Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor

Abstract

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Mechanism of HIV antiretroviral drugs progress toward drug resistance

“…It has been shown that mutations at codon 10, 63, or 71 compensated for a reduced viability of HIV-1 variants with a primary resistance mutation at codon 82 [78,79]. High-level resistance caused by the accumulation of primary and secondary mutations can lead to clinically significant reductions in drug susceptibility [80,81]. A mutation at codon 63 has been shown to be the most polymorphic mutation in the protease gene [82].…”

Hepatitis B virus surface antigen and polymerase gene variants: Potential virological and clinical significance

“…This has been the experience in HIV therapy, especially with the HIV-protease inhibitors. [35][36] Thus, in hepatitis B where two antiviral agents, which have overlap- NOTE. Examples of mutations reported in HBV polymerase protein associated with drug resistance to Lamivudine and Famciclovir with the corresponding changes in HBsAg.…”

Viral Protease Inhibitors

“…Monotherapy trials demonstrated up to a 3.1log 10 decline in HIV-1 RNA levels (Stein et al 1996). The genetic correlates of in vivo resistance revealed variable patterns of multiple substitutions, indicating that resistance evolved through multiple pathways during ongoing replication; however, resistant isolates typically had substitutions at codons 46 and/or 82 (Condra et al 1996).…”