Assuming that the patients were taking their medication daily, and that their medication was good quality, and that it’s not a <15 detected (because this may SVR - Tina here was <15 DET at EOT, UND @ SVR2 and UND @ SVR4)
Virological breakthrough happens when the patient's remaining HCV virus is not efficiently killed by the medications being taken and can continue to grow in their presence.
Resistant mutants are not created by taking DAAs. They are created because the HCV replication process does not reliably produce accurate copies of the original RNA genetic code. Most of these inaccurate copies (mutants) produce nonfunctional, or poorly functional viruses, however some may be resistant to drugs.
When we give drugs all the other HCV gets killed, and like weeds in a garden the mutants now have a chance to grow.
Although Sofosbuvir resistance is rare it is possible. In the original dose scoping trial for Sofosbuvir a dose of 200 mg suppressed virus on treatment to < LLOQ for 100% , but at EOT only 94% were still < LLOQ. SVR was 90%. On the dose of 400 mg on treatment and EOT were 100%. Interestingly SVR was only 1% higher - 91%
The next step for patients who have relapsed depends on how sick they are. If they are not sick careful consideration should be given to waiting - as more people fail DAAs we learn more.
If they are sick and must be treated urgently:
1b - Sof+Dac+/-Riba, Sof+Dac+Simeprevir or Viekira Pak would be reasonable options
2 - Sof+Dac+/-Riba, Sof+Dac+Simeprevir would be a reasonable options (note that the total reported trials for Sof+Dac in GT2 are 49/53 although I have some unpublished data that will increase those numbers)
Note that Simprevir is active against all but GT3 - http://www.catie.ca/en/treatmentupdate/treatmentupdate-191/anti-hcv-agents/simeprevir-and-different-strains-hcv (GT1 is not mentioned but it is in the guidelines for GT1 with Sof)
In broad terms for retreatment we would pick at least one, probably 2, and maybe all 3 of:
1) Use different drug(s) - the resistance profile for each varies a bit
2) Treat for longer
3) Add something extra - (proven) Riba, Simeprevir (not GT3), or (experimental) Chlorcyclizine
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