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HCV Resistance Testing
How I Use Resistance Testing to Guide Management of Patients With Chronic Hepatitis C

Released: September 15, 2015

Expiration: September 13, 2016

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Recently, I have begun to hear many questions from colleagues and trainees regarding the use of resistance testing in the management of HCV-infected patients. To be honest, my answers to their questions are not always straightforward, as this is a rapidly evolving area of discussion in the field and I am confident that my opinion will evolve along with the data.

When Resistance Testing Is Recommended
That said, the AASLD/IDSA guidance has now highlighted at least one patient population for whom resistance testing with commercially available assays can be used to guide treatment decisions: Persons for whom treatment is urgent and previous treatment with NS5A inhibitors has failed to achieve cure. This would include previous exposure to such regimens as ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, and daclatasvir plus sofosbuvir. We know from follow-up data of patients treated in clinical trials that resistance associated variants (RAVs) against any of the available DAAs are likely to be detected upon on-treatment virologic breakthrough or posttreatment relapse with the exception of the nucleotide analogue NS5B inhibitor sofosbuvir. More importantly, we know that variants that are associated with resistance to NS5A inhibitors, including ledipasvir, ombitasvir, and daclatasvir, are likely to be stable and detectable for as long as 2 years after treatment.

Based on these data, updated AASLD/IDSA guidance recommends that, if treatment is urgent, patients who are not cured after receiving an NS5A inhibitor should undergo testing for the presence of resistance associated variants in the NS5A region and NS3 region (selected by protease inhibitors which target NS3, such as paritaprevir and simeprevir). Per the guidance, such patients who have no NS5A RAVs can be treated with 24 weeks of ledipasvir/sofosbuvir and ribavirin, those with NS5A RAVs but no NS3 RAVs can be treated with 24 weeks of simeprevir plus sofosbuvir and ribavirin, and those with both RAVs should be treated in clinical trial settings only.

The utility of testing for RAVs in the NS5B polymerase region is much less clear. Resistance to nucleotide analogues that target the NS5B active site (ie, sofosbuvir) is rare, and data indicate that retreatment with sofosbuvir-containing regimens is feasible in patients for whom a previous sofosbuvir-containing treatment has failed. Given the rarity of resistance to the NS5B active site, resistance testing is not routinely recommended. Currently, dasabuvir is the only other NS5B inhibitor available; however, it is a nonnucleoside inhibitor that targets domains of the NS5B polymerase distinct from sofosbuvir. Dasabuvir is used only with the NS5A inhibitor ombitasvir and the protease inhibitor paritaprevir, against which RAVs are more common. Thus, the results of NS5B inhibitor resistance testing would be unlikely to change the treatment decision.

Utilizing Resistance Testing in Practice: A Case Example
Of course, recommendations are only helpful if they can be applied to the care of real patients in clinical practice. A recent patient from my clinic is one such example. The case patient was a 54-year-old man with genotype 1a HCV infection and compensated cirrhosis who had a null response to treatment with peginterferon/ribavirin years before the availability of DAAs. He was subsequently treated with ledipasvir/sofosbuvir and ribavirin for 12 weeks and had an outstanding initial drop in HCV RNA. However, he unfortunately experienced relapse after stopping therapy. HCV drug resistance testing revealed a mutation in the NS5A region at position 93 (Y93H) that confers decreased susceptibility to ledipasvir (and ombitasvir and daclatasvir). However, testing of the NS3 protease domain revealed no Q80K mutation, suggesting that simeprevir would be active in this patient.

Case Treatment Decision
Based on the presence of an NS5A RAV but absence of NS3 RAVs, we elected to retreat this patient with sofosbuvir and simeprevir plus ribavirin for 24 weeks.

Why 24 weeks? Because longer therapy appears to decrease the risk of HCV relapse in patients with cirrhosis.

Why add ribavirin? Because ribavirin appears to decrease the emergence of HCV variants resistant to the DAAs in this regimen.

Can we anticipate insurance challenges? Based on this being the recommended approach in national guidelines, I expect insurance would cover this regimen for our patient.

Upcoming Discussions on Resistance Testing
To discuss the latest data on resistance to DAAs and the implications for therapy, Nezam H. Afdhal, MD, FRCPI; Jordan J. Feld, MD, MPH; Norah Terrault, MD, MPH; and I will each host upcoming live Webinars. I hope you will join us for one of these events, which feature a live question and answer session. We are especially interested in hearing what questions you might want addressed. Please let us know by leaving a comment below.

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