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Because HCV is typically considered a primary infection of the liver, its eradication is thought to result in health benefits primarily from improved hepatic outcomes, with most literature supporting reductions in the development of cirrhosis and its complications.1 The paradigm that HCV is a liver disease and mortality is driven by liver-related complications has guided clinical decision-making, and more recently, reimbursement criteria.1,2 However, HCV is actually a multiorgan disease, with evidence of viral replication documented in various human tissues from the bone marrow to the brain, with a variety of direct and indirect extrahepatic manifestations (EHM).3 The clinical consequences and long-term health outcomes related to EHM may have important considerations.
By following a Taiwanese cohort of 1095 anti-HCV (positive) patients and comparing them to a similar cohort of 18,541 anti-HCV (negative) people, Lee and colleagues were able to report and compare mortality data during the period of 1991-2008. Using mortality rates per 100,000 person years, hazard ratios were reported and after multivariable adjustment confirmed that the main drivers of mortality in patients with HCV were hepatic disease (adjusted HR 12.48 [9.34-16.66]) and liver cancer (adjusted HR 21.63, [14.83-31.54]). However, extrahepatic mortality was also increased in this analysis with renal disease (adjusted HR 2.77 ([1.49-5.15)] and circulatory disease (adjusted HR 1.50 [1.10-2.03]), both contributing significantly to mortality. Extrahepatic cancer mortality was also increased, particularly esophageal, prostate, and thyroid cancer. The consequences of both liver and nonliver-related complications of HCV were most notable in those who were viremic, highlighting the importance of active infection on health outcomes rather than risk factors associated with disease acquisition. Cumulative mortality from all extrahepatic disease, as well as specifically from circulatory and renal disease, was significantly increased in patients who remained HCV RNA positive (P < .01).
The power of this study is the very large cohort and relatively long follow-up period (mean 16.2 years). However, the average age of the cohort was relatively young (47.6 years), which may lead to underestimates of the consequences of some extrahepatic manifestations that may have larger impacts at later ages (eg, CVD). Considering this study only included a Taiwanese population, generalizability of the results from this study to other regions of the world may be limited.4
In summary, in this study, renal and cardiovascular disease showed the most significant effects on mortality. Renal mortality may be directly related to HCV as a consequence of symptomatic MC or independent renal disease (rare), or alternatively may be due to indirect effects of HCV such as diabetic renal disease. Similarly, cardiovascular disease may also be mediated by diabetes, or there may be a direct vascular effect related to the chronic inflammatory state.
Overall, these findings not only confirm the importance of HCV infection in increasing liver-related mortality but also provide evidence that extrahepatic manifestations can have significant impact on mortality in patients with HCV.
References:
- Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a systematic review. JAMA. 2014 Aug 13;312(6):631-640.
- Chhatwal J, He T, Lopez-Olivo MA. Systematic Review of Modelling Approaches for the Cost Effectiveness of Hepatitis C Treatment with Direct-Acting Antivirals. Pharmacoeconomics. 2016 Jun;34(6):551-567.3. Cacoub P, Comarmond C, Domont F, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016 Feb;3(1):3-14.
- GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117-171.
Article: Lee MH, Yang HI, Lu SN, et al; R.E.V.E.A.L.- HCV Study Group. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012 Aug 15;206(4):469-477.
Source: eViralHepatitis Review, Vol 4, Issue 13: http://eviralhepatitisreview.org/newsletters/2016/volume04_issue13.pdf