Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs.
OBJECTIVE
To evaluate phenotypic drug susceptibility and non-nucleoside reverse transcriptase inhibitor hypersusceptibility as predictors of the time to virological failure.


METHODS
In a randomized clinical trial, phenotypic susceptibility was retrospectively determined among 131 exclusively nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients with baseline HIV-RNA levels greater than 2000 copies/ml. Subjects were assigned two NRTI drugs and were randomly assigned to nelfinavir, efavirenz, or both. Virological failure was defined as two HIV-RNA measurements of 2000 copies/ml or greater at or after week 16 and before treatment discontinuation.


METHODS
Using biological cut-offs to define resistance, assigned NRTI and randomized drug regimens, continuous and dichotomous phenotypic susceptibility scores (PSS) were calculated for each virus. Efavirenz hypersusceptibility as a dichotomous value was defined as less than 0.4-fold resistance. Associations between virological failure and continuous and dichotomous PSS were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models.


RESULTS
A higher baseline viral load (P < 0.02) and lower dichotomous or continuous baseline PSS (P = 0.004 and P < 0.001, respectively) were independently associated with virological failure. In the 85 subjects who received efavirenz, efavirenz hypersusceptibility (P = 0.042, hazard ratio 0.43, 95% confidence interval 0.19-0.97) was independently associated with a reduced risk of virological failure.


CONCLUSIONS
Reduced phenotypic susceptibility was a significant independent risk factor for virological failure. The presence of efavirenz hypersusceptibility appeared to enhance virological responses during treatment with efavirenz in combination with NRTIs. The retrospective calculation of continuous PSS accurately identified treatment regimens containing sufficient drug activity to prevent virological failure.
Katzenstein
David A
DA
Center for AIDS Research, Stanford, CA, USA. davidkk@leland.stanford.edu
Bosch
Ronald J
RJ
Hellmann
Nicholas
N
Wang
Nan
N
Bacheler
Lee
L
Albrecht
Mary A
MA
D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010078:Oxazines / Q000627:therapeutic use; D010641:Phenotype; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D012307:Risk Factors; D017211:Treatment Failure; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz