NRTI

Nucleoside reverse transcriptase inhibitors (NRTIs) are a class of antiretroviral drugs used to treat HIV infection. They are nucleoside or nucleotide analogs that, after cellular activation, compete with natural nucleotides and, when incorporated into viral DNA by reverse transcriptase, cause chain termination due to the absence of a 3' hydroxyl group. Activation requires phosphorylation by host cell kinases, producing active triphosphate forms.

Common NRTIs include zidovudine (AZT), lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), and the nucleotide analogs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Older or less frequently used agents include didanosine (DDI), zalcitabine (ddC), and stavudine (d4T). NRTIs are frequently used as the backbone of combination antiretroviral therapy, paired with a third agent such as an integrase inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor.

Resistance to NRTIs arises from mutations in reverse transcriptase. For example, M184V reduces susceptibility to lamivudine and emtricitabine but can reduce viral fitness and increase susceptibility to zidovudine; K65R and thymidine analogue mutations can cause cross-resistance among several NRTIs.

Safety and tolerability vary among agents. Zidovudine can cause bone marrow suppression; older NRTIs are associated with mitochondrial toxicity, lactic acidosis, and peripheral neuropathy. Abacavir carries a risk of hypersensitivity reaction linked to HLA-B*57:01, requiring testing before use. Tenofovir may cause nephrotoxicity and reduced bone mineral density, with TAF generally having a more favorable renal and bone safety profile than TDF. Lamivudine and emtricitabine are usually well tolerated and also have activity against hepatitis B virus, as do tenofovir compounds, making them useful in HIV/HBV coinfection.

In summary, NRTIs form a foundational class in HIV therapy, with varied pharmacology and safety profiles that influence regimen selection and monitoring.