Raltegravir and Atazanavir Dosing Strategy Study

Study Overview
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Brief Summary
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To compare the steady-state pharmacokinetics and short-term efficacy and safety of two dosing strategies of raltegravir and atazanavir in virologically suppressed HIV-infected adults receiving atazanavir-containing combination antiretroviral therapy.

Detailed Description
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Current HIV treatment guidelines recommend the construction of combination regimens comprising a minimum of three agents from at least two drug classes. There are problems with the current recommendations for although treatments are effective, their success is often limited by tolerability, adverse effects and the need to take many pills. Antiretroviral adherence remains vital and regimens should be simplified wherever possible to facilitate maximal adherence. The recent availability of the potent HIV integrase inhibitor, raltegravir, provides an opportunity to explore moves away from current regimen components. Evidence to support the use of novel regimens must be generated through adequately powered randomized clinical trials. However, before such trials can be undertaken, preliminary data to define the pharmacokinetics, safety and tolerability of these regimens are needed to minimize unnecessary risk for participants. This eight week study will investigate the steady-state pharmacokinetics, and short-term safety and efficacy of two dosing strategies (once and twice daily) of raltegravir plus atazanavir in treatment experienced HIV-infected adults.

Official Title
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A Randomised, Open-label, Cross-over Study to Examine the Pharmacokinetics and Short-term Safety and Efficacy of Two Dosing Strategies of Raltegravir Plus Atazanavir in HIV-infected Patients

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: atazanavir plus raltegravir
* Drug: atazanavir plus raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged ≥ 18 years with laboratory evidence of HIV-1 infection currently receiving 3 or more unchanged antiretroviral agents including atazanavir (with or without ritonavir boosting) for at least 24 weeks prior to study entry plasma HIV RNA less than 50 copies/mL for at least 24 weeks prior to study entry provide written, informed consent. Exclusion Criteria : prior clinical/virological failure on a PI-containing regimen no clinical history of primary HIV-1 protease mutations identified in local baseline genotypic analysis of HIV with interpretation using current IAS-USA Drug Resistance Mutations in HIV-1 women: pregnant, breastfeeding, or not willing to use adequate contraception (including barrier contraception) if of child-bearing potential laboratory abnormalities at screening: absolute neutrophil count (ANC) < 750 cells/mL haemoglobin less than 8.5 g/dL platelet count less than 50 000 cells/mL AST, ALT > 5 times the upper limit of normal serum bilirubin > 5 times the upper limit of normal chronic active hepatitis B infection defined by presence of serum viral hepatitis B surface antigen (HBsAg) or HBV DNA-positive any malabsorption syndrome likely to affect drug absorption concurrent therapy with human growth hormone or other immunomodulatory agents concomitant medication contraindicated for use with either atazanavir or raltegravir therapy any inter-current illness requiring hospitalisation current excessive alcohol or illicit substance use unlikely to be able to remain in follow-up for the protocol-defined period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br> | Drug: atazanavir plus raltegravir<br>* atazanavir 300 mg + raltegravir 400 mg twice daily for 4 weeks then atazanavir 300 mg + ritonavir 100 mg + raltegravir 800 mg once daily for 4 weeks<br>* Other names: Isentress;|
| Active Comparator: Arm B<br> | Drug: atazanavir plus raltegravir<br>* atazanavir 300 mg + ritonavir 100 mg + raltegravir 800 mg once daily for 4 weeks then atazanavir 300 mg + raltegravir 400 mg twice daily for 4 weeks<br>* Other names: Isentress;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| comparison of the mean steady-state atazanavir trough plasma concentrations for once (C24) and twice (C12) daily dosing strategies |  | 4 and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| comparison of mean steady-state raltegravir trough plasma concentrations for once (C24) and twice (C12) daily dosing |  | 4 and 8 weeks | 
| comparison of steady-state pharmacokinetic profiles of once and twice-daily atazanavir |  | 4 and 8 weeks | 
| comparison of the steady-state pharmacokinetic profiles of once and twice-daily raltegravir |  | 4 and 8 weeks | 
| change from baseline in fasting lipid and glycaemic parameters |  | weeks 4 and 8 and overall | 
| change from baseline in CD4+ T-lymphocyte count |  | weeks 4 and 8 and overall | 
| change from baseline in HIV-RNA |  | weeks 4 and 8 and overall | 
| all adverse events attributable to study treatment |  | week 8 | 
| all serious, grade 3 or 4 clinical adverse events, and any adverse event leading to premature cessation of study treatment |  | week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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raltegravir, atazanavir, HIV infections, pharmacokinetics, antiretroviral agents, treatment experienced