2 The M184V/I mutation results in high level reduced susceptibility to both drugs (>100-fold) due to decreased incorporation into the viral DNA. 2, 13, 14 and 15 Codon M184 is located in the YMDD motif of RT which is involved in the binding of the incoming
nucleotide during reverse transcription. 2 Both FTC and 3TC are substrate analogues of the deoxynucleosides required for HIV-1 DNA synthesis and are phosphorylated by intracellular kinases to triphosphate metabolites. Akt inhibitor review Despite similar chemical structures, different pharmacokinetic and pharmacodynamic properties have been reported between the two agents. FTC has been shown to be between four- and ten-fold more potent than 3TC in vitro and the active metabolite FTC 5′-triphosphate (FTC-TP) is incorporated nine- to ten-fold more efficiently than 3TC-TP during HIV-1 DNA synthesis. 12, 13, 16, 17 and 18 Additionally, FTC-TP has a longer intracellular half Epacadostat price life (mean 39h: range 29–59) than 3TC-TP (15 h–32 h). 16 The lysine to arginine substitution at residue 65 (K65R) in HIV-1 RT results
from a single G-A point mutation (AAA to AGA).19 The K65R mutation is selected by TDF in vitro and has been reported in both treatment naïve and treatment experienced patients, conferring three- to four-fold reduced susceptibility to tenofovir and reducing phenotypic susceptibility to other NRTIs including FTC, 3TC and ABC. 18 An advantageous interaction has been described between TDF and FTC, leading to an increase in the intracellular metabolites compared with the levels seen with the individual agents. 16 and 20 Several studies have suggested that the emergence of resistance
mutation is more common in 3TC treated than FTC treated patients. We have analysed data from the UK HIV Drug Resistance Database (HDRD) and the UK Collaborative HIV Cohort (CHIC) Study to investigate the prevalence of genotypic resistance profiles in patients failing on regimens of TDF, efavirenz (EFV) and either 3TC or FTC. The UK HDRD was established in 2001 as a central repository of resistance tests performed as part of routine clinical care in the UK. HSP90 The UK CHIC Study is an observational cohort of HIV-infected individuals attending some of the largest HIV clinical centres in the UK. The dataset used for the current analysis includes information from 13 centres (see Appendix). Both studies have been extensively described in the literature.21, 22 and 23 All patients receiving tenofovir (TDF) and efavirenz (EFV) with either lamivudine (3TC) or emtricitabine (FTC), and no other drugs, were eligible for analysis. Patients were not required to be treatment naïve. Additionally, the analysis was not restricted to the first prescription of TDF/EFV and either 3TC or FTC and subsequent prescriptions were therefore identified as separate treatment episodes.