Clinical trial NCT01258374: Dual Therapy With Raltegravir and Darunavir/Ritonavir in HIV Infected Patients.
Official title: Dual Therapy With Raltegravir 400 mg BID and Darunavir/Ritonavir 800/100 mg QD in HIV Infected Patients Failing to Nucleoside Reverse Transcriptase Inhibitors Based Regimens
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Integrase Inhibitors, HIV; HIV PROTEASE INHIB
Keywords: Pharmacokinetics, raltegravir, darunavir, NRTI sparing regimen
Lead sponsor: Hospital Clinic of Barcelona
Sponsor class: OTHER
First posted: 2010-12-13
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: A total of 20 HIV-infected patients failing NRTI based regimens will be included . At least 12 of these patients will undergo a complete pharmacokinetic study.

Brief summary: While 3-drug regimens remain standard of care, concerns exist regarding the safety of multi-drug regimens taken for a lifetime. Problems with nucleoside analogue therapy prompted successful trials with ritonavir (RTV) boosted PI monotherapy, however long term safety and efficacy of such regimens remains unknown. Clinical trials have shown Raltegravir (RAL) to have potent activity when patients have few active background drugs; it has a superior lipid profile compared with EFV and LPV/RTV. Darunavir/r (DRV) is a potent, well tolerated PI with few GI side effects and lipid disturbances and with a high genetic barrier. The investigators hypothesized that RAL/DRV would be a well tolerated and effective regimen for those patients who are failing nucleoside reverse transcriptase inhibitors based regimens, due to poor tolerability or resistance. The investigators also would like to explore the plasma pharmacokinetics of Raltegravir combined with Darunavir in a sub-group of 12 HIV-infected patients.

Detailed description: Hypothesis

* NRTI-sparing regimens are attractive options to avoid NRTI-associated toxicity and to provide a full active regimen in patients with some extent of NRTI resistance.
* Raltegravir (RAL) and Darunavir (DRV) are potent "third drugs" and they provide a synergistic inhibition of 2 different steps in HIV replication.
* DRV has a high genetic barrier, and could be an excellent accompanying drug for Raltegravir, providing a potent, safe and well tolerated dual therapy to patients who are failing NNRTI based treatments.

Objectives:

* To describe the safety, tolerability and efficacy of the combination of Raltegravir and Darunavir after 24 weeks of follow up in HIV infected patients failing a NRTI based regimen.
* To describe plasma pharmacokinetics of Raltegravir when combined with Darunavir 800mg QD in HIV-infected patients.

Eligibility criteria: Inclusion Criteria:

* Documented HIV infection
* Naïve to Raltegravir.
* CD4 cell count above 200 cell/mm3.
* No history of failure to PI containing regimens.
* No evidence of PI mutations (IAS-mutation list) by genotype test.
* Failing to a NRTI based regimen.
* The treating physician decides a NRTI sparing regimen which includes DRV/r 800/100 mg QD plus Raltegravir 400 mg BID.
* Signed informed consent form
* In opinion of the investigator, the patient should be considered clinically stable and could follow regular visits as scheduled per protocol.

Exclusion Criteria:

* Patients receiving drugs considered contraindicated to Raltegravir and DRV/r. Contraindicated drugs are: rifampin, fenitoin, phenobarbital in the case of raltegravir. Pravastatin, astemizole, sildenafil, are contraindicated in combination with DRV/r.
* Pregnancy
* Documented PI mutations

Primary outcomes:
measure: Geometric Mean of C-Trough, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
timeFrame: After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.
measure: Geometric Mean of AUC, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
timeFrame: After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.
measure: Geometric Mean of C-max, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
timeFrame: After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.
measure: Geometric Mean of t1/2, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy
timeFrame: After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.
Secondary outcomes:
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Clinic
Study officials:
affiliation: Hospital Clinic of Barcelona
name: Josep Mallolas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martinez-Rebollar M, Munoz A, Perez I, Hidalgo S, Brunet M, Laguno M, Gonzalez A, Calvo M, Lonca M, Blanco JL, Martinez E, Gatell JM, Mallolas J. Pharmacokinetic study of dual therapy with raltegravir 400 mg twice daily and Darunavir/Ritonavir 800/100 mg once daily in HIV-1-infected patients. Ther Drug Monit. 2013 Aug;35(4):552-6. doi: 10.1097/FTD.0b013e31828d50ef.