Clinical implications of stopping nevirapine-based antiretroviral therapy: relative pharmacokinetics and avoidance of drug resistance.
OBJECTIVE
To determine the pharmacokinetics of cessation of nevirapine (NVP) in order to design clinical protocols which will reduce the risk of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs).


METHODS
In a case study, NNRTI genotypic resistance was demonstrated in a patient discontinuing therapy for toxicity. Subsequently, nine patients receiving NVP-containing antiretroviral regimens and stopping treatment were recruited. Patients were advised to continue the nucleoside analogue reverse transcriptase inhibitor (NRTI) backbone for 5 days following cessation of NVP. Plasma NVP concentrations were determined over 7-10 days after the last dose. HIV-1 reverse transcriptase genotyping was performed at viral load rebound (approximately day 21 following cessation) to detect mutations associated with reduced NNRTI sensitivity.


RESULTS
The median predicted time for plasma NVP concentration to fall below the inhibitory concentration (IC)(50) of wild-type virus was 168 h (range 108-264 h). De novo genotypic mutations conferring resistance to NRTIs or NNRTIs were not demonstrated following cessation of therapy.


CONCLUSIONS
The prolonged elimination half-life of NVP compared with NRTIs, which persists even after 20 weeks of therapy, raises concern over the development of NNRTI resistance if all three drugs are stopped together. Continuation of the NRTI backbone for a further 5 days, allowing the elimination of NVP, may avoid the development of drug resistance.
Mackie
N E
NE
Genito-Urinary Medicine and Communicable Diseases, Faculty of Medicine, Imperial College, London, UK. n.mackie@ic.ac.uk
Fidler
S
S
Tamm
N
N
Clarke
J R
JR
Back
D
D
Weber
J N
JN
Taylor
G P
GP
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D019562:Viral Load
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine