Hepatitis C: New Direct-Acting Antivirals Expand Primary Care Physicians’ Role

An expanding arsenal of interferon-free, direct-acting antiviral (DAA) medications has transformed the treatment of chronic hepatitis C virus (HCV) infection. DAAs are simpler to use, easier to tolerate and much more effective than interferon and ribavirin in achieving virologic cure.

Gone are the days when specialists alone managed HCV antiviral treatment, according to Nizar Zein, MD, Chief of Hepatology, Mikati Foundation Chair in Liver Diseases, and Chair of Global Patient Services at Cleveland Clinic. “DAA medications offer primary care physicians a wider role in managing this chronic disease,” he says.

An often silent epidemic

Approximately 2.2 to 3.2 million people in the United States are chronically infected with HCV. Adding prison, homeless and active military populations to that estimate increases the total to 5.2 million. Chronic HCV is usually asymptomatic, with an estimated one-half of individuals being unaware of their infection.

Untreated HCV may lead to complications, including progression to liver cirrhosis (in approximately 20 percent of patients after 20 years), hepatocellular carcinoma, and liver failure requiring liver transplantation. Annual deaths related to chronic HCV likely exceed the 20,000 recorded on death certificates, according to the Centers for Disease Control and Prevention.

Primary care workup

For the largest group cohort of HCV-infected individuals in the United States — the 75 percent born between 1945 and 1965 — the CDC recommends one-time screening with an FDA-approved anti-HCV antibody test. This protocol is expected to identify 487,000 people with chronic HCV in the next 10 years, with many diagnoses by primary care practitioners.

“The next important assessment is to confirm any positive anti-HCV antibody test with HCV RNA testing. This ensures the presence of viremia, as opposed to just antibodies from exposure,” says Dr. Zein.

If both tests are positive, order a hepatitis C genotype assessment and tests for HIV, hepatitis A and hepatitis B, he advises. “Vaccinate individuals without evidence of antibodies from previous exposure to hepatitis A or hepatitis B infections,” says Dr. Zein.

Cirrhosis evaluation

For baseline assessments of liver damage associated with HCV infection, a liver biopsy — with its risks of pain, bleeding and (rarely) death — is no longer routine. Newer, noninvasive tests are sufficient for approximately 60 percent of patients, according to Dr. Zein.

Direct serum biomarker tests offer computed measures of liver scarring that correspond to the METAVIR staging system. The fastest option — transient elastography (FibroScan®) — uses ultrasound to determine the extent of fibrosis. The operator places a handheld probe in the intercostal space near the liver’s right lobe, and the velocity of returning shear waves is converted into a liver stiffness measurement. The device was FDA-approved in 2013 and is available at Cleveland Clinic.

Elastography accurately distinguishes minimal (little or no) scarring and maximal (severe scarring/cirrhosis) liver damage. However, like the biomarker tests, it is less sensitive in differentiating fibrosis between those two extremes, according to Dr. Zein.

“Either a biomarker test or elastography will be sufficient in evaluations performed to exclude cirrhosis and determine the frequency of follow-up or the urgency of treatment. If there is any uncertainty about the diagnosis or a need to know the specific stage of liver fibrosis, then a liver biopsy remains the gold standard,” he explains.

Triaging patients for treatment

American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America guidelines call for antiviral therapy for nearly everyone with chronic HCV infection. Even so, the high cost of medications can limit physicians’ ability to treat this disease in its early stages. “The issue is that no country, including the United States, can afford to treat everyone immediately,” Dr. Zein says.

Given this reality, AASLD guidelines give treatment priority to HCV patients at high risk for liver-related complications, including evidence of advanced fibrosis (METAVIR stage F3) or compensated cirrhosis (stage F4), a history of liver transplant, or severe extrahepatic conditions.

Insurance companies usually require physicians to submit a fibrosis assessment with treatment plans. “Even if we decide someone could benefit from therapy now, the insurance company could deny it based on their own criteria. A significant amount of work goes into appealing and trying to justify treatment,” Dr. Zein says.

Treatment and monitoring

When a treatment plan is approved, DAA drug use is highly defined. “Some primary care physicians will follow treatment guidelines and familiarize themselves with three or four oral regimens that are given for three or six months. Others ask us to assume complete care of the patient during DAA therapy,” Dr. Zein adds. A patient with cirrhosis who achieves virologic cure will continue to require monitoring for liver cancer, perhaps for life.

Monitoring also is necessary while patients wait months or years for treatment plans to be approved. For individuals with cirrhosis, Dr. Zein recommends liver function tests and ultrasound monitoring every six months, with periodic upper GI endoscopy for varicose veins. For individuals with very early liver fibrosis and no complications, annual monitoring with liver function tests would be sufficient.

Dr. Zein remains optimistic about the impact of DAA treatments, despite their limited availability. “Some predictive models indicate we can eradicate hepatitis C in the United States in the next 22 years. We could achieve that goal even sooner if treatment becomes less costly and screening is expanded. In that case, we will rely on extensive participation of primary care physicians in managing these patients,” he says.