Which mutations cause resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Resistance to NRTIs occurs by one of two mechanisms: (1) impaired incorporation into the proviral DNA chain or (2) removal from the proviral DNA chain. [12] Mutations typically occur gradually, with accumulation of several mutations required before clinically significantly resistance develops. An exception is the M184V mutation, which confers high-level resistance to lamivudine and emtricitabine in a single step. Mutations that selectively impair incorporation into the proviral DNA chain include M184V, Q151M, and K65R.

Thymidine analog mutations (mutations associated with zidovudine resistance [M41L, D67N, K70R, L210W, T215Y, T215F, K219Q, K219E]) remove NRTIs from the DNA chain by fostering a conformational change in the reverse transcriptase domain that allows the addition of ATP or pyrophosphate to the end. This placement causes a break in the proviral DNA and NRTI bond, enabling continued elongation of the proviral DNA strand. [11, 12]

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