Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

crop_square Key points

  • check_circle Direct and non-competitive inhibition of HIV-1 reverse transcriptase
  • check_circle Only active against HIV-1
  • check_circle Single mutations may cause viral drug resistance in first-generation NNRTIs
  • check_circle Generally well-tolerated drugs but may cause neuropsychiatric side effects

crop_square Background and biochemistry

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiviral drugs exclusively used to treat HIV-1 infections. In 1996, Nevirapine became the first NNRTI on the market. Nucleoside/nucleotide reverse transcriptase inhibitors and protease inhibitors were already available at that point. Two generations of NNRTIs have been developed since. They are a structurally diverse class of antivirals. Second-generation drugs were developed to overcome viral resistances. NNRTIs significantly improved therapeutic outcomes in patients living with HIV.

crop_square Mechanism of action

NNRTIs bind directly to the p66 subunit of HIV-1’s reverse transcriptase (RT). This binding causes a change to the enzyme conformation resulting in a loss of function. Reverse transcription is an essential stage in the HIV life cycle. NNRTIs are non-competitive RT inhibitors. Resistance against this class of antivirals may occur due to various mutations to the p66 subunit, which directly or indirectly inhibit NNRTI binding. In first-generation NNRTIs, a single mutation affecting the binding site may cause viral drug resistance. In second-generation NNRTIs, several mutations are necessary to confer drug resistance. HIV-2 and other retroviruses are intrinsically resistant to NNRTIs.

crop_square Drugs and spectrum of activity

First-generation NNRTIs
  • Nevi­rapine
  • Dela­virdine
  • Efa­virenz

Next-generation NNRTIs
  • Etravirine
  • Rilpivirine
  • Doravirine

crop_square Pharmacokinetics

NNRTIs are a diverse class of antivirals, and pharmacokinetics are fairly variable. Serum half-lives tend to be long , ranging between 11-55h. All currently available NNRTIs undergo hepatic metabolization. Bioavailability may be as low as 50% in Efavirenz and as high as 90% in Nevirapine. NNRTIs are excreted via urine and faeces but proportions vary greatly.

crop_square Adverse drug effects

NNRTIs are generally well-tolerated drugs. Common adverse effects include nausea, insomnia and skin rashes, which tend to improve after a few weeks of therapy. More severe NNRTI adverse effects are neuropsychiatric symptoms (including increased suicidality in efavirenz), hepatotoxicity and Stevens-Johnson syndrome.