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

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ClinicalTrials.gov Identifier: NCT00122590
Recruitment Status : Terminated
First Posted : July 22, 2005
Last Update Posted : August 1, 2005
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by:
French National Agency for Research on AIDS and Viral Hepatitis

Study Description
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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.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: nelfinavir Drug: lopinavir/r Drug: indinavir Drug: ritonavir Not Applicable

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Enrollment : 115 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)
Study Start Date : July 2002
Study Completion Date : March 2005

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MedlinePlus related topics: HIV/AIDS

Arms and Interventions
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Outcome Measures
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Primary Outcome Measures :
  1. 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)
  2. 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 :
  1. 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)
  2. 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
  3. patients with trough plasma concentrations outside the therapeutic range at W24 and W48
  4. concentration changes with dosage variation
  5. time to obtain a viral load below 200 copies/ml
  6. relationship between adverse events grade 3 or 4 related to PI and plasma concentration at week 2 (W2)
  7. 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)
  8. relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after week 24 [W24])
  9. PI pharmacokinetic parameter estimation and evaluation of variability
  10. pharmacokinetic variability of nucleoside analogues at W2
  11. intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events
  12. relationship between inhibitory quotient of indinavir and virological response

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00122590


Locations
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France
Service de Medecine Interne Hopital Cochin
Paris, France, 75014
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
Hoffmann-La Roche
Investigators
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Principal Investigator: Dominique Salmon, MD Service de Medecine Interne Hopital Cochin Paris
Study Chair: France Mentre, MD Inserm EMI 03 57
More Information
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ClinicalTrials.gov Identifier: NCT00122590    
Other Study ID Numbers: ANRS111 COPHAR 2
First Posted: July 22, 2005    Key Record Dates
Last Update Posted: August 1, 2005
Last Verified: July 2005
Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:
protease inhibitors
nelfinavir
lopinavir
indinavir
Pharmacokinetics
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
Nelfinavir
 Indinavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors