In the context of lifelong antiretroviral treatment (ART) as early as possible and to end the HIV/AIDS epidemic as a public health treat by 2030, it is important to evaluate the potential risk of transmission of HIV-1 drug resistance (HIVDR) in resource limited countries (RLCs). Since HIV transmission is driven by HIV-1 RNA viral load (VL), we studied the association between plasma VL and HIVDR profiles in 451 adults failing first-line ART from the 2LADY-ANRS12169/EDCTP trial in Burkina Faso, Cameroon and Senegal. Median duration on first-line ART was 49 months (IQR:33-69) and 91% patients were asymptomatic. Genotypic drug resistance testing was successful for 446 patients and 98.7% of them were resistant to at least one of the first-line drugs; 40.6% and 55.8% were highly resistant to two or three drugs of their ongoing first-line ART, respectively. The median VL was higher in patients with HIVDR to all ongoing first-line drugs than in those still susceptible to at least one drug; 4.7 log10 copies/mL (IQR:4.3-5.2) versus 4.2 log10 copies/mL (IQR:3.7-4.7), respectively (p<0.001). The proportion of patients with HIVDR to all ongoing first-line drugs was highest (77.9% (95/122)) in patients with VL >5.0 log10 copies/mL. High rates of cross-resistance to other nucleoside reverse-transcriptase inhibitors (NRTIs) were observed and were also highest in patients with high VL. Without improvement of patient monitoring to avoid late switch to second-line regimens, a potential new epidemic caused by HIVDR strains could emerge in sub-Saharan Africa and compromise all efforts to reach 90-90-90 UNAIDS objective by 2020.