2′-branched nucleosides and Flaviviridae mutation

A method for treating a hepatitis C virus infection in a host, comprising (a) administering an effective amount of a 2′-branched nucleoside of formula IV:

• or a pharmaceutically acceptable prodrug or salt thereof to the host, wherein:
• Base is a pyrimidine;
• R6 is alkyl, CH3, CF3, azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, fluoro, chloro, bromo, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• R7 is OR2, hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, halo-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), fluorine, chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• R9 is hydrogen, OR3, hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
• R10 is H, alkyl, fluorine, chlorine, bromine or iodine;
• R1, R2 and R3 are independently H, phosphate;
• straight chained, branched or cyclic alkyl;
• acyl;
• CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester;
• benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein;
• alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipid;
• amino acid;
• carbohydrate;
• peptide;
• cholesterol;
• or a pharmaceutically acceptable leaving group that provides a compound wherein R1, R2 or R3 is independently H or phosphate when administered in vivo;
• and
• X is O, S, SO2 or CH2;
• (b) identifying viral resistance to the 2′-branched nucleoside in the host by detecting an amino acid 282 Ser to Thr mutation in the RNA polymerase region of the hepatitis C virus;
• and
• (c) administering to the host infected with the virus resistant to the 2′-branched nucleoside, an effective amount of one or more drugs that directly or indirectly induce a mutation in a hepatitis C virus at a location other than nucleotide 8443 (G to C) of the HCV genome or amino acid 282 Ser to Thr of the RNA polymerase region of HCV.