Successes and Challenges on the Road to Cure Hepatitis C

Hepatitis C virus (HCV) represents a significant health burden worldwide, with an estimated 185 million people chronically infected [1]. A leading cause of liver transplantation, HCV infection can result in severe liver disease including cirrhosis and hepatocellular carcinoma [2]. Cure of HCV infection results in substantial decreases in such liver-related morbidity and mortality [3]. Prior therapies for HCV offered only 40% cure for the most difficult-to-treat genotype-1 infection, required 48 weeks of therapy with an injectable interferon, and included significant adverse events [4]. The past year has seen the approval of five interferon-free direct-acting antiviral (DAA) regimens for HCV, including combinations of DAAs and fixed-dose combination pills (Tables ​(Tables11 and ​and2)2) [5–13]. Sustained virologic response (SVR), the virologic surrogate for clinical cure, has improved to >90% for most populations across all HCV genotypes (Table 2). While the successes attributable to DAA combination therapies will be many, there also remain challenges and much for us to learn as we embark on this journey to eradicate HCV. Here, we will discuss several of the greatest successes and future challenges in HCV therapeutics today. Table 1 All-oral direct acting antiviral regimens available for clinical use. Table 2 Sustained virologic response for all-oral direct acting antiviral regimens. Potent DAA Combinations Are Closing the Gap for Unique Patient Populations Although all patients with HCV infection will benefit from the availability of oral DAA combination therapies, several unique patient populations have seen dramatic improvements in SVR, revealing the great clinical impact of these therapies. Specifically, patients with HIV/HCV dual infection, patients with compensated and decompensated cirrhosis, and patients who have had liver transplantation for HCV-associated liver disease are exhibiting fantastic (87%–98%) SVR rates with oral DAA combination therapy [14–16]. These patients, who have a greater risk of progression of liver disease, hepatocellular carcinoma, and death, previously had low response rates or even absolute contraindications to treatments with interferon [17–18]. The potential impact of HCV eradication for these highest-risk populations could be enormous, including decreases in hepatocellular carcinoma and liver transplantation, as well as prolonged survival for those already living with liver grafts. And yet, we do not know for sure how this story ends. While the liver has the ability to repair injured tissue [19] and there is evidence to suggest that fibrosis induced by chronic HCV infection is reversible [3], is there a point of no return? Previously, patients with HCV-associated decompensated liver disease (ascites, hepatic encephalopathy, and variceal bleeding) had only one choice for survival: organ transplantation. Is viral eradication enough to change their fate? The largest study to date in patients with decompensated cirrhosis reported SVR of nearly 90% with a DAA combination regimen [15]. Importantly, the study also reported on improvement in serum markers of synthetic liver function for a majority (>50%) of patients at post-treatment week 4. Whether these improvements translate to improved clinical outcomes over time remains to be seen, but there is reason for optimism.