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Objectives We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor ( NNRTI) administered with zidovudine ( ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non- TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non- TA group). Methods Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non- TA. Results A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non- TA. No significant differences were observed between the non- TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log10 copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors ( RTIs) occurred at a significant lower frequency in the non- TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor ( NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non- TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non- TA group (18.5%; P < 0.001). Conclusions At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non- TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure. [ABSTRACT FROM AUTHOR]