Non-responders to interferon-free therapy
Non-response to DAA treatment can be defined simply by detectable serum HCV RNA after treatment. Non-response to a first-line DAA regimen can be due to true virological failure (virological break-through during DAA therapy, or virological relapse after treatment in a patient who achieved complete virological suppression during treatment), non-virological failure due to non-adherence, or HCV reinfection. True virological failure is attributable to the emergence of HCV variants that have selected RASs. It is more common in people with cirrhosis, especially advanced cirrhosis, as well as in those with Gt 3 HCV infection.
For people who do not respond to IFN-free DAA therapy, details of the first treatment course should be documented. A careful history should be taken to identify treatment adherence, as well as other factors that may have had limited adherence (social factors, adverse events or possible drug–drug interactions that may have led to inadvertent underdosing). Risk factors for reinfection should be explored. Clinicians should carefully assess for the presence of cirrhosis, which may not have been diagnosed before the first treatment course. People with cirrhosis should be referred to a specialist centre with experience in treating HCV infection (including salvage therapy) and advanced liver disease. Differentiating true virological failure from relapse caused by non-adherence, or from reinfection, may be difficult. True virological failure can be defined by HCV resistance testing; this is useful but, in practice, is not widely available, is not reimbursed and is unlikely to change management. HCV genotyping should be repeated, as a genotype switch indicates reinfection. However, the absence of a genotype switch does not exclude HCV reinfection.
In the setting of a confident diagnosis of HCV reinfection, we recommend treatment as for people who are treatment-naive. Otherwise, we recommend treatment for virological failure as described below.