The NNRTI class includes nevirapine (NVP), efavirenz (EFV), rilpivirine (RPV), etravirine (ETR) and doravirine (DOR). NNRTIs bind directly to the reverse transcriptase enzyme and block the RNA-dependent and DNA-dependent polymerase activities by causing a disruption of the enzyme’s catalytic site. This reduces enzyme activity and diminishes viral replication. Importantly NNRTIs are not active against HIV-2 as the reverse transcriptase binding site has a different structure. Also, NNRTIs do not inhibit human DNA polymerases. Furthermore, as a class, NNRTIs are considered to have a low genetic barrier to the development of antiretroviral drug resistance with suboptimal adherence and treatment interruptions of as little as 48 hours leading to selection of single mutations that confer high-level resistance to these agents.^[22]

Nevirapine was the first NNRTI developed for use in people with HIV infection and while it remains an effective antiretroviral drug, it is currently not recommended for initial therapy due to the risk of hepatotoxicity, especially in women with a CD4+ T cell count >250/μL and men with a CD4+ T cell count >400/μL. Efavirenz was the next NNRTI available and from the late 1990s until 2015 was a recommended third agent to add to an NRTI backbone in all major guidelines and was the recommended third agent in the World Health Organization (WHO) guidelines targeted for use in low-middle income countries.^[23] It was removed from the recommended category of the 2015 DHHS guidelines as a result of the availability of equipotent and better tolerated agents available as single dose FDC tablets. The main reason for the removal of efavirenz was an association with neuropsychiatric adverse effects, including depression and suicidality.

Etravirine and rilpivirine are second-generation NNRTIs that have efficacy in the presence of the classic NNRTI resistance mutation K103N.  The virological impact of these drugs diminishes in the presence of other NNRTI mutations (of which 15 have been identified) that each confer variable impact on virological efficacy^.[24] Rilpivirine is also available in a once-daily coformulated tablet. Despite a lower side effect profile than efavirenz, US and European guideline panels recommend initiation of rilpivirine only if baseline HIV viral load is < 100,000 copies/mL because increased numbers of virological failures have been observed in subjects with high HIV viral loads.²⁵ Because etravirine has been principally studied in people with previous virological failure and HIV drug resistance, it is not recommended for ART-naïve people but rather be used in conjunction with a boosted protease inhibitor for treatment of ART-experienced people infected with HIV exhibiting resistance to multiple classes of antiretroviral drugs.^[26][27] 

Doravirine is a newer NNRTI, which has been shown to be virologically non-inferior to efavirenz or darunavir for treatment ART-naïve patients. It retains activity against the commonest efavirenz resistance mutation (K103N) and does not have the neuropsychiatric toxicities associated with efavirenz. There are also no food requirements with doravirine. The drug is metabolised through CYP3A4 but is not an inducer or inhibitor of this system. It is a substrate for P-GP and as such will be affected by ritonavir or cobisistat co-administration. It has not yet been compared with integrase inhibitor-based therapy and as such its role as initial therapy remains unclear.

Guidelines for NNRTI dosing are presented in Table 2 and adverse effects listed in Table 3.

Table 2. Guidelines for NNRTI dosing

Table 3. Adverse effects of NNRTIs