brains of noncirrhotics with HCV, implying a low-grade inflammatory state, with the microglial cells being a focus of activation.[7, 8] In a small study, Byrnes and colleagues demonstrated that successful treatment with pegylated interferon and ribavirin led to normalisation of these central nervous system metabolic changes. Crucially, however, normalisation occurred gradually and improvement in metabolic abnormalities continued until 12 weeks post therapy, implying that the neuroinflammatory process may take time to settle after HCV therapy.[9] While the underlying mechanisms for improved quality of life are of interest, this study adds to the weight of evidence for the overall benefits of direct-acting antiviral therapies for HCV.

http://onlinelibrary.wiley.com/doi/10.1111/apt.14467/full

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection—Author's reply
Z. M. Younossi

First published: 17 January 2018
DOI: 10.1111/apt.14481

Abstract
Linked Content
This article is linked to Younossi et al and Sanagapalli and Danta papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14467.

We appreciate the Editorial comments by Drs. Sanagapalli and Danta about our recent study reporting patient-reported outcomes in patients with hepatitis C virus infection who were treated with sofosbuvir (SOF), velpatasvir (VEL) with or without voxilaprevir (VOX).[1, 2] We agree with their comments and would like to emphasise the importance of these findings in the context of the “comprehensive benefit” of HCV cure.

To fully understand the comprehensive benefit of HCV treatment, we believe it is important to assess the comprehensive impact of HCV infection including all the pertinent clinical consequences (hepatic and extrahepatic manifestations of HCV infection), the impact on patient-reported outcomes (health-related quality of life or HRQL) and the economic burden of HCV (resource utilisation and cost of illness).[3] Similarly, the benefit of anti-HCV treatment must be assessed in this comprehensive manner.[3] The most clinically relevant endpoint of HCV treatment is achieving sustained virologic response (SVR), a surrogate of improving survival by reducing the hepatic and extrahepatic complications.[3] Another important endpoint of HCV treatment should be its positive impact on patient-reported outcomes, a surrogate of HCV patients' experience.[4] Finally, we must assess the impact of anti-HCV treatment on important economic outcomes (resource utilisation, cost of illness, cost-effectiveness of treatment) must also be assessed.[5] Although the total impact of HCV infection has been well established,[3, 6] the comprehensive benefit of “HCV cure” has only recently been recognised.[1-6] In this context, our study provides additional evidence that the new regimen of SOF/VEL+/-VOX not only has superior clinical outcomes (high SVR) but also improves patient-reported outcomes during treatment and after SVR.[2]

In their Editorial, the authors have reflected about the mechanism of patient-reported outcome improvement post-SVR-12; we agree that this improvement is partly related to viral eradication. It is plausible that the additional patient-reported benefits of SVR may be related to the amelioration of the inflammatory environment of chronic hepatitis, which takes longer to resolve. This “inflammatory milieu” of HCV infection may exert its influence on the brain or the periphery of the infected patients. In fact, HCV has been associated with a number of extrahepatic manifestations such as neuropsychiatric diseases, chronic fatigue and others.[7, 8] In this context, neurocognition, fatigue and their changes after SVR may be differentially affected which in turn can influence changes in patient-reported outcome scores.[7, 8] In fact, the impact of SVR on fatigue has been recently substantiated and the data have shown that while most patients with HCV improve fatigue scores post-SVR, some do not improve.[9] Furthermore, these subjects who continue to report disabling fatigue post-SVR seem to have significant comorbidities such as depression, anxiety, type 2 diabetes.[9] Nevertheless, in the majority of HCV subjects with SVR, fatigue continues to improve and seems to maximise by post-treatment week 48.[10]

In summary, we believe that the initial patient-reported outcome improvements are due to viral eradication. The subsequent improvement may be due to a number of post-SVR changes including improvement of the inflammatory milieu and its impact of HCV on the brain and other extrahepatic targets. In contrast, patients with HCV who continue to show residual patient-reported outcome impairments post-SVR seem to have other comorbidities, which will require other treatment modalities to optimise their well-being. In this context, we believe that patient-reported outcomes must be a routine part of assessment of any chronic liver disease. These assessments will complement the clinical outcomes and provide evidence for the comprehensive impact of treatment on the patients and the society.

http://onlinelibrary.wiley.com/doi/10.1111/apt.14481/full