Atazanavir or Boosted Atazanavir Substitution for Ritonavir Boosted PI in Patients With Hyperlipidemia
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||The De-Escalate Trial: Atazanavir or Atazanavir/Ritonavir Substitution for Ritonavir Boosted PI Therapy in HIV-Infected Individuals Experiencing Ongoing HIV Viremia and Hyperlipidemia: A Randomized Controlled Pilot Study|
- Compare the three arms (ATV, ATV/r and continued ritonavir boosted-PI) in the following primary endpoint: % subjects who have normal serum lipid profile off lipid lowering agents and maintain CD4 counts > 75% of baseline line values. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
- % subjects with serum lipids within normal limits at week 48 off of any lipid lowering agent. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
- % subjects who maintain CD4 counts > 75% of baseline values at week 48. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
- Compare the change in CD4 count and CD4 % at 24 and 48 weeks between the three study arms.1.2.4Compare HIV plasma viral load profile over 24 and 48 weeks as DAVG between the three study arms. [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
- Compare lipid profile over 48 weeks, change in total cholesterol, TC/HDL ratio and triglycerides. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
- Compare the evolution of genotypic and phenotypic drug resistance over 12 and 48 weeks between the three arms. [ Time Frame: 12 and 48 weeks ] [ Designated as safety issue: No ]
- Compare the evolution of viral fitness as measured by replication capacity assay at 12 and 48 weeks between the three arms. [ Time Frame: 12 and 48 weeks ] [ Designated as safety issue: No ]
- Explore determinates of viral fitness and the relationship of viral fitness with the 'CD4/VL disconnect' state. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||January 2004|
|Study Completion Date:||March 2009|
|Primary Completion Date:||April 2007 (Final data collection date for primary outcome measure)|
This is a randomized controlled pilot study to compare the safety and efficacy of substitution of atazanavir (ATV) or ATV/RTV for ritonavir boosted PI in patients with ongoing viremia who are experiencing hyperlipidemia and/or requiring treatment with lipid lowering agents. In this study 60 subjects on a ritonavir boosted PI-containing antiretroviral regimen who are experiencing hyperlipidemia and ongoing HIV viremia will be randomized in a 1:1:1 ratio to either switch the ritonavir boosted PI component of the antiretroviral regimen to ATV or ATV/RTV, or continue the ritonavir boosted PI-based regimen.
No other changes in the antiretroviral regimen will be allowed for the first 12 weeks. Thereafter, the investigator may change background ARVs based on the results of the screening resistance test. No new class of antiretrovirals will be allowed to be added through 48 weeks. Subjects will be monitored closely over 48 weeks with careful assessment of CD4 profile, viral loads and lipid profiles as well as drug resistance and replication capacity. Stopping rules will be implemented based on CD4 and viral load profile to ensure subject safety. The objective of this study is to determine whether protease inhibitor regimens that have less of an adverse impact on lipid profiles can maintain a stable CD4 profile compared to standard ritonavir boosted PI regimens.
Antiretroviral regimens that include ritonavir-boosted protease inhibitors are commonly recommended and prescribed, particularly in patients with some degree of drug resistance. Despite the potency of boosted regimens, many HIV-infected patients receiving these regimens have incomplete viral suppression and yet maintain clinical stability and CD4 counts above nadir levels: the so called 'CD4/HIV disconnect' state. It is likely that this state of CD4/HIV discordance is due in part to the maintenance of drug resistant HIV virus that is relatively unfit, that is its replication capacity and ability to infect and destroy CD4 cells is compromised. The selective pressure exerted by antiretroviral therapy appears to be important in maintaining these drug resistant but relatively unfit quasispecies. It has been shown that even patients with CD4 counts below 50 cells/cc and ongoing viremia maintain a clinical benefit from continued therapy.
Unfortunately, lipid abnormalities are commonly seen in patients receiving boosted PI regimens. For example, in a clinical trial in which lopinavir/ritonavir (LPV/r) was given to treatment naïve subjects, approximately 1/3 developed grade 2 or higher lipid abnormalities over 48 weeks. There is a growing concern that these lipid abnormalities will increase the risk of cardiovascular morbidity and mortality. In fact, recent data suggest an increased risk of cardiovascular morbidity and mortality related to HIV infection and/or antiretroviral therapy. There are increasing efforts directed at minimizing long-term toxicities of antiretroviral therapy while maintaining its clinical benefit. (Witness the high degree of interest in treatment interruptions as a strategy to limit toxicities associated with long-term antiretroviral therapy.)
Atazanavir (ATV), a recently approved PI, appears to have little to no impact on the lipid profile in subjects enrolled in clinical trials. Other advantages with atazanavir are its dosing schedule and overall tolerability. Furthermore, recent studies using ritonavir-boosted ATV also show favorable lipid effects compared to LPV/r. Ritonavir boosting provides higher drug levels and therefore may improve the potency of ATV, especially against PI-resistant virus.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00160329
|United States, California|
|Stanford University School of Medicine|
|Stanford, California, United States, 94305|
|Principal Investigator:||Andrew R Zolopa||Stanford University|