Hepatitis C Virus – Identifying and Managing Resistance Associated Variants

Gish, Robert, MD
Robert G. Gish Consultants, LLC Also by this Author 

The introduction of direct-acting antiviral agents (DAAs) has transformed hepatitis C virus (HCV) treatment over the last 18 months. While the majority treated are effectively cured after a regimen of typically 12 weeks, there is a significant minority who are either ineligible for certain DAA treatments, or who fail initial DAA treatment, due to drug resistance.

Dr. Robert Gish, Principal, Robert G. Gish Consultants, reviews the nature of DAA drug resistance herein, its manifestation in different genotypes and the implications for patient management once drug resistance is identified.

HCV in the United States – An Epidemic on Two Levels

There is now widespread awareness of the overall HCV epidemic in the United States.1 “It was estimated that in 2013 over 5 million were infected with HCV but about 500,000 have since been treated with DAAs,”1 says Dr. Gish. “The scale of the problem has led to an ‘epidemic of awareness’ relating to HCV,” says Dr. Gish, “ but at the same time there is another ‘mini-epidemic’ occurring due to the outbreak of IV drug use, and associated use of dirty needles, caused by changes in the laws for obtaining pain medications such as Oxycontin and other narcotics. So, while dealing with the overall challenge of widespread HCV infection, we are now having to deal with the new cases caused by this phenomenon.”

Standard of Care

Guidelines recommend that those undergoing HCV testing should first be tested for HCV antibody.2,3 A positive result is followed by a nucleic acid test (NAT) such as quantitative PCR for HCV RNA to confirm active infection.2,3  “Ideally a reactive antibody result will reflex to the HCV RNA test,” says Dr. Gish. “If NAT testing is positive, then ideally genotype and sub-type testing should be performed. If genotype 1a is identified, then resistance testing should be considered, especially if you are considering Zepatier use,” he continues, noting that resistance testing may be useful in other settings with other DAAs. “The patient must be simultaneously staged for the severity of liver disease, their HCV treatment history is verified and their viral load is measured.” Guidelines recommend that treatment is initiated for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy or a patient who will not be compliant with therapy.4

Baseline Resistance

“There are two types of resistance in a quantitative sense,” notes Dr. Gish. “One type is where there is resistance at baseline, which is linked to two types of polymorphisms. One of them may be programmed into the specific genotype at a certain prevalence like the Q80K in genotype 1a, which is resistant to simeprevir. The other resistance associated variants (RAVs) are more sporadic. They have no specific prevalence in the population but can also set up resistance to compounds such as protease inhibitors or NS5A inhibitors. Such an RAV is referred to in the package insert for the compound grazoprevir and elbasvir (ZepatierTM)5, as well as ledipasvir/sofosbuvir (Harvoni®).6  These are resistance mutations that occur randomly at a certain frequency decreasing the response rate to elbasvir to the point that one needs to add ribavirin or extend therapy or both to maximize the chance of cure.”

Emergent Resistant Mutations

“The second type of resistance is caused by emergent resistant mutations that take place during treatment,” continues Dr. Gish. “Some patients, who appear to have cleared infection based on blood tests, then relapse are typically due to some form of viral resistance. This can occur with protease inhibitors, NS5A inhibitors or the NS5B polymerase inhibitors.” If treatment fails due to the occurrence of these resistant mutations re-treatment becomes more complicated. “The best option is to choose a “new” therapy that covers the RAP/RAVs that were treatment emergent. You may also have to extend treatment, and can choose to re-treat with the same drug and ribavirin for longer periods, if ribavirin was not used originally. When we change the drug combination that we’re treating with and add ribavirin to the second treatment course and often use sofosbuvir.”

“To determine the treatment regimen, once resistance is identified, it’s important to know the specific variant with each amino acid change specified,” says Dr. Gish. “There are different amino acid changes identified by a letter, that can take place with each variant position that is noted by a number, which imply different levels of resistance to different drugs such as Y93H. So the approach becomes quite sophisticated at this point. To help in the process some laboratories are now starting not only to identify resistance mutations but also to provide information on the expected relative response to different medications.”

Identifying Resistance

“For patients with genotype 1 the laboratory automatically reports the sub-type -1a or 1b,” explains Dr. Gish. “If it’s 1a and treatment with Zepatieris being considered, resistance testing should be performed.5 One recent advance is that some laboratories, such as Quest Diagnostics, offer testing that can automatically perform resistance testing for all genotype 1a patients. The test will automatically reflex to resistance testing if genotype 1a is identified, so the provider does not need to place another order when they receive the result.”

“In the package insert for Harvoni, which is the other treatment option for genotype 1a, there is no recommendation for resistance testing,” continues Dr. Gish. It’s clear from the data, however, that resistance in patients with genotype 1a who are cirrhotic and treatment experienced has a significant impact on the rate of sustained virologic response (SVR).6 It can cut the cure rate by about 10% points, which means a reduction from 96% to 86% cure. So, while resistance testing for genotype 1a is recommended when intending to treat with Zepatier, it is also helpful with Harvoni in special settings.”6

With the other genotypes there is no baseline resistance testing. Resistance testing is only performed when patients fail treatment. “If a patient fails treatment the physician will need to assess the response, the treatment regimen and the resistance profile,” notes Dr. Gish. “They also need to review the interpretation about relative resistance to different drugs. The process becomes quite complicated at this point because there are very subtle changes in the point mutations, relating to the amino acid substitutions that have taken place and their effect on sensitivity to different drugs.”

Rates of Resistance

“In genotype 2 the treatment failure rate is about 5%,”7 notes Dr. Gish. “That’s low, but when you’re treating thousands and thousands of patients the numbers can become significant - resistance in the NS5b region may explain some of these failures. With genotype type 3 treatment failures range 10% to 15% and that’s obviously a significant number of patients.7 Studies have shown that with genotype 1 the treatment failure rate tends to run 3% to 5%7 and in real world settings around 10%.8 Overall there is about a 10% failure rate of DAAs and nearly all those patients have resistance. With about 500,000 patients treated over the last 18 months1 this means around 40,000 patients might be facing testing and then complex re-treatment options.”



  1. HCV Epidemiology in the United States. Hepatitis C Online. http://www.hepatitisc.uw.edu/pdf/screening-diagnosis/epidemiology-us/core-concept/all. Accessed March 24, 2016.
  2. Testing for HCV Infection: An Update of Guidance for Clinicians and Laboratorians. Centers for Disease Control and Prevention. MMWR / May 7, 2013 / Vol. 62
  3. AASLD-IDSA. HCV Testing and Linkage to Care. Recommendations for testing, managing, and treating hepatitis C.  http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care . Accessed on March 2, 2016.
  4. AASLD-IDSA. When and In Whom to Initiate HCV Therapy. Recommendations for testing, managing, and treating hepatitis C.http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy . Accessed on March 2, 2016.
  5. Prescribing Information for Zepatier. Merck Sharp & Dohme Corp., a subsidiary of Merck &                            Co.Inc.  https://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf. Accessed March 2, 2016.
  6. Prescribing Information for Harvoni. Gilead Sciences, Inc.  http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed on March 2, 2016.
  7. AASLD-IDSA. HCV Testing and Linkage to Care. Recommendations for testing, managing, and treating hepatitis C. Initial treatment of HCV infection. http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection.  Accessed on April 6, 2016.
  8. Treating hepatitis C in Veterans Affairs (VA): early experience with Sofosbuvir-based regimens. VA Office of Public Health/Population Health and VA Pharmacy Benefits Management Services. October 31, 2014.  http://www.hepatitis.va.gov/pdf/white-paper-sofosbuvir-regimens.pdf

Zepatier is a trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 

Harvoni is a trademark of Gilead Sciences, Inc