Clinical trial NCT00122590: Evaluation of Therapeutic Drug Monitoring of Protease Inhibitors on Virologic Success and Tolerance of Highly Active Antiretroviral Therapy (HAART)
Official title: Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: HIV Infections
Keywords: protease inhibitors
nelfinavir
lopinavir
indinavir
Pharmacokinetics
Lead sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Sponsor class: OTHER_GOV
Collaborators: name: Hoffmann-La Roche
First posted: 2005-07-22
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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

Primary outcomes:
measure: treatment failure defined as viral load greater than 200 copies/ml between week 16 (W16) and week 48 (W48) (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method)
measure: toxicity related to PI, defined as adverse event grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value
Secondary outcomes:
measure: virological failure: viral load over 200 copies/ml between W16 and W48 (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method)
measure: toxicity related to PI: adverse events grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value
measure: patients with trough plasma concentrations outside the therapeutic range at W24 and W48
measure: concentration changes with dosage variation
measure: time to obtain a viral load below 200 copies/ml
measure: relationship between adverse events grade 3 or 4 related to PI and plasma concentration at week 2 (W2)
measure: relationship between pharmacokinetic parameters and/or plasma concentrations and the drop of viral load between day 0 (D0) and W2 and between D0 and week 4 (W4)
measure: relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after week 24 [W24])
measure: PI pharmacokinetic parameter estimation and evaluation of variability
measure: pharmacokinetic variability of nucleoside analogues at W2
measure: intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events
measure: relationship between inhibitory quotient of indinavir and virological response
Other outcomes:
Locations:
city: Paris
country: France
facility: Service de Medecine Interne Hopital Cochin
Study officials:
affiliation: Service de Medecine Interne Hopital Cochin Paris
name: Dominique Salmon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inserm EMI 03 57
name: France Mentre, MD
role: STUDY_CHAIR
References: