hepdart paper - data analysis, page-19

Resistance doesn't occur when the viral load is zero: mutations that cause resistance can only occur when the virus is replicating as this is when the reverse transcriptase or viral polymerase enzyme is active. Due to the lack of a proofreading function, these enzymes make a mistake every few hundred to thousands of nucleotides which gets incorporated into the new daughter viral RNA or DNA. Most of the time the mistake is either lethal to the new virus or neutral, but very very occasionally it alters a key protein in such as way that it retains its function and becomes resistant to an inhibitory drug. The chances of this beneficial mutation (to the virus) increases as the viral load increases as there are more viruses replicating and making these mistakes. A very potent drug or combination will generally have a lower rate of resistance because it reduces the amount of replicating viruses.

The Pharmasset study was conducted in non-cirrhotic G2 and 3 patients as it was considered unethical to treat HCV patients without interferon, and if the study combination had no benefit then they would still have a close to 90% chance of cure by getting a 6 month course of standard treatment at the end. Just to clarify, RVR is virus negativity at 4 weeks of treatment, EVR or cEVR is virus negativity at 12 weeks of treatment, EOTR is virus negativity at the end of treatment whenever that is (12, 24 or 48 weeks depending on protocol), and SVR is virus negativity 6 months after treatment ends = cured.

I'm sceptical that monotherapy will work in all HCV given its proclivity to mutate, and the phase II study was small and only in the easiest to treat group. That said, the results were dramatic, and point to a small number of DAAs only being necessary in the near future. This will open HCV treatment up to a large number of people we haven't been able to treat before due the the IFN side-effects, such as those with psychiatric problems who make up a large portion of our hepatitis clinics these days.