From the Guidelines
The major site where antiviral action is blocked by NNRTIs is the reverse transcriptase enzyme of HIV-1. This is because NNRTIs target a hydrophobic pocket near the active site of the reverse transcriptase enzyme, causing conformational changes that significantly reduce its catalytic activity 1. The reverse transcriptase enzyme is crucial for the conversion of viral RNA into DNA, a critical step in the HIV life cycle. By inhibiting this enzyme, NNRTIs prevent the replication of the virus. Some common NNRTIs include efavirenz, nevirapine, rilpivirine, doravirine, and etravirine, which are typically used as part of combination antiretroviral therapy regimens 1.
Key points to consider when using NNRTIs include:
- They are always used in combination with other antiretroviral drug classes to prevent resistance
- Resistance to NNRTIs can develop through mutations in the reverse transcriptase gene, particularly in the region that forms the NNRTI-binding pocket
- NNRTIs such as efavirenz and rilpivirine have been shown to demonstrate high rates of virologic suppression as initial therapy when used in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) 1
- The choice of NNRTI may depend on factors such as the patient's baseline HIV RNA level and CD4 cell count, as well as the potential for adverse effects 1.
From the FDA Drug Label
Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The major site where antiviral action is blocked by NNRTIs is the reverse transcriptase (RT) enzyme.
- Specifically, NNRTIs like nevirapine bind to the RT enzyme and disrupt its catalytic site, blocking its ability to perform RNA-dependent and DNA-dependent DNA polymerase activities.
- This blockade prevents the virus from replicating its genetic material, thereby inhibiting the spread of the virus 2, 3.
From the Research
Mechanism of Action of NNRTIs
- NNRTIs primarily block HIV-1 replication by preventing reverse transcriptase (RT) from completing reverse transcription of the viral single-stranded RNA genome into DNA 4.
- The major site where antiviral action is blocked by NNRTIs is the reverse transcriptase enzyme, specifically by binding to the enzyme and inducing conformational changes that inhibit its catalytic activities 5.
Site of Action
- The site of action of NNRTIs is the "pocket" site on the reverse transcriptase enzyme, where they bind and induce conformational changes that inhibit the enzyme's activity 6.
- This site is located on the amino acid residues aligning the NNRTI-binding "pocket" site, and high-level resistance is often associated with a single point mutation that develops within this site 6.
Resistance and Efficacy
- NNRTIs are characterized by their specificity for HIV-1, which makes them very selective inhibitors of the virus 5.
- However, the emergence of resistant virus to NNRTIs can occur rapidly, especially in cases of incomplete viral suppression, and patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations 6.