Rilpivirine (RPV) and Etravirine (ETR) are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are not used for HIV-1 treatment in Kenya. In this cross-sectional study, we sequenced and analyzed the reverse transcriptase and pol regions of HIV-1 genome from 140 HIV infected individuals from Busia County Referral Hospital, Western Kenya, who were on anti-HIV treatment with confirmed virologic failure. All the participants were on first-generation NRTI's and NNRTI's for more than 12 months at the time of the study. Briefly, HIV RNA was extracted from plasma samples and sequenced to analyze for the presence of HIV-1 drug resistance mutations. The study findings showed that approximately 46% of the population had genotypic drug resistance against both Etravirine and Rilpivirine which were classified as ranging from potentially low level resistance to high level resistance despite being exposed to first-generation NNRTIs only. The study thus reveals that cross-resistance was demonstrated between primary and secondary NNRTI drugs. The development of cross resistance for RPV and ETR in patients on EFV and NVP poses a challenge in the use of these drugs as second generation NNRTI drugs.