7th Annual Conference Of The British HIV Association [BHIVA] 27 – 29 April 2001, The Hove Centre, Brighton

[AUTHOR(S):] M Hennessy¹, M Barry¹, S Clarke², C Bergin², S Khoo³, D Back³, FM Mulcahy^2
1 Department of Clinical Pharmacology and Therapeutics and ² GUIDE Clinic, St James' Hospital, Dublin, and ³ Department of Pharmacology, University of Liverpool

BHIVA Conf 2001 Apr 27-29;7:O17

OBJECTIVE: Highly active antiretroviral therapy (HAART) still lacks sufficient potency and durability. As viral replication takes place intracellularly, treatment success may depend upon intracellular (IC) PI concentrations. We examined the relationship between plasma and IC PI concentrations in peripheral blood lymphocytes (PBLs) of HIV patients.

METHODS:

RESULTS: Patients receiving indinavir (IDV; n=11) and nelfinavir (NFV; n=14) were studied. PBLs were isolated by density centrifugation, stained and counted. Plasma and IC PI concentrations were assayed by LC/MS. AUC, time to peak (T_max) and half-life (t1.2) were derived. Data were correlated with HIV plasma RNA levels. IC IDV AUC was lower than plasma (P<0.05; 9,470±2,239 vs 31,788±6,392) while NFV underwent a ninefold IC accumulation (P<0.05; 283,251±6,687 vs 31,034±6,911). Two patients receiving IDV had IC levels below the MEC despite acceptable plasma levels and were unsuppressed. In contrast, two patients with subtherapeutic plasma IDV levels had IC concentrations above the MEC and remained suppressed (VL<50cpm). IC IDV T_max was delayed compared with plasma. IC t1.2 was longer, thus the mean residence time of IDV within the cell was prolonged (P<0.05) this may contribute to efficacy despite poor IC accumulation.

DISCUSSION: For discordant patients, IC IDV concentrations may provide better correlation with virological response than plasma levels. All patients on NFV remained suppressed. This highlights marked differences between PIs with respect to IC accumulation and pharmacokinetic behaviour and has important implications for drug penetration into sanctuary sites and therapeutic drug monitoring. The correlation between plasma and IC AUC was r²= 0.6 (P<0.05), in contrast to NRTIs.

PRESENTING AUTHOR: M Hennessy

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