Value anti–hepatitis C virus therapy by its clinical efficacy
Authors: Adriaan J. van der Meer
Journal: Hepatology (2015)

Potential conflict of interest: Dr. van der Meer consults for and is on the speakers' bureau for Gilead. He is on the speakers' bureau for MSD. See Article on Page 355 Sustained virological response (SVR) is considered to be the primary marker of successful therapy for chronic hepatitis C virus (HCV) infection. Over the last three decades, the continuous efforts to optimize interferon (IFN)‐based treatment regimens resulted in a gradual increase in SVR rate. However, it was only with the development of direct‐acting antivirals (DAAs) that anti‐HCV therapy really gained momentum. Short‐term regimens with various combinations of these DAAs proved to induce SVR in approximately 95% of patients, with only limited influence of baseline patient characteristics. As a bonus, these highly effective drugs do not seem to be hampered by substantial side effects. The catch? The costs! However, rather than to attain SVR, antiviral therapy (AVT) aims to improve quality of life, reduce the incidence of serious clinical complications and, above all, prolong overall survival. Especially in light of the discussion on treatment costs, reimbursement, and availability, it is thus essential to evaluate the clinical impact of AVT. However, adequate randomized, placebo‐controlled trials on solid clinical endpoints have never been performed. The field has moved forward nonetheless as the important drug developments came in parallel with the results of large cohort studies, which linked SVR to a beneficial clinical outcome. Today, trial protocols in which patients are submitted to long‐term follow‐up after being dosed with a placebo are no longer opportune. Alternative approaches to assess the clinical efficacy of AVT are thus needed. An important aspect of this scientific challenge is to further characterize and understand the association between SVR and clinical outcome. As the title of the report by Innes et al. in the current issue of Hepatology already indicates, their study does just that.1 In their article, the researchers describe the results of a nation‐wide cohort study from Scotland, which is expected to include over 80% of all chronic HCV‐infected patients who underwent IFN‐based therapy between 1996 and 2011. In total, 3,385 patients with various stages of hepatic fibrosis (HF) were followed for a median duration of 5.3 years. Importantly, this study confirms the association between SVR and reduced all‐cause mortality, as the most definite clinical endpoint, which was independent from many potential confounders (adjusted hazard ratio [aHR]: 0.49; P < 0.001). As one would expect, there was a reduced risk of severe liver morbidity and, consequently, liver‐related mortality among those with SVR. This is not new. The novelty of the current study is in the potential benefits of successful AVT outside of the liver and their possible contribution to prolonged overall survival. Indeed, Innes et al. show that the risk of non‐liver‐related mortality was approximately 1.5‐fold lower in the case of SVR, which remained statistically significant in multivariate analysis (P < 0.026). Thus far, this has only been observed among patients with an HCV and human immunodeficiency virus coinfection, a specific subgroup with a substantially more progressive natural history.2 We are shown that the lower rate of liver‐unrelated death post‐SVR may be attributable to a reduced risk of cardiovascular disease, which is indeed a well‐known extrahepatic manifestation of chronic HCV infection.3 This recent finding from Taiwan is now immediately confirmed in a large cohort from Europe (aHR, 0.70; P < 0.001), where the incidence of cardiovascular events is higher. Other biologically plausible extrahepatic benefits of successful AVT that may contribute to the reduced non‐liver‐related mortality include the lower incidence in renal failure and malignant lymphomas.3 Innes et al. describe that SVR was also independently associated with a reduced risk of hospitalization because of acute alcohol intoxication (aHR, 0.52; P = 0.003) or because of violence‐induced injuries (aHR, 0.51; P = 0.002), which suggests a favorable lifestyle after successful therapy. Improved health behavior could very well reduce the risk of both liver‐related and non‐liver‐related mortality. In line with these data, Omland et al. previously showed a lower incidence of unnatural deaths among patients with a cleared HCV infection (either spontaneous or treatment induced), as compared to patients with chronic HCV infection.5 To explain the association between SVR and improved health behavior, the researchers propose the psychological Hawthorne and Epiphany effect and subsequently warn us that these phenomena may be less influential in case SVR is (too) easily attained by the IFN‐free regimens with little to no side effects. Although this hypothesis seems reasonable, it cannot be excluded that (neuro)physiological improvements upon HCV eradication have a positive impact on the patient's lifestyle as well.6 Patients with SVR were found to be less fatigued and had an improved health‐related quality of life (HRQoL), which should make it easier to sustain healthy behavior.7 Fortunately, there is no specific reason to presume that such effects would not be preserved in the case of DAA‐induced SVR. Another aim of the current study was to assess the absolute risk reductions (ARRs) associated with SVR, which are insightful and did not receive much attention thus far. As shown, the overall ARRs were rather low, which puts the potential benefits as well as the costs of AVT into perspective. However, it should be realized that ARRs are highly dependent on the characteristics of the assessed population: The more complications that occur, the more that can be prevented. We recently showed this among patients with advanced liver disease by estimating the number needed to treat (NNT) to prevent one death within 5 years (an absolute clinical efficacy measure that takes both the ARR with SVR and the SVR rate into account) for the individual patient.9 Our analyses indicated that, despite the presence of cirrhosis and 95% SVR, the NNT with IFN‐free therapy remained quite high for a substantial number of patients in whom 5‐year mortality risk was low. Of course, risk of clinical complications is even lower, if not negligible, among patients with mild liver disease, and this limits the direct clinical impact of AVT within this favorable population. Moreover, in the stratified analyses according to liver disease severity presented here, the relative risk reductions with SVR among those with mild HF were rather low and not statistically significant. Therefore, because we cannot afford to treat all patients with IFN‐free therapy at this time, the data by Innes et al. support the prioritization of patients with advanced liver disease. These patients simply have the highest health risks and seem to experience the most solid clinical benefits of SVR. Still, limiting the availability of DAAs should be regarded as a necessary evil, which is only required because of our limited resources or, rather, the high costs of these new drugs. Indeed, patients with mild liver disease should also be treated as soon as possible. Especially now that the side effects of AVT have largely diminished, there are not many medical arguments to withhold them from attaining SVR. Eradicating HCV infection can improve HRQoL, reduce the extent of HF, and prevent cirrhosis. Postponing effective AVT until patients show evidence of advanced HF would also be careless given that SVR does not free patients from cirrhosis‐related complications at that stage. However, as the current study again exemplifies, it remains difficult to capture the direct impact of successful AVT on solid clinical endpoint among those without advanced HF. Because not all patients are prone to develop the complications of their HCV infection, the average clinical efficacy of AVT is indeed likely to be more limited among those with mild disease. The current data could thus make one question the high costs of the DAAs and whether these costs are reasonable for the majority of the HCV‐infected population. In the end, even though we have gotten used to evaluate AVT by its virological efficacy, we should focus on the clinical efficacy to properly value it.