Background:  HIV-1C is the most widespread HIV-1 subtype globally. Although the non-B viruses appear to be susceptible to the currently used ART, some differences between HIV-1 subtypes in response to ART regimens have been reported. Little is known about the evolutionary pathways of drug resistance in HIV-1 non-B subtypes treated with HAART.

Methods:  The patterns of drug-resistant mutation development in HIV-1C infection treated with zidovudine (ZDV)/didanosine (ddI) -containing regimens as a first-line HAART were analyzed. Drug-naïve adults in Botswana were treated in an open-label, randomized 3x2x2 factorial study comparing ZDV/lamivudine (3TC) vs ZDV/ddI vs stavudine (d4T)/3TC and efavirenz (EFV) vs nevirapine (NVP) regimens. Bulk genotyping of viral RNA in plasma was performed by ViroSeq v.2. A total of 23 cases of virologic failure in HIV-1C infection treated by the ZDV/ddI-containing regimen were included in the analysis.

Results:  Known ART-associated mutations were present in 78% of cases at the time of virologic failure. The frequency of nucleoside reverse transcriptase inhibitor (NRTI) -associated mutations was 52%, and the frequency of non-NRTI (NNRTI) -associated mutations was 74%. At the time of virologic failure the 67N 70R 215Y genotype with wild type amino acids at codon positions 41 and 210 was a dominant pattern of NRTI-associated mutations (after initial suppression of plasma viral load below 400 copies/mL, the rebound of viral RNA in plasma occurred between 24 and 40 weeks). The mutation T215Y was the most common NRTI-associated mutation, and was the first step in the evolution of the 67N 70R 215Y genotype followed by mutations K70R and D67N.

Conclusions:  Representing a mixture of thymidine analog mutation (TAM) -1 (41L/210W/215Y) and TAM-2 (67N/70R/215F/219Q) pathways, the 67N 70R 215Y genotype with wild type amino acids at codon positions 41M, 210L, and 219K is a unique TAM pathway that is rarely seen in HIV-1B infection. The 67N 70R 215Y genotype is the HIV-1C-specific response to the ZDV/ddI-containing HAART regimen at the time of virologic failure. The predominance of the 67N 70R 215Y genotype in HIV-1C infection provides evidence that the evolution of NRTI-associated mutations might be specific to HIV-1 subtype or to ART regimen. Our results support the idea that ART-associated mutations in non-B subtype epidemics may not necessarily follow the patterns observed in HIV-1B infection, and the non-B subtype viruses might have unique pathways to drug resistance. The clinical implications of the evolutionary pathways of drug resistance in non-B subtypes warrant further studies.