Understanding HCV and evolving treatment guidelines

Feb. 20, 2018

Hepatitis C virus (HCV) infection can lead to cirrhosis and its related complications, hepatocellular carcinoma (HCC), liver failure and death. Once one of the leading indications for liver transplantation, HCV frequently goes undetected, mainly because it can take decades for symptoms to appear. In an article recently published in Gastroenterology and Hepatology, Mayo Clinic author Hugo E. Vargas, M.D., and co-author Jennifer L. Horsley-Silva, M.D., provided a comprehensive overview about HCV infection and treatment. Dr. Vargas addresses some of these issues in the questions and answers that follow.

How common is HCV?

According to the World Health Organization, 130 million to 150 million people worldwide are infected with HCV, and this population is expected to increase by an average of 3 million to 4 million cases annually.

What challenges are associated with HCV?

Recent estimates suggest that 3.2 million Americans have chronic HCV infection, yet only 50 percent of patients infected with HCV are aware of their viral status, and only 7 to 11 percent of those patients receive treatment. Additionally, researchers believe that by 2020, the burden of cirrhosis due to HCV infection could reach 37.2 percent of infected patients.

What principles guide the most recent treatment guidelines?

The central premise is that HCV infection is curable and all HCV-infected patients should receive treatment. Patients who will derive the most immediate benefit from treatment include those with cirrhosis, those who are still HCV positive after transplantation, those with HIV coinfection, and those with extrahepatic manifestations of HCV infection. Providers should make every effort to identify and treat patients with a high risk of transmitting the disease to the community, including active intravenous drug users. The only patients for whom treatment is not recommended are those with a life expectancy of one year or less.

How do direct-acting antiviral (DAA) agents work against the HCV virus, and how has their introduction impacted HCV treatment and patient outcomes?

Direct-acting antiviral agents attack specific targets within the HCV replication cycle. These agents block virus replication and induce eventual eradication of the virus through immune cellular clearance of infected cells. While these agents are very potent, they are subject to potential viral resistance to their effect. Treatment regimens that combine two or three agents that work on different viral targets, increasing treatment duration and adding ribavirin to the treatment regimen are some of the strategies deployed to decrease the likelihood of selecting resistant strains.

Now that several classes of antiviral medications are available, what advice can you provide about their use?

Guide for HCV treatment
Guide for HCV treatment

The experience to date with these drugs demonstrated few contraindications to treating patients infected with HCV. Understanding the classes of drugs and treatment regimens available and expected results can facilitate high rates of response to treatment. Appropriate treatment can now be selected based upon genotype, clinical situation, contraindication and drug-drug interactions. The drug class and optimal regimens tables included here provide details about available medications and updated specific treatment regimens for genotypes 1 through 6.

Classes of drugs to treat HCV

  • Nonstructural 3/4A protease inhibitors. Protease inhibitors block NS3/4A serine protease, inhibiting functional viral proteins from being created.
  • Nonstructural 5A complex inhibitors. Although the exact antiviral action of NS5A inhibitors is unclear, they are thought to cause faulty HCV assembly by inhibiting hyperphosphorylation of the NS5A protein and altering the protein's location from the endoplasmic reticulum.
  • Nonstructural 5B polymerase inhibitors. There are two distinct classes of these drugs: nucleos(t)ide inhibitors and nonnucleoside inhibitors. Nucleos(t)ide inhibitors are analogues that are incorporated into the viral RNA genome by RNA-dependent RNA polymerase (RdRp). This causes termination of further replication and competitively binds the active polymerase site. This class of NS5B polymerase inhibitors has a high barrier to resistance and works broadly against genotypes with intermediate potency. On the other hand, nonnucleoside inhibitors are small molecules that inhibit the RdRp by binding an allosteric site in a noncompetitive fashion, which changes the biochemical activity of the polymerase.

What new challenges lie ahead?

Advancing physician determination to the diagnosis of HCV is most important. As more data on the tolerability and effectiveness of DAA agents emerge, we must direct our efforts toward identifying more patients with active infection and finding ways to help patients manage the costs of these medications. If we continue to diagnose these patients at the pace we did in years past, these new medications are likely to have a much smaller impact than we desire.

For more information

Horsley-Silva JL, et al. New therapies for hepatitis C virus infection. Gastroenterology & Hepatology. 2017;13:22.