Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness

David Bangsberg, Edward P. Acosta, Reena Gupta, David Guzman, Elise D. Riley, P. Richard Harrigan, Neil Parkin, Steven G. Deeks

Research output: Contribution to journalArticle

238 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-231
Number of pages9
JournalAIDS
Volume20
Issue number2
DOIs
StatePublished - Jan 2006
Externally publishedYes

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Reverse Transcriptase Inhibitors
Peptide Hydrolases
Pharmaceutical Preparations
Protease Inhibitors
Viruses
Viral Load

Keywords

  • Adherence
  • Non-nucleoside reverse transcriptase inhibitors
  • Protease inhibitors
  • Replicative capacity
  • Resistance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness. / Bangsberg, David; Acosta, Edward P.; Gupta, Reena; Guzman, David; Riley, Elise D.; Harrigan, P. Richard; Parkin, Neil; Deeks, Steven G.

In: AIDS, Vol. 20, No. 2, 01.2006, p. 223-231.

Research output: Contribution to journalArticle

Bangsberg, David ; Acosta, Edward P. ; Gupta, Reena ; Guzman, David ; Riley, Elise D. ; Harrigan, P. Richard ; Parkin, Neil ; Deeks, Steven G. / Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness. In: AIDS. 2006 ; Vol. 20, No. 2. pp. 223-231.
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AU - Bangsberg, David

AU - Acosta, Edward P.

AU - Gupta, Reena

AU - Guzman, David

AU - Riley, Elise D.

AU - Harrigan, P. Richard

AU - Parkin, Neil

AU - Deeks, Steven G.

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AB - 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.

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KW - Protease inhibitors

KW - Replicative capacity

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