NRTI
Summary
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) are antiretroviral drugs used to treat HIV by inhibiting the reverse transcriptase enzyme, blocking conversion of viral RNA to DNA. Examples include tenofovir, emtricitabine, abacavir, lamivudine, and zidovudine (AZT). They form the backbone of most combination antiretroviral therapy (ART) regimens.
Detail
Mechanism: NRTIs are synthetic nucleoside/nucleotide analogs that require intracellular phosphorylation to become active triphosphate forms. Once activated, they competitively inhibit HIV reverse transcriptase and get incorporated into the growing viral DNA chain, causing chain termination due to lack of a 3'-OH group needed for further elongation.
Key drugs: Zidovudine (AZT) - first approved antiretroviral, used in prevention of mother-to-child transmission; associated with bone marrow suppression (anemia, neutropenia) and myopathy. Lamivudine (3TC) - well tolerated, also active against HBV. Emtricitabine (FTC) - similar to lamivudine, combined with tenofovir in PrEP regimens (Truvada). Tenofovir (TDF/TAF) - nucleotide analog, associated with nephrotoxicity and decreased bone density (TDF more than TAF). Abacavir - risk of hypersensitivity reaction, strongly associated with HLA-B*5701 allele (screening required before starting). Didanosine (ddI) and Stavudine (d4T) - older agents, largely discontinued due to toxicity (pancreatitis, peripheral neuropathy, lactic acidosis/lipodystrophy from mitochondrial toxicity).
Class toxicity: Mitochondrial toxicity is a hallmark adverse effect across NRTIs due to inhibition of mitochondrial DNA polymerase gamma, leading to lactic acidosis, hepatic steatosis, lipodystrophy, myopathy, and peripheral neuropathy (especially with ddI, d4T).
Clinical use: NRTIs are typically combined with an integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitor as part of combination ART (cART) to prevent resistance. Common backbone combinations include tenofovir/emtricitabine or abacavir/lamivudine.
Resistance: Resistance mutations in reverse transcriptase (e.g., M184V with lamivudine/emtricitabine, K65R with tenofovir) can reduce efficacy; thymidine analog mutations (TAMs) with zidovudine/stavudine can cause cross-resistance.
Board relevance: Know mechanism (chain termination), key adverse effects per drug (zidovudine-bone marrow suppression, abacavir-hypersensitivity reaction and HLA-B*5701 testing, tenofovir-renal/bone toxicity), and general mitochondrial toxicity theme distinguishing NRTIs from NNRTIs (which inhibit RT via a different allosteric site, no chain termination, class effects include hepatotoxicity and rash).
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic & Clinical Pharmacology
- UpToDate: Overview of antiretroviral agents used to treat HIV
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