The Ongoing Debate of Who to Treat for Chronic Hepatitis C Virus

Chronic hepatitis C virus (HCV) infection accounts for approximately 30% of cases of cirrhosis and one-quarter of hepatocellular carcinomas worldwide and is the leading indication for liver transplant in the adult US population.1Although the incidenceof chronicHCV infection is declining in the United States, the number of deaths is projected to rise over the next decade because of complications among persons infected 30 to 40 years ago.2 Hence, the major reasons for treating chronic HCV infection are to mitigate the morbidity and mortality associated with the infection, alleviate patient symptoms, and prevent person-toperson transmission. Successful eradicationorvirological cure is possible, anda reduction in liver-relatedoutcomeshasbeen demonstrated in patients with advanced liver disease who achieve this desirable end point.3 Despite these facts, only 7% to 11% of US patients are treated according to an analysis conducted by the Division of Viral Hepatitis at the Centers for Disease Control and Prevention of 2 large data sets containing more than 18 000 individuals.4 This is partly because treatment of chronic HCV infection has been challenging for both the patient and clinician. Available regimenswere complex to administer, of long duration, were associated with substantial toxic effects, and weremoderately effective in that only approximately 50% of patients with the most common genotype of the virus-HCV genotype 1 responded.Patientshad tobe carefully selected for therapy. Only those with more advanced liver disease based on liver biopsy findings andhad a reasonable likelihood of responding to treatment,with limited comorbid conditions and who could be expected to tolerate treatment, were recommended for therapy. All others, particularly those with mild disease, were advised to be followed up, perhaps with a repeated liverbiopsyevery5years, to reassess theneed for treatment. Consequently, many infected individuals were ineligible to receive therapyowing tocontraindicationsor if treated, had to prematurely discontinue therapy because of intolerance, or optednot to receive therapy, preferring towait for the promise of safer, more effective treatment. The other reason for the low treatment ratewas related to our understanding of the natural history of chronic HCV infection. Liver disease is thought to progress slowly in themajority of patients, particularly if certain factors that can accelerate fibrosis progression are absent such as older age at infection, male sex, heavy alcohol consumption, obesity, insulin resistance, and coinfection with human immunodeficiencyvirusorhepatitisBvirus.5-7 It is estimated that approximately 25% of individuals will progress to cirrhosis or decompensated liver disease over a period of 25 to 30 years.5 Therefore, treating a patient early in the course of their diseasewould expose them to unnecessary toxicity and complications from treatmentwith unproven benefit on outcome of their liver disease. In this issue of JAMA Internal Medicine, Butt and colleagues8 report rather provocative results from an analysis of a Department of Veterans Affairs database, which suggests that after infection with HCV, patients may experience amore rapidprogressionof liver fibrosis and accelerated time to development of cirrhosis than previously thought. However, once cirrhosis develops, the disease appears to stabilize, and the development of hepatic decompensation in the first 10 years is infrequent. Does this mean that we should change our approach to treatment and recommend therapy for patients earlier in the course of their disease? Before addressing this question, we need to revisit the current state of therapy. Therapyof chronic HCV infection is at awatershedmoment.Multiple oral agents have been developed that specifically target key viral proteins necessary for the viral lifecycle and tested in different combinations for variable durations ranging from 12 to 24 weeks.9-11 These new regimens are highly effective and increase the response rate from approximately 50% to greater than 90%. More importantly, these new treatment regimens havebecomemuch simpler to administer, safer, andmore tolerable with minimal adverse effects. So given these interestingdata onnatural history coupled with the prospect for more effective and safer therapies, effectively removing many of the previous barriers to therapy, onemaymake a strong argument for treating everyone. Why delay therapy when we are unsure how best to monitor untreated patients and we are unsure which patients will rapidly advance toend-stagedisease thatmayadversely affect future response rates and increase the riskof complications from the disease? In response, there are several epidemiological studies indicating thatmost individualswithHCVwill diewith rather than from their infection.12 Furthermore, evidence of the benefits of treating patients with mild disease is lacking, and the new impediment to treatment is now the cost of therapy.The recently approvedoral agents sofosbuvir, anHCV polymerase inhibitor, costs $84 000 dollars for a 12-week course, equating to approximately $1000.00 per pill,13 and simeprevir, an HCV protease inhibitor, costs $66 000 for 12 weeks or approximately $786.00 per pill.14 The price of these Related article page 178 Opinion