Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

Abstract

There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs

Antiretroviral resistance and genetic diversity of human immunodeficiency virus type 1 isolates from the Federal District, Central Brazil

“…At the RT gene, K103N was the most frequent (18%) NNRTI-associated mutation, which agrees with data reporting that this mutation occurs more commonly than any other mutation in patients receiving NNRTI and may cause resistance to each one of them (Shafer 2002). Amino acid substitutions at codon 135 were detected at a high frequency (58%).…”

“…Of great importance was the high level of resistance to the PI amprenavir (38%), and to the NNRTI delavirdine and nevirapine (31%). This might result from the fact that a single mutation may cause high-level resistance to NNRTI(s) and may also reflect the high level of cross resistance among these drugs, as well as their wide use in the Federal District (Shafer 2002).…”

“…Amino acid substitutions at codon 135 were detected at a high frequency (58%). This position comprises one of the three mutations that have recently been identified as novel sites that may influence susceptibility to NNRTI (Magiorkinis et al 2002, Shafer 2003.…”

“…However, data have shown the emergence of HIV-1 drug resistance mutations in treated and untreated individuals (Hirsch et al 2003, Shafer 2003.…”

Detecting and understanding combinatorial mutation patterns responsible for HIV drug resistance

“…By sequencing viral strains in the treated-patient isolates, genotypic data have been accumulated for the drugs targeting two viral enzymes, protease and reverse transcriptase, that are essential to the virus's replication. Because each mutation of the viral protein is not equally important for drug resistance, the observed, complicated mutation patterns are difficult to interpret (3,4) and are limited in helping physicians design the best therapeutic regimen for a patient (5) (Fig. 1A).…”