Direct acting antivirals for patients without advanced liver disease: All for treatment and treatment for all?
Authors: Marina Serper
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE 827 The recent advent of all‐oral direct‐acting antivirals (DAAs) has revolutionized the treatment of hepatitis C virus (HCV). Although access to HCV treatment has been improving in the United States (attributed to increased competition, negotiated lower drug prices, and evolving payer policies), considerable barriers to linkage to care remain for many such as those on Medicaid, the uninsured, and incarcerated patients.1 Though payer policies are highly variable, restrictions based on the prescribing provider, psychosocial comorbidities, and degree of fibrosis persist, and the past authorization process can be burdensome for many practitioners. Traditionally, fibrosis‐based HCV coverage restrictions stem from the fact that HCV is characterized as a slowly progressive disease with a low annual fibrosis rate. However, estimates come from retrospective studies with heterogeneous populations and can range widely, whereas the effects of HCV on chronic inflammation and health‐related quality of life are not considered. Among patients with advanced fibrosis (AF), previous data have consistently shown the long‐term benefits of viral eradication in decreasing liver‐related mortality, decompensation, and hepatocellular carcinoma (HCC), both for interferon (IFN)‐based and all‐oral DAA regimens.2 However, the impact of DAA therapy on clinical outcomes in the absence of advanced liver disease has not yet been well characterized. In the current issue of Hepatology, Dr. Backus et al. examine an important and understudied issue of the impact of DAA therapy on all‐cause mortality in HCV‐infected patients receiving care in the U.S. Department of Veterans Affairs (VA).4 As the largest integrated health care system in the United States and the largest provider of HCV care nationally, the VA has prioritized HCV screening and eradication, treating nearly 100,000 veterans with sustained virological response (SVR) rates above 90%.5 The researchers report on outcomes among 40,664 of these HCV monoinfected veterans who were engaged in VA care and had no apparent evidence of advanced liver disease (defined either the absence of cirrhosis or liver decompensation diagnosis codes, including HCC and history of liver transplantation, or fibrosis 4 [FIB‐4] scores of <3.25). Of this cohort, nearly 97% of the treated patients with available data achieved SVR, and their outcomes were compared to the other 3% of non‐SVR patients as well as 62,882 DAA unexposed patients without apparent AF. Impressively, around 90% of eligible patients had end‐of‐treatment data available, underscoring the success of this single integrated system of care for maintaining patient follow‐up. In this cohort without advanced liver disease, SVR was associated with a 59% unadjusted all‐cause mortality reduction when compared to no‐SVR, and a 69% reduction compared to no treatment when calculated in deaths per 100 person‐years. In absolute terms, 1‐year mortality rates were reduced by 1.3% with SVR compared to no‐SVR and by 2.9% with SVR compared to no treatment. The benefit was noted across genotypes, and though the mortality benefit was attenuated among veterans with the lowest fibrosis scores (FIB‐4 <1.45), it was still highly clinically significant. In adjusted models, SVR was associated with a 56% reduction in mortality compared to no‐SVR and a 65% reduction when compared to no DAA treatment. By providing data from a large, population‐based cohort, the study significantly adds to our understanding of the effects of SVR in the DAA era in the absence of AF. Taking the current results in context, the researchers' previous work in a VA cohort during the IFN treatment era showed a 30%‐49% all‐cause mortality reduction associated with SVR.6 When comparing the all‐cause mortality benefit of DAAs in this study to recently published data in patients with AF, the benefits, though less sizeable, are still highly clinically significant.2 At first glance, the mortality benefit of SVR after just 1.2 years of follow‐up and in the absence of fibrosis could appear confounded. However, DAA‐treated patients had more comorbid conditions and were more likely to have baseline diabetes, chronic obstructive pulmonary disease, hypertension, and alcohol abuse than untreated patients. The researchers also evaluated whether survival differences may have been attributed to differences in access to medical care. Interestingly, all the patient subgroups (SVR, no‐SVR, and untreated) had similar access to providers with a median of three primary care office visits in the year preceding cohort entry, suggesting that engagement with the health care system could not entirely explain the differences in mortality. A possible mechanism of the short‐term mortality benefit may be the decrease in chronic inflammation associated with viral eradication. A sizeable body of literature has noted HCV's role in inducing proinflammatory mediators in the liver and extrahepatic sites.7 Increased levels of interleukin (IL)‐1β, tumor necrosis factor alpha (TNF‐α), and transforming growth factor beta have, as well as altered proinflammatory/anti‐inflammatory cytokine ratios (TNF‐α/IL10 and IL‐6/IL‐10), been shown to be associated with fibrosis progression and HCC. In addition to the well‐described extrahepatic inflammatory conditions, such as cryoglobulinemia, B‐cell lymphoproliferative neoplasms, and autoimmune diseases, chronic HCV has been shown to increase oxidative stress and be associated with hepatic steatosis and insulin resistance. The interaction between chronic HCV, diabetes, and metabolic syndrome is associated with accelerated fibrosis progression, hepatic decompensation, and HCC. Further supporting the role of chronic inflammation, HCV‐infected individuals have higher levels of proinflammatory markers, such as erythrocyte sedimentation rate, C‐reactive protein, and fibrinogen, and are at higher‐than‐expected risk of cardiovascular disease when compared to non‐HCV‐infected controls. Though not the focus of the main analyses, in a multivariable model, the researchers showed that both DAA treatment with SVR (hazard ratio [HR], 0.32) and DAA treatment without SVR (HR, 0.74) compared to no treatment were associated with a mortality benefit. Although speculative at this stage, the step‐wise relationship suggests that DAA therapy may be beneficial by decreasing inflammation even in the absence of SVR. A recent study showed a high burden of HCV‐associated extrahepatic diseases (EHDs) and a decrease in all‐cause medical costs post‐SVR, which was largely attributed to decreased EHD‐related spending.8 It is therefore possible that the survival benefit noted in the current study was partially mediated through diminished chronic inflammation. Unfortunately, VA data do not include cause of death, making it difficult to draw definitive conclusions of the myriad pathophysiological mechanisms of DAAs benefits. As such, evaluation of whether DAA‐associated mortality improvements may be attributed to decreased cardiovascular events or related to other etiologies is highly needed in future studies. Another important finding not specifically emphasized in this study was the notable improved SVR‐associated survival in females compared to males (HR, 0.55) and in blacks compared to whites (HR, 0.74). The specific mechanisms of sex‐ and race‐based differences in outcomes post‐HCV eradication merit further investigation. Finally, beyond mortality, the effects of long‐term viral eradication with DAAs on neuropsychiatric symptoms, health‐related quality of life, overall productivity, and health care costs have yet to be well elucidated. An important consideration is the generalizability of these results to non‐VA populations in the United States and worldwide. Broadly speaking, HCV‐infected veterans are slightly older that nonveterans and expectedly predominantly male; however, there are insufficient data to compare the prevalence of metabolic comorbidities and other EHDs to non‐VA populations, making it difficult to more broadly estimate potential SVR benefits in the absence of fibrosis. It is also possible that veterans treated for HCV in an integrated health care system received more preventative, mental health, and addiction services than the general population at large and therefore derived additional clinical benefits with DAA treatment. Although the specific causal mechanisms of DAA treatment and SVR in improving overall survival are not yet established, the researchers' findings have important public health implications. The results of this study make a strong case for early identification, linkage to care, and treatment of HCV‐infected individuals, irrespective of fibrosis stage, and provide the hepatology community with the much needed ammunition to advocate for our patients' best interests.