NRTIs

NRTIs are analogs of natural nucleosides/nucleotides that lack a 3'-OH group. After intracellular phosphorylation to their active triphosphate form, they competitively inhibit HIV reverse transcriptase and get incorporated into the growing viral DNA chain, causing chain termination due to the missing 3'-OH needed for the next phosphodiester bond. This prevents reverse transcription of viral RNA into DNA, halting viral replication. NRTIs require intracellular activation by host kinases (unlike NNRTIs which act directly). Key drugs: Zidovudine (AZT) - first approved, causes bone marrow suppression (macrocytic anemia, neutropenia) and myopathy; used in prevention of vertical transmission. Lamivudine (3TC) and Emtricitabine (FTC) - well-tolerated, used in combination regimens, active against HBV too. Tenofovir (TDF/TAF) - nucleotide analog, associated with nephrotoxicity and decreased bone density (especially TDF); TAF has improved renal/bone safety profile. Abacavir - risk of hypersensitivity reaction associated with HLA-B*5701 allele (screening required before use); also linked to increased cardiovascular risk. Didanosine (ddI) and Stavudine (d4T) - older agents, largely discontinued due to toxicity (pancreatitis, peripheral neuropathy, lipodystrophy) - mitochondrial toxicity is a class effect due to inhibition of host mitochondrial DNA polymerase gamma, causing lactic acidosis, hepatic steatosis, peripheral neuropathy, and lipoatrophy. Clinical use: NRTIs are typically combined with an integrase strand transfer inhibitor (INSTI), NNRTI, or protease inhibitor as part of standard ART regimens. Common backbone combinations include tenofovir/emtricitabine or abacavir/lamivudine paired with a third agent. Resistance mutations (e.g., M184V for lamivudine, K65R for tenofovir, thymidine analog mutations for AZT) can develop with virologic failure, and cross-resistance patterns are important for regimen selection.