Expanded benefits of curing the extrahepatic manifestations of HCV infection

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Article

Reference

Expanded benefits of curing the extrahepatic manifestations of HCV infection

NEGRO, Francesco

NEGRO, Francesco. Expanded benefits of curing the extrahepatic manifestations of HCV infection. Gut , 2018, vol. 67, no. 11, p. 1917-1919

DOI : 10.1136/gutjnl-2018-316578 PMID : 29871969

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1917 Lemoine M, Tillmann HL. Gut November 2018 Vol 67 No 11

Commentary

Expanded benefits of curing the extrahepatic manifestations of HCV infection

Francesco Negro

HCV infection is a major global health threat. HCV is estimated to

infect ~71.1 million persons worldwide and to cause approximately 400 000 deaths annually.¹ Although HCV-related mortality is reportedly due to the end-stage complications of chronic hepatitis C (decompensated cirrhosis and

hepatocellular carcinoma), the above offi- cial figures do not take into consideration the mortality attributable to the multifac- eted extrahepatic disorders caused by this pathogen.^{2 3} The list of such extrahepatic manifestations (EHM) is long and includes—but is not limited to—the cryoglobulinaemia-associated syndrome (char- acterised by fatigue, arthralgia, skin vasculitis, glomerulonephritis and cereb- ritis, among others), some subtypes of non-Hodgkin’s B cell lymphoma, insulin resistance (which may progress to type 2 diabetes and its cardiovascular sequelae) and various neurological conditions, such as cognitive dysfunction. The causal link Correspondence to Professor Francesco Negro,

Divisions of Clinical Pathology and of Gastroenterology and Hepatology, University Hospital, Geneva 1211, Switzerland; francesco. negro@ hcuge. ch

copyright. on October 4, 2019 at Bibliotheque Faculte Medecine Geneve. Protected byhttp://gut.bmj.com/Gut: first published as 10.1136/gutjnl-2018-316578 on 5 June 2018. Downloaded from

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Commentary

between most of these EHM and HCV infection has been established, thanks to a wealth of epidemiological and clinical data, and especially based on the repeated observation that treatment-induced viral clearance is associated with clinical improvement.² Their pathogenesis encom- passes direct and indirect mechanisms, and may involve autoimmune reactions.

Incidentally, for the latter reason, some EHMs have been for long time considered a contraindication to interferon (IFN)-α therapy. The recent advent of safe, well-tolerated direct acting antivirals (DAA) will allow treating all of these disorders, and the broaden use of DAA will expand our understanding of the purported causal link between HCV and some EHM for which IFN-α-based therapy was problematic.

In Gut, Cacoub and collaborators⁴ report a systematic review—supported by a rigorous assessment of data quality—of published articles evaluating the effect of treatment-induced viral clearance on HCV-associated EHM.

Based on published evidence, a sustained virological response (SVR) was found to be associated with an ~50% reduction in HCV-related extrahepatic mortality. In addition, SVR-induced complete remis- sion of selected EHM was proven for cryoglobulinaemia vasculitis while an increased objective response was also observed in patients with malignant B cell lymphoproliferative diseases, thus confirming another recent meta-analysis on this specific, ominous association.⁵ Finally, SVR led to a decreased level of insulin resistance and a reduced risk of incident diabetes.

This meta-analysis provides substan- tial evidence in favour of the causal link between HCV and some EHM. In addition, it raises some clinically relevant points that merit discussion and warrant further work.

First, the authors rightly emphasise the fact that the strength of evidence supporting the benefits of SVR is often hindered by the lack of randomisation of patients and by the heterogeneity of case definitions, notably in the case of fatigue scoring. For some EHM, such as sicca syndrome and cognitive dysfunction, no data could be analysed. For others, such as cardiovascular outcomes, the data were still too limited, although it must be mentioned that the same author has recently contributed another important work supporting the importance of SVR in reducing the incidence of major adverse cardiovascular events.⁶ On the other hand, the exceptionally

high rate of SVR and the short-term follow-up intrinsic of DAA-based trials are additional hurdles to the feasibility of meta-analyses assessing the risk of EHM in non-SVR patients. Thus, one must concur with the authors that in spite of the large amount of published evidence there is need of better quality data gath- ered over longer periods of follow-up to assess the genuine impact of antiviral therapy on some HCV-associated EHM.

Second, in line with international recommendations,⁷ this work implies the importance of carefully investi- gating symptoms and signs suggestive of EHM in all HCV-infected persons, irrespectively of the severity of under- lying liver damage, since the clinical benefits afforded by DAA in potentially lethal disorders can hardly be overstated.

There is also growing evidence that antiviral treatment should be started earlier rather than later, since the benefit of viral clearance on the risk of severe extrahepatic damage—such as cryoglobulinaemia-associated glomerulonephritis, B cell lymphoma and vascular disorders—may decrease with time.⁸ The same seems to apply to glucose metabolic alterations.

A large study from Taiwan has shown that in order to significantly reduce the risk of post-SVR untoward events (such as the development of hepatocellular carcinoma), antiviral treatment should start before diabetes and even impaired glucose tolerance occurs, including in 589 patients with F0 to F2 fibrosis stages.⁹

Finally, although the economic aspects of EHM were not analysed, the article has the undisputed merit of indirectly raising the awareness about the health burden of HCV-associated EHM at a time when DAAs are still the focus of heated debate regarding their price and acces- sibility. The costs of untreated HCV are significant, although most studies have been focusing only on direct costs associated with the management of HCV-associated liver disease, that is, excluding indirect costs related to loss of produc- tivity, which are estimated to be at least twofold the direct ones.¹⁰ More impor- tantly, the costs related to the management of EHM³—and the indirect costs thereof—have so far not been included in cost-effectiveness analyses. Should this be the case, it is easy to assume that the incremental cost-effectiveness ratio would fall well below the affordability threshold, even when treating every patient with costly DAA-based regimens.

This scenario would be even more likely when considering the societal return on

investment, for which proxies are diffi- cult to monetise (eg, extrafinancial values like self-esteem, stigma, social relation- ships, negative and positive externalities, and surpluses) but that would undoubt- edly expand the long-term economic benefits of universal treatment. Thus, to recognise in full the health and economic impact of hepatic and extrahepatic diseases due to HCV (and the expected benefits associated with viral clearance) would prove a formidable leverage to implement serious strategy plans to reach the WHO goals of eliminating HCV as a public health threat by the next decade.¹ Contributors FN wrote the entire manuscript.

Competing interests The corresponding author has received research grant from Gilead Sciences, and is advising Merck, Gilead and AbbVie.

Patient consent Not required.

Provenance and peer review Commissioned;

internally peer reviewed.

To cite Negro F. Gut 2018;67:1917–1919.

Received 10 May 2018 Revised 15 March 2018 Accepted 11 May 2018 Published Online First 5 June 2018

►http:// dx. doi. org/ 10. 1136/ gutjnl- 2018- 316234 Gut 2018;67:1917–1919.

doi:10.1136/gutjnl-2018-316578

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en/

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Electronic address: easloffice@ easloffice. eu European Association for the Study of the Liver. EASL

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Commentary

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