Global prevalence of pre-existing HCV variants resistant to direct-acting antiviral agents (DAAs): mining the GenBank HCV genome data
Direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) proteins open a whole new era for anti-HCV therapy, but DAA resistance associated variants (RAVs) could jeopardize the effectiveness of DAAs. We reported the global prevalence of DAA RAVs using published GenBank data. 58.7% of sequences (854/1455) harbored at least one dominant resistance variant and the highest RAV frequency occurred in Asia (74.1%), followed by Africa (71.9%), America (53.5%) and Europe (51.4%). The highest RAV frequency was observed in genotype (GT) 6 sequences (99%), followed by GT2 (87.9%), GT4 (85.5%), GT1a (56%), GT3 (50.0%) and GT1b (34.3%). Furthermore, 40.0% and 29.6% of sequences were detected RAVs of non-structural (NS) 5A inhibitors and NS3 protease inhibitors, respectively. However, RAVs to NS5B nucleo(t)ide inhibitor (NI) and NI-based combinations were uncommon (<4% of sequences). As expected, combinations of multiple RAVs to the IFN-free regimens recommended by current guidelines were rarely detected (0.2%–2.0%). Our results showed that the overall global prevalence of DAA RAVs was high irrespective of geography or genotype. However, the NI-based multi-DAA regimens had a low RAV prevalence, suggesting that these regimens are the most promising strategies for cure of the long-term HCV infection.
It doesn't appear that specialists here in Oz are checking for any of these RAV's before writing out scripts for standard Genotype specific DAA treatment. I have read many times that testing for certain strains of RAV's are recommended prior to treatment, as obviously this would factor into duration and combination alterations.
Perhaps the wording should be changed from 'recommended'' to 'required'?
Requiring HCV drug resistance testing prior to initial therapy is not currently advised. Dr. Freeman recently linked a study that covered some of the reasons - nicely summed up in the last paragraph below.
There are many conditions for broad use of HCV resistance tests in clinical practice.
First, a standardized assay should be available as a purchasable kit, externally validated for its performance, and easy to use routinely in any virology laboratory with experience in molecular biology. Whatever the technology used, the assay should reliably report the presence of RASs with a validated and repeatable sensitivity of 15%, equivalent to population sequencing.
Second, interpretation and reporting of HCV resistance data should be homogenized and standardized through recommendations by an international organization.
Thirdly, clinically relevant RASs should be clearly identified, and only these should be reported and used for treatment decisions.
Finally, guidelines should be provided by international societies for treatment decisions based on results of drug resistance tests. The guidelines should be based on data from clinical trials and real-life studies that reported strong predictive values of the different RAS profiles.
Because none of these conditions have yet been met, systematic testing for HCV resistance before treatment should not be recommended. Systematic testing would seriously limit access to care and lead to erroneous decisions for a number of cases. Instead, treatment can be optimized for groups of patients known to have specific RASs in NS5A that reduce response to therapy.
The authors do reference the current exception for Merck’s Zepatier (elbasvir + grazoprevir) where pre-treatment NS5A resistance testing is prescribed to determine length of therapy and/or the addition of ribavirin for patients with GT1a (detail linked below).