Emerging reverse transcriptase inhibitors for HIV-1 infection

There are 36.7 million people living with HIV with 20.9 million having access to antiretroviral therapy (ART). Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the 'backbone' of ART. However, the currently available nine NRTIs and five non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significant side effects and resistance profiles. Areas covered: We summarize the mechanisms of resistance and other limitations of the existing NRTIs/NNRTIs. GS-9131, MK-8591, Elsulfavirine and Doravirine are four new agents that are furthest along in development. Expert opinion: ART development has evolved with several new promising agents. Longer-acting agents, like MK-8591 are extremely attractive to enhance drug adherence and patient satisfaction. Doravirine offers an NNRTI effective against common mutations that has fewer side effects, limitations on dosing and drug interactions. GS-9131 is very potent and active against a variety of NRTI mutants but it is too early in its development to understand its full risks and benefits. Finally, Elsulfavirine has a long half-life and preliminary data suggests fewer side effects than the most commonly used NNRTI, efavirenz. Each of these new agents shows promise and potential to improve ART in the future. The newer generation of reverse transcriptase inhibitors have longer half-lives, more favorable adverse effect profiles, and fewer drug interactions.