Abstract Late initiation of antiretroviral treatment (ART) has been shown to impair response to the regimen administered. We assessed whether low CD4 count and high viral load (VL) affect the response to currently preferred ART. We performed a systematic review of randomized controlled clinical trials analyzing preferred first-line ART and a subgroup analysis by CD4 count (≤ or >200 CD4/µL) or VL (≤ or >100,000 copies/mL). We computed the OR of treatment failure (TF) for each subgroup and individual treatment arm. Patients with ≤200 CD4 cells or VL ≥100,000 copies/mL showed an increased likelihood of TF at 48W: OR 1.94 (95%CI 1.45–2.61) and OR 1.75 (95%CI 1.30–2.35), respectively. A similar increase in the risk of TF was observed at 96W. There was no significant heterogeneity regarding INSTI or NRTI backbone. These results show that CD4 count <200 cells/µL and VL ≥100,000 copies/mL impair the efficacy of ART across all the preferred regimens.