Which mutations cause resistance to first-generation protease inhibitors 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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Answer

Answer

Resistance to first-generation protease inhibitors (indinavir, ritonavir, nelfinavir, saquinavir) occurs with the development of one or more of the following primary mutations [43] :

  • G48V, L90M (saquinavir)

  • M46I, V82A/L/F, I84V (indinavir)

  • V82A/L/F, I84V (ritonavir)

  • D30N, L90M (nelfinavir)

  • I50L, I84V, N88S (atazanavir)

  • I50V, I84V (fosamprenavir)

Multiple mutations are typically necessary to cause high-level resistance to boosted protease inhibitors (i.e., coadministered with cobicistat or low-dose ritonavir to decrease intestinal and hepatic 3A metabolism, thereby increasing protease inhibitor serum concentration levels), which exhibit a higher genetic threshold for resistance than unboosted protease inhibitors. [44] Cross-resistance to other protease inhibitors develops as the number of mutations increases.


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