evaluation of therapeutic drug monitoring of protease inhibitors on virologic success and tolerance of highly active antiretroviral therapy (haart)

Conditions: HIV Infections

Summary: this cophar2 study is a trial which evaluates repeated early therapeutic drug monitoring, from weeks 2 to 24, after the initiation of haart including either indinavir/r, lopinavir/r or the new 625 mg formulation of nelfinavir twice-a-day (bid). if trough concentrations were out of the range given for each protease inhibitor (pi), the pi dose was adjusted.

because of the large pharmacokinetic inter-patient variability of protease inhibitors (pi), therapeutic drug monitoring (tdm) of protease inhibitor (pi) has been proposed to improve efficacy and tolerance of pi-containing haart. the objective of the cophar2 trial is to evaluate the feasibility and the impact of an early therapeutic drug monitoring in pi-naive hiv-1 infected patients in order to warrant virological success and safety of haart. it is a prospective, open, multicenter trial with repeated early tdm (weeks 2, 8 or 16, 24) after the initiation of haart including either indinavir/r (idv), lopinavir/r (lpv) or the new 625 mg formulation of nelfinavir (nfv) bid. it was planned to include 99 pi-naïve hiv-1 infected patients over 18 years old, 33 for each pi. concentrations were measured by hplc in each center. if trough concentrations were out of the range of 150-500, 2500-7000 or 1500-5500 ng/ml for idv, lpv and nfv respectively, the pi doses were adjusted possibly more than once during the first 24 weeks of follow-up. adjustments were done by steps of one pill (200, 133/33 or 250 mg for idv, lpv/r or nfv, respectively) bid. failure of the strategy was defined by either two consecutive viral loads over 200 copies/ml between weeks 16 and 48, or a validated pi-related adverse event grade iii or iv or a grade ii diarrhoea or renal lithiasis. patients without adverse events before week 16 were defined as assessable if they had at least the virological assessment of week 16.

Eligibility criteria:
inclusion criteria: * patients infected with hiv-1 * needing an antiretroviral treatment according to standard of care * hiv viral load greater than 1000 copies/ml * beginning a treatment containing a pi (indinavir with or without ritonavir, nelfinavir, lopinavir + ritonavir) and 2 reverse transcriptase inhibitors * pi-naive * antiretroviral treatment-naive or already treated with reverse transcriptase inhibitors but if the viral genotypic test does not show more than 2 major mutations (including t215y/f, q151m, m184v/i, v75m/s, l74v) and if 3 nucleoside analogues are still active except for didanosine. exclusion criteria: * pregnant women and nursing mothers * acute hiv infection * diabetes * renal insufficiency with creatinine clearance below 30 ml/min * cardiac insufficiency * hepatic insufficiency with tp below 60% * treatment with known interactions with pi * chemotherapy against kaposi's sarcoma, lymphoma, neoplasia * treatment containing interferon (inf) or interleukin-2 (il2) or hiv- immune vaccine * treatment with hypolipemic drugs * laxative treatment * previous renal colic * diarrhoea with more than 5 stools/day since one week

Keywords: protease inhibitors nelfinavir lopinavir indinavir pharmacokinetics