Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness.
OBJECTIVE
To compare the prevalence of resistance by adherence level in patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI). Also to examine the mechanism of differential class-specific adherence-resistance relationships, focusing on the patient-derived capacity of wild-type and drug-resistant recombinant variants to replicate in vitro in the presence of variable drug levels.


METHODS
Participants received unannounced pill count measures to assess adherence, viral load monitoring, and genotypic resistance testing. The replicative capacity of drug-susceptible and drug-resistant recombinants was determined using a single-cycle recombinant phenotypic susceptibility assay. Drug exposure was estimated using population-averaged pharmacological measurements adjusted by participant-specific levels of adherence.


RESULTS
In the NNRTI-treated group, 69% had resistance at 0-48% adherence compared to 13% at 95-100% (P = 0.01). PI resistance was less common than NNRTI resistance at 0-48% adherence (69% versus 23%; P = 0.01). In multivariate analysis, the odds for PI resistance increased (P = 0.03) while the odds for NNRTI resistance decreased (P = 0.04) with improving adherence. Individuals with drug-resistant variants were more likely to have levels of drug exposure where the resistant variant was more fit than the drug-susceptible variant in vitro, while those with drug-susceptible virus were more likely to have levels of drug exposure where the drug-susceptible virus was more fit than the drug-resistant variant (P = 0.005).


CONCLUSIONS
NNRTI resistance was more common than PI resistance at low levels of adherence. Class-specific adherence-resistance relationships are associated with the relative replicative capacity of drug-resistant versus wild-type variants to replicate in the presence of clinically relevant drug levels.
Bangsberg
David R
DR
Epidemiology and Prevention Interventions Center, Division of Infectious Diseases, San Francisco General Hospital, UCSF, San Francisco, California 94143-1372, USA. db@epi-center.ucsf.edu
Acosta
Edward P
EP
Gupta
Reena
R
Guzman
David
D
Riley
Elise D
ED
Harrigan
P Richard
PR
Parkin
Neil
N
Deeks
Steven G
SG
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000523:psychology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006703:Ill-Housed Persons; D006801:Humans; D008297:Male; D010349:Patient Compliance; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase