A Research Study to See if a Change in Therapy for HIV Infection Can Improve the Immune Response to Treatment

This study has been completed.
Sponsor:
Collaborator:
Abbott
Information provided by (Responsible Party):
David Pitrak, University of Chicago
ClinicalTrials.gov Identifier:
NCT00145795
First received: September 1, 2005
Last updated: August 23, 2013
Last verified: August 2013

September 1, 2005
August 23, 2013
April 2004
June 2009   (final data collection date for primary outcome measure)
  • Immune Reconstitution [3 Months] [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Immune reconstitution is defined as the absolute CD4+ lymphocyte count after 3 months of therapy. Absolute CD4+ T cell count, our measure of immune recovery, was assessed in the clinical laboratory using fluorescent labeled monoclonal antibodies to the CD4 on lymphocytes. This is the main target cell for HIV infection. The absolute CD4+ T cell count is also the only clinically validated surrogate marker of immune dysfunction in HIV. CD4+ count is also our best predictor of morbidity and mortality outcomes.
  • Immune Reconstitution [6 Months] [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Immune reconstitution is defined as the absolute CD4+ lymphocyte count after 6 months of therapy. Absolute CD4+ T cell count, our measure of immune recovery, was assessed in the clinical laboratory using fluorescent labeled monoclonal antibodies to the CD4 on lymphocytes. This is the main target cell for HIV infection. The absolute CD4+ T cell count is also the only clinically validated surrogate marker of immune dysfunction in HIV. CD4+ count is also our best predictor of morbidity and mortality outcomes.
Immune reconstitution measured as increase in absolute CD4+ lymphocyte count after 3 and 6 months of therapy
Complete list of historical versions of study NCT00145795 on ClinicalTrials.gov Archive Site
  • Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [3 Months] [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Ex vivo T cell apoptosis can be assessed many different ways. The use of propidium iodide staining to determine the proportion of isolated cells that have undergone apoptosis after ex vivo incubation is a standard method that has been used by many investigators. Apoptotic cells intercalate less PI into their DNA, and on flow cytometry, this cell population is identified by a decrease in mean fluorescence (shift to the left). We have experience with this assay, and we have published on the use of method for determining rates of ex vivo apoptosis for different immune effector cells.
  • Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [3 Months] [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Ex vivo T cell apoptosis can be assessed many different ways. The use of propidium iodide staining to determine the proportion of isolated cells that have undergone apoptosis after ex vivo incubation is a standard method that has been used by many investigators. Apoptotic cells intercalate less PI into their DNA, and on flow cytometry, this cell population is identified by a decrease in mean fluorescence (shift to the left). We have experience with this assay, and we have published on the use of method for determining rates of ex vivo apoptosis for different immune effector cells.
  • Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [6 Months] [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [6 Months] [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [3 Months] [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [6 Months] [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Clinical HIV-related Events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Number of participants experiencing clinical HIV-related events as defined by category A, category B, and Appendix B in the "1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults" (http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm).
  • Rates of Virologic Failure [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Virologic failure defined as HIV RNA > 2,000 copies/mL
1.) Rates of ex vivo T cell apoptosis, CD4+, CD8+, both memory and naïve cell populations, 2.) Clinical HIV-related events, and 3.) virologic failure defined as HIV RNA > 2,000 copies/mL
Not Provided
Not Provided
 
A Research Study to See if a Change in Therapy for HIV Infection Can Improve the Immune Response to Treatment
Randomized Trial of a Switch to a Kaletra + Current Dual Nucleoside Reverse Transcriptase Inhibitor (NRTI) Backbone Versus Continuation of the Current Regimen in Patients With Poor Immune Responses to Highly Active Antiretroviral Therapy (HAART) in Patients With Complete Viral Suppression: A Pilot Study

Our goal is to determine if a change in therapy to one containing Kaletra can improve the immune response in patients who have previously been immune partial responders or non-responders. We also are interested in knowing if this agent improves immune response by affecting cluster of differentiation 4 (CD4) + T cell death (apoptosis) or by further inhibiting (preventing) ongoing, low-level, viral replication to levels below detection by current viral load measurements. This will help us understand why immune responses to effective antiretroviral therapy are so different and help determine some possible guidelines for managing patients with poor immune responses.

Hypothesis: Patients with poor immune responses to HAART who receive Kaletra in place of their current PI or Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) while continuing their current 2 NRTI backbone will have improved immune response to therapy compared to patients who continue their current regimen.

To our knowledge our study is the first study showing persistent apoptosis in a subgroup of patients with complete viral suppression in association with poor immune recovery. Immune alterations independent of active viral replication may be responsible. Recent data suggests that immune responses to antiretroviral therapy depend on residual or restored thymic function. Improved CD4+ counts in patients despite virologic treatment failure are associated with greater thymic function, while poor T cell responses despite suppression of HIV are seen with decreased thymic function. Discordant immune responses may also be due to differential effects of particular antiretroviral agents on T cell apoptosis independent of viral suppression. For example, protease inhibitors have been shown to decrease rates of apoptosis of uninfected T cells. Viral replication is never completely suppressed with HAART, even when patients have undetectable plasma HIV RNA. Therefore, varying degrees of low level viral replication or replication in certain cellular compartments may continue to drive T cell apoptosis. Finally, our data suggests that ex vivo rates of Peripheral blood mononuclear cell (PBMC) apoptosis could potentially be used predict immune recovery or identify subgroups of patients who may benefit most from changes in HAART or adjunctive immunomodulatory therapies.

At this time, although there are excellent guidelines for how to evaluate and change therapy for patients with virologic failure, there are no recommendation and little data on approaches or strategies to change therapy for patients with poor immune responses. Kaletra (lopinavir/ritonavir) may be of benefit to patients with poor immune responses to HAART despite viral suppression. Kaletra may have greater potency and better suppression of viral replication that is below the level of detection by plasma polymerase chain reaction (PCR) for HIV-1 RNA. Kaletra also has an excellent pharmacokinetic profile which may result in superior inhibition of T cell apoptosis in vivo.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
HIV Infections
  • Drug: Kaletra + Current Dual NRTI Backbone
    Other Name: Lopinavir/ritonavir (LPV/r) + Current Dual NRTI Backbone
  • Drug: Current Regimen
    Other Name: Current HIV treatment regimen
  • Experimental: Kaletra + Current Dual NRTI Backbone
    Patients in this arm received Kaletra in addition to their current Dual NRTI Backbone.
    Intervention: Drug: Kaletra + Current Dual NRTI Backbone
  • Active Comparator: Current Regimen
    Patients in this study arm continued their current regimen.
    Intervention: Drug: Current Regimen
Pitrak DL, Estes R, Novak RM, Linnares-Diaz M, Tschampa JM. Beneficial effects of a switch to a Lopinavir/ritonavir-containing regimen for patients with partial or no immune reconstitution with highly active antiretroviral therapy despite complete viral suppression. AIDS Res Hum Retroviruses. 2011 Jun;27(6):659-67. doi: 10.1089/AID.2010.0230. Epub 2010 Dec 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
20
December 2009
June 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV Infection documented CD4+ count within the last 30 days (or drawn with screening labs)
  • Currently on a stable 3-drug HAART regimen including 2 NRTIs for > 6 month viral load (VL) < 50/mm3 for > 6 months, last within the last 30 days (or drawn with screening labs)
  • Partial immune responder or immune non-responder
  • Age > 18 years
  • Labs (drawn at screening)
  • Alanine transaminase (ALT) < 5 X the upper limit of normal (ULN)
  • Total bili < 2 X ULN
  • Creatinine < 2.0 mg/dL

Exclusion Criteria:

  • Prior therapy with Kaletra
  • Known hypersensitivity to Ritonavir
  • Therapy the drugs with potential serious drug interactions: flecainide, propafenone, astemizole, terfenadine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, lovastatin, simvastatin, midazolam, triazolam, and St. John's wart.
  • Pregnancy; breast feeding
  • Current malignancy requiring CT
  • Use of systemic corticosteroids, immunosuppressive, or cytotoxic agents within the last 45 days
  • Fever and/or evidence of an active infectious complication
  • Currently in another interventional clinical trial
  • Receiving Interleukin-2 (IL-2) or any other cytokine or growth factor
  • Enrollment in another interventional clinical trial
Both
18 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00145795
11711B
Yes
David Pitrak, University of Chicago
University of Chicago
Abbott
Principal Investigator: David Pitrak, MD University of Chicago
University of Chicago
August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP