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The Impact of NAFLD on Chronic HCV Progression, Treatment Response

Issue: May 2015

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Nonalcoholic fatty liver disease is the most common form of liver disease in North America, affecting an estimated 30% of the population. It is widely considered to be the hepatic manifestation of metabolic syndrome.

Dina Halegoua-De Marzio

Metabolic syndrome is the presence of at least three of these five key symptoms: obesity, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure or elevated fasting glucose. The clinical spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis, which puts patients at risk for hepatic decompensation and hepatocellular carcinoma (Figure).

The prevalence of metabolic syndrome is rising in the general population. This is thought to be due to obesity, one of the major characteristics of metabolic syndrome, becoming increasingly prevalent. Commonly, though, patients infected with chronic hepatitis C virus also have NAFLD. It is estimated that 1.3%, or 3.2 million people are infected with HCV. It has been hypothesized that HCV increases a patient’s risk to develop metabolic syndrome. With those 3 million people infected with HCV in the United States, it may be a contributor to the high prevalence of metabolic syndrome in the overall population.

HCV and Metabolic Syndrome

Studies have shown that HCV may directly influence glucose metabolism, increase the risk for diabetes and predispose patients to obesity. Beyond the metabolic factors, patients with chronic HCV and insulin resistance may have higher viral loads based on retrospective studies.

The proposed mechanism for HCV-related insulin resistance and diabetes include direct pancreatic beta-cell injury, autoimmune beta-cell injury and the formation of hepatic steatosis. A comparison of HCV patients with and without NAFLD found that the prevalence of obesity was significantly higher among patients with NAFLD and HCV compared with patients with HCV alone. In total, 90% of the population with HCV and NAFLD have metabolic syndrome vs. 35% of patients with HCV alone. It is possible that HCV elicits some of the characteristic metabolic abnormalities associated with metabolic syndrome.

Together, HCV and NAFLD place patients at a significant risk for accelerated liver damage and complications of metabolic syndrome including heart disease and cancer. In all, approximately 50% of patients with HCV have hepatic steatosis, but this appears to vary based on HCV genotype. Several studies have shown an increased risk for hepatic steatosis with genotype 3 infection. Steatosis also is independently associated with increased hepatic fibrosis. Of note, steatosis appears to be reversible among patients infected with HCV treatment who achieve sustained virologic response.

Metabolic Syndrome and Treatment Response

Beyond the effect of metabolic syndrome on fibrosis progression, obesity and insulin resistance have been identified as independent variables for poor response to HCV treatment. A number of mechanisms have been proposed as reasons for a decreased SVR among patients with metabolic syndrome. The combination of HCV and NASH leads to more fibrosis, which is a known factor negatively affecting SVR. Additionally, truncal obesity also is directly associated with an increased production of proinflammatory adipocytokines, which attenuate the biological response to interferon-based regimens. Increased adipose tissue also simply lowers interferon bioavailability.

Fortunately, we are now facing a new dawn for HCV treatment with highly effective direct-acting antivirals. The landscape of treatment for HCV infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies in 2011. The pace of change is expected to increase rapidly, as numerous new drugs with different mechanisms of action will likely become available in the next few years.

In light of the new treatments available, the Infectious Diseases Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA, have released online guidelines (hcvguidelines.org), with frequent updates, to cover information on when to begin therapy and in which patients with HCV infection. The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, due to availability and cost, priority should be given to those with the most urgent need. Recently, for example, HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi, Gilead Sciences) has emerged as an important component of currently recommended regimens due to its suppression of HCV replication.

Based on these guidelines, one group that should be given priority is those patients at high risk for liver-related complications, which includes those patients with both NALFD and HCV. Due to the presence of so many new therapies for HCV, it remains unclear if metabolic syndrome will lead to a lower rate of SVR with DAAs, as it did with interferon-based regimens. The best data we currently have is from the Neutrino study published in The New England Journal of Medicine in May 2013 using a sofosbuvir-based treatment regimen and revealing a similar SVR rates in obese and nonobese patients (Table).

Summary

HCV, NAFLD and metabolic syndrome often coexist in the same patient. Attention must be paid not only to optimizing and expediting the antiviral response but also to screening for and the treatment of metabolic derangements. Newly available, interferon-free based DAAs allow us the ability to successfully treat HCV-infected patients and, hopefully, improve their overall health, beyond the liver. In a time when DAAs are rationed secondary to cost, we should prioritize the treatment in those with NAFLD and HCV. However, after successful treatment of HCV, many patients will be left with metabolic syndrome and NAFLD, both of which should be monitored.