Rilpivirine is the only NNRTI approved, in combination with cabotegravir, as a long-acting regimen for HIV treatment. However, rilpivirine cold chain requirements could make it difficult for this drug to be implemented in LMICs. Additionally, it has been reported that rilpivirine could increase the risk for depressive disorders and hepatic adverse effects. Furthermore, rilpivirine resistance would largely exclude future use of the NNRTI class drugs. Finally, cabotegravir and rilpivirine are currently not listed in WHO HIV treatment guidelines.