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Statements of Disclosure of Relevant Financial Relationships have been obtained from Paul Kwo, MD. Dr. Kwo has disclosed that he has received honoraria and grant support from Merck, Vertex, Bristol-Myers Squibb, Abbott, Gilead, Janssen, GlaxoSmithKline, and Novartis.
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After reading this article, the reader should be able to:
- Identify the segment of the US population with the highest incidence of chronic hepatitis C virus (HCV) infection.
- Describe the current standard of care for chronic HCV infection according to genotype.
- Determine which patients with chronic HCV infection require immediate treatment and those in whom therapy can be safely postponed.
- Discuss how the treatment of chronic HCV infection is expected to change in 2014 and beyond.
- Summarize the screening recommendations for chronic HCV infection issued by the Centers for Disease Control and Prevention.
Date of original release: October 2013
Date of expiration: October 2014
Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.
Overview of HCV in the United States
Approximately four million people in the United States—or nearly two percent of the population—are infected with HCV (Figure 1), of whom about 70 percent are undiagnosed. The vast majority of individuals with HCV are baby boomers who acquired the infection between 1960 and 1980, primarily as a result of intravenous drug use or through transfusions of tainted blood and blood products (see CDC Recommendations for Identifying People With Chronic HCV Infection). Fifteen to 40 percent of people infected with HCV fully recover from acute infection, while the remaining 60 percent become chronic carriers. Chronic HCV infection is a major cause of cirrhosis, hepatocellular carcinoma, and end-stage liver disease, and it is the leading indication for liver transplantation. Between 5,000 to 10,000 deaths are attributed to HCV annually, and in 2007, the number of HCV-related deaths surpassed that of HIV for the first time.1
Once advanced fibrosis develops in a patient with chronic HCV infection, the rate of liver-related disease progression is high. Each year, an estimated 10 percent of those with bridging fibrosis progress to cirrhosis, and five percent of patients with cirrhosis die or undergo liver transplantation.2
“The current standard of care for patients with genotype 1 infection, which accounts for more than 70 percent of all US cases of chronic HCV infection, is 24 to 48 weeks of peginterferon alfa-2a (PegIFN) plus ribavirin (RBV) together with 12 to 44 weeks of an oral protease inhibitor that directly inhibits viral replication,” reports Paul Kwo, MD, staff physician with IU Health Physicians Digestive & Liver Disorders, and professor of medicine and medical director of liver transplantation at Indiana University School of Medicine. “Because patients with genotype 2 or 3 infection have a significantly better sustained viral response (SVR)* to dual-therapy with peginterferon and ribavirin than do those with genotype 1 infection (≥80 percent SVR vs 40 to 50 percent SVR, respectively), patients with genotype 2 or 3 infection do not currently require the addition of a direct-acting antiviral agent.”3
Using a triple-drug combination of weekly subcutaneous injections of PegIFN plus oral RBV and a protease inhibitor (i.e., boceprevir or telaprevir), about 63 to 75 percent of patients with genotype 1 infection who have had no previous treatment achieve a SVR (Figure 2). Treatment can be arduous with interferon-based therapies, however, and is associated with significant adverse reactions. Flu-like symptoms, depression, fatigue, and cytopenias may occur with PegIFN; anemia, neutropenia, and dysgeusia are linked to boceprevir; and anemia, rash and anorectal discomfort are the most common side effects of telaprevir. Drug-drug interactions should be addressed with the currently available protease inhibitors, and their concomitant use with a number of medications, including certain statins, antidepressants, anticonvulsants, analgesics, and sedatives, is contraindicated or requires dose adjustment. Furthermore, while the protease inhibitors boceprevir and telaprevir dramatically improve SVR, if a sustained response is not achieved, a similar pattern of drug resistant mutations will emerge, meaning that if resistance-associated variants emerge when one agent is used, the other agent will also be ineffective.
*Defined as undetectable HCV RNA in serum 12 weeks after treatment has been stopped. This end point is predictive of long-term virus eradication and correlates with a reduction in symptoms and the rate of negative clinical outcomes.
Fortunately, better tolerated, more efficacious HCV drugs are on the horizon, some of which are expected to become clinically available in early 2014 (Figure 3).
“We are in a transition era where a cure will soon be possible for most people with chronic HCV infection using treatment regimens that are simpler, shorter in duration, and better tolerated,” Dr. Kwo states. “Thus, the question confronting physicians today is whether to treat patients immediately or to postpone therapy until these new drugs become available.
“Patients with advanced fibrosis should be evaluated for treatment,* as they are at the highest risk for disease progression, and the benefits of a sustained virologic response—lower rates of hepatic decompensation, amelioration of symptoms, and a reduction in the risk of liver-related death—with current drug therapy have been firmly established,” Dr. Kwo continues. “For previously untreated patients with milder HCV, on the other hand, the disease progresses slowly, and treatment can be safely deferred.”
*Ishak fibrosis score 4, 5, or 6 on liver biopsy.
A 57-year-old white male with chronic hepatitis C virus (HCV) infection presents at Indiana University Health to discuss treatment options. His past medical history includes type 2 diabetes mellitus (recent HbA1C = 8.1 percent), depression, and hyperlipidemia. Diabetes is controlled with diet; current medications are escitalopram and atorvastatin. He has never been treated for HCV disease, his HCV genotype is 1b, and a liver biopsy shows bridging fibrosis (stage 3).
Direct-Acting Antiviral Therapies in Clinical Development
At least a dozen second-generation protease inhibitors are in phase 2 to 3 development. Investigational agents (e.g., faldaprevir and simeprevir) need to be taken just once a day, in contrast to the thrice-daily schedule for boceprevir and telaprevir, and have an improved safety profile. In addition, two classes of non-structural (NS) 5B polymerase inhibitors—nucleoside inhibitors (chain
terminators) and non-nucleoside inhibitors (allosteric inhibitors)—and NS5A inhibitors are being tested in clinical trials (Table 1). Among all of these direct-acting antiviral agents, Dr. Kwo says two will likely be approved in early 2014: 1) the protease inhibitor simeprevir, available for use in combination with PegIFN and RBV for genotype 1, and 2) the nucleoside inhibitor sofosbuvir, initially approved for use in patients with genotypes 2 and 3 infection in combination with RBV in an all-oral regimen and in combination with PegIFN and RBV for genotype 1.
In a phase 3 trial, 499 previously untreated patients with HCV genotype 2 or 3 infection with or without cirrhosis were randomly assigned to 12 weeks of sofosbuvir plus RBV or 24 weeks of PegIFN plus RBV.4 Overall, 67 percent of patients in both groups achieved a SVR, with this percentage higher for those with genotype 2 infection (97 percent) compared with genotype 3 infection (56 percent). Adverse events, including fatigue, headache, nausea, and neutropenia, were less common with sofosbuvir than with PegIFN.
Two other randomized phase 3 trials evaluated sofosbuvir plus RBV in 479 patients with chronic HCV genotype 2 or 3 infection with or without cirrhosis who could not take PegIFN or had previously failed PegIFN treatment.5 After 12 weeks of treatment, the SVR was 78 percent among patients for whom treatment with PegIFN was not an option. In previously treated patients, response rates were 50 percent and 73 percent for 12 weeks and 16 weeks of treatment, respectively.
Sofosbuvir was also studied in an open-label study that enrolled 35 patients with HCV genotype 1 infection without cirrhosis—25 treatment-naïve patients and 10 patients who had no response to prior therapy.6 An all-oral regimen was used consisting of sofosbuvir plus RBV alone or in combination with ledipasvir, a NS5A inhibitor, or GS-9669, a non-nucleoside inhibitor. After 12 weeks of treatment, the virus was successfully eradicated in 100 percent of the patients in all three study arms, and the SVR 12 weeks after the completion of treatment ranged from 84 to 100 percent for previously untreated patients (Table 2).
While simeprevir and sofosbuvir will be the first new drugs to be approved and marketed, others will follow within the next couple of years.
A triple-drug, interferon-free investigational regimen has yielded very favorable results in a phase 2 trial in patients with HCV genotype 1 infection without cirrhosis.7 Twelve weeks of combination treatment with the protease inhibitor ABT-450, the NS5A inhibitor ABT-267, and the non-nucleoside NS5B protease inhibitor ABT-333 plus RBV achieved SVR rates of up to 99 percent in untreated patients and up to 98 percent in patients who had failed previous treatment.
“Combining drugs with different targets of action is expected to have an additive or synergistic antiviral effect while reducing the likelihood of antiviral resistance. The challenge is to identify the right combination of drugs with the highest potency and barrier to resistance together with the best side effect profile,” Dr. Kwo points out. “What that final regimen will be remains to be determined, and it is likely that multiple regimens will give excellent results. Nonetheless, accumulating evidence suggests that interferon-free oral regimens of approximately 12 weeks duration will achieve sustained virologic response rates exceeding 90 percent in HCV patients without cirrhosis.”
Case Study (cont.)
The patient was presented with three treatment options: 1) begin treatment immediately with PegIFN, RBV, and boceprevir or telaprevir in the expectation of a 65 to 70 percent likelihood of a SVR after six to 12 months of therapy; 2) postpone treatment until new drugs become available in early 2014 and undergo close monitoring of liver status in the interim; 3) participate in a clinical trial of an investigational HCV regimen through IU Health. The patient chose the third option and is enrolled in a phase 2 study of combination therapy with different classes of direct-acting antiviral agents.
CDC Recommendations for Identifying People With Chronic HCV Infection
Although baby boomers (persons born from 1945 to 1965) comprise about one-quarter of the US population, they account for 75 percent of all HCV infections, 73 percent of HCV-associated mortality, and have the highest risk for hepatocellular carcinoma and other HCV-related liver disease. With the availability of therapies that can halt disease progression and provide a virologic cure in most persons, targeted testing and care for infected persons in this birth cohort is expected to reduce HCV-related morbidity and mortality. Consequently, the Centers for Disease Control and Prevention (CDC) is recommending one-time testing for all individuals in this population. Anyone identified as having HCV infection should then receive a brief screening for alcohol use and intervention as clinically indicated followed by referral for appropriate care for HCV infection and related conditions.
Additionally, the CDC recommends routine HCV testing for:
- Anyone who has ever injected illegal drugs
- Persons with selected medical conditions, including those
- Who received clotting factor concentrates produced before 1987
- With persistently abnormal alanine aminotransferase levels
- Who were ever on long-term hemodialysis
- Recipients of transfusions or organ transplants prior to 1992
- Healthcare, emergency, medical, and public safety workers after needle sticks or mucosal exposures to HCV-positive blood
- Children born to HCV-positive women
HCV is inefficiently transmitted through sexual activity. However the prevalence of HCV antibodies among persons who report having had ≥20 sex partners is 4.5 times greater than that of the general population.
Dr. Kwo received his medical degree from Wayne State University School of Medicine in Detroit, MI, did a medical residency at the University of Maryland/Baltimore V.A. Hospitals, and completed a fellowship in gastroenterology/hepatology at the Mayo Clinic in Rochester, MN. His clinical research interests include HCV and hepatocellular carcinoma, and he is currently an investigator for more than 20 active clinical trials.
Dr. Kwo is certified by the American Board of Internal Medicine, the Gastroenterology American Board of Internal Medicine, and the Transplant Hepatology CAQ American Board of Internal Medicine. A reviewer for several professional publications, Dr. Kwo is the author of more than 90 medical journal articles and textbook chapters and teaches and lectures extensively in the United States and abroad.
In 2010, Dr. Kwo was named Outstanding Teacher, Gastroenterology/Hepatology Division at the IU School of Medicine, and in 2011, he received the IUSM Trustee Teaching Award.
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