Evaluation of Therapeutic Drug Monitoring of Protease Inhibitors on Virologic Success and Tolerance of Highly Active Antiretroviral Therapy (HAART)

Study Overview
=================
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.

Official Title
-----------------
Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: nelfinavir
* Drug: lopinavir/r
* Drug: indinavir
* Drug: ritonavir


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: nelfinavir|nan|
|Drug: lopinavir/r|nan|
|Drug: indinavir|nan|
|Drug: ritonavir|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  |  | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  |  | 
| 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 |  |  | 
| patients with trough plasma concentrations outside the therapeutic range at W24 and W48 |  |  | 
| concentration changes with dosage variation |  |  | 
| time to obtain a viral load below 200 copies/ml |  |  | 
| relationship between adverse events grade 3 or 4 related to PI and plasma concentration at week 2 (W2) |  |  | 
| 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) |  |  | 
| relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after week 24 [W24]) |  |  | 
| PI pharmacokinetic parameter estimation and evaluation of variability |  |  | 
| pharmacokinetic variability of nucleoside analogues at W2 |  |  | 
| intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events |  |  | 
| relationship between inhibitory quotient of indinavir and virological response |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
protease inhibitors, nelfinavir, lopinavir, indinavir, Pharmacokinetics