Analysis of hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938.
BACKGROUND
Sofosbuvir (GS-7977) and GS-0938 are nucleotide analogue HCV polymerase inhibitors, with sofosbuvir being a pyrimidine and GS-0938 being a purine. Mathematical modelling has provided important insights for characterizing HCV RNA decline and for estimating the in vivo effectiveness of single direct-acting antiviral agents (DAAs); however it has not been used to characterize viral kinetics with combination DAA therapy.


METHODS
We evaluated the antiviral activity of sofosbuvir and GS-0938 given alone and in combination for 14 days in 32 HCV genotype 1 treatment-naive patients (P2938-0212; NUCLEAR study).


RESULTS
Viral load declined rapidly in a biphasic manner in all subjects and could be well fitted by assuming that both drugs had a similar and additive level of effectiveness in reducing viral production equal to 99.96%, on average. The model predicted that this level of effectiveness was not reached until 0.6 and 2 days for GS-0938 and sofosbuvir, respectively, and likely represents the time needed to accumulate intracellular triphosphates. Subsequently, both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d(-1). No effect of IL28B-polymorphism was found on viral kinetic parameters.


CONCLUSIONS
Both sofosbuvir and GS-0938 are highly effective at blocking viral production from HCV-infected cells. Both drugs led to a rapid and consistent second phase viral decline and exhibited no breakthroughs or other signs of resistance. From a kinetics perspective, because both drugs were of the same class there was little benefit in combining them, suggesting that future DAA combinations should consider utilizing drugs with different modes of action.
INSERM UMR 738, University Paris Diderot, F-75018 Paris, France.
Jeremie
J
Guedj
Phillip S
PS
Pang
Jill
J
Denning
Maribel
M
Rodriguez-Torres
Eric
E
Lawitz
William
W
Symonds
Alan S
AS
Perelson
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003498:Cyclic P-Oxides / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000627:therapeutic use*; D012367:RNA, Viral; D000069474:Sofosbuvir; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load; D055815:Young Adult
D000998:Antiviral Agents; D003498:Cyclic P-Oxides; D009705:Nucleosides; C556498:PSI 352938; D012367:RNA, Viral; D014542:Uridine Monophosphate; D000069474:Sofosbuvir