Evolution of genotypic resistance algorithms and their impact on the interpretation of clinical trials: an OPTIMA trial substudy.
OBJECTIVE
The outdated rules of older HIV genotypic resistance algorithms can affect virologic responses. This study was designed to determine how often these incorrect resistance interpretations affect analyses of long-term clinical trials, antiretroviral (ARV) choices, and HIV disease progression rates.


METHODS
Baseline VIRCO virtual phenotypes (VVP) from patients screened in 2001-2002 for OPTIMA were compared to 2005 Stanford HIV resistance database algorithm (HIVDB-10/05, version 4.1.4) interpretations of the HIV-1 pol sequences. Drugs were called discordant if resistant by one algorithm and sensitive by the other.


RESULTS
Of 2,341 drug comparisons, 501 (21.4%) were discordant, affecting 140 (86.4%) of 162 screened patients. NRTI/NtRTIs were more discordant than NNRTIs and PIs (38.6% vs. 4.3% vs. 12.8%; p < .0001). Sixty-nine (53%) patients were placed on 2 drugs reported as sensitive by VVP but resistant by HIVDB-10/05; they had higher than expected rates of disease progression and a similar time to first event or death as patients on ARVs classified as resistant by both algorithms (p = .61).


CONCLUSIONS
Underestimation of drug resistance by older genotypic algorithms resulted in using ARVs incorrectly thought to be sensitive and in higher than expected rates of HIV disease progression. The use of older genotypes to interpret long-term clinical trials should account for this underestimation, because results may be different if viral sequences are interpreted with newer algorithms.
Desai
Samit
S
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, VA Connecticut Healthcare System, New Haven, Connecticut, USA. sdesai@humed.com
Kyriakides
Tassos
T
Holodniy
Mark
M
Al-Salman
Jameela
J
Griffith
Brigitte
B
Kozal
Michael
M
D000465:Algorithms; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D015751:Genes, pol; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014773:Virology / Q000379:methods
D019380:Anti-HIV Agents