Determination of clinically relevant cutoffs for HIV-1 phenotypic resistance estimates through a combined analysis of clinical trial and cohort data.
BACKGROUND
Clinically relevant cutoffs are needed for the interpretation of HIV-1 phenotypic resistance estimates as predicted by "virtual" phenotype HIV resistance analysis.


METHODS
Using a clinical data set containing 2596 treatment change episodes in 2217 patients in 8 clinical trials and 2 population-based cohorts, drug-specific linear regression models were developed to describe the relation between baseline characteristics (resistance, viral load, and treatment history), new treatment regimen selected, and 8-week virologic outcome.


RESULTS
These models were used to derive clinical cutoffs (CCOs) for 6 nucleoside/nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, abacavir, and tenofovir), 3 unboosted protease inhibitors (PIs; indinavir, amprenavir, and nelfinavir), and 4 ritonavir-boosted PIs (indinavir/ritonavir, amprenavir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir). The CCOs were defined as the phenotypic resistance levels (fold change [FC]) associated with a 20% and 80% loss of predicted wild-type drug effect and depended on the drug-specific dynamic range of the assay.


CONCLUSIONS
The proposed CCOs were better correlated with virologic response than were biological cutoffs and provide a relevant tool for estimating the resistance to antiretroviral drug combinations used in clinical practice. They can be applied to diverse patient populations and are based on a consistent methodologic approach to interpreting phenotypic drug resistance.
Winters
Bart
B
Virco BVBA, Mechelen, Belgium. bwinters@vrcbe.jnj.com
Montaner
Julio
J
Harrigan
P Richard
PR
Gazzard
Brian
B
Pozniak
Anton
A
Miller
Michael D
MD
Emery
Sean
S
van Leth
Frank
F
Robinson
Patrick
P
Baxter
John D
JD
Perez-Elias
Marie
M
Castor
Delivette
D
Hammer
Scott
S
Rinehart
Alex
A
Vermeiren
Hans
H
Van Craenenbroeck
Elke
E
Bacheler
Lee
L
D002986:Clinical Trials as Topic; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors