[Choice of a two nucleos(t)ide analogs fixed dose coformulation for initial antiretroviral therapy: a rational based...

The choice of an initial antiretroviral triple therapy is based mainly on two nucleoside/tide analogs (NRTIs/NtRTIs) plus either a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI). Three fixed dose coformulations are available (AZT/3TC, Combivir^®; ABC/3TC, Kivexa^®; TDF/FTC, Truvada^®). In this review, we describe how to select one of these fixed-dose coformulations on the basis of their specific genotypic drug resistance profile. Mutations conferring resistance to NRTIs/NtRTIs are classified accord- ing to their molecular mechanism of action. A first group of mutations (K65R, L74V, Q151M, M184V) favors the incorporation of the natural dNTP into the active site of the reverse transcriptase (RT) and leads to resistance by decreasing the incorporation of the inhibitor. A second group of mutations including TAMs (thymidine analog mutations) leads to the removal of the NRTIs previously incorporated in the growing DNA chain. M184V mutation is selected by the three fixed-dose coformulations. The fixed-dose AZT/3TC selects at first M184V mutation then the TAMs that progressively confer a cross-resistance to most of NRTIs/NtRTIs. The fixed-dose coformulation ABC/3TC selects more frequently L74V mutation than K65R or Y115F mutation. The fixed-dose coformulation TDF/FTC selects the K65R mutation. Second-line therapeutic options will be chosen on the basis of these resistance profiles: ABC, ddI, or TDF as a fonction of the number and the nature of TAMs; AZT, D4T, or TDF in case of L74V mutation; AZT or D4T in case of K65R mutation.