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

• ClinicalTrials.gov Identifier: NCT00145795
• Recruitment Status: Completed
• First Posted: September 5, 2005
• Results First Posted: August 27, 2013
• Last Update Posted: August 27, 2013
• Sponsor: University of Chicago
• Collaborator: Abbott
• Information provided by (Responsible Party): David Pitrak, University of Chicago

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Drug: Kaletra + Current Dual NRTI Backbone; Drug: Current Regimen	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: April 2004
• Actual Primary Completion Date: June 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Kaletra + Current Dual NRTI Backbone; Patients in this arm received Kaletra in addition to their current Dual NRTI Backbone.	Drug: Kaletra + Current Dual NRTI Backbone; Other Name: Lopinavir/ritonavir (LPV/r) + Current Dual NRTI Backbone
Active Comparator: Current Regimen; Patients in this study arm continued their current regimen.	Drug: Current Regimen; Other Name: Current HIV treatment regimen

Outcome Measures

Primary Outcome Measures :

1. Immune Reconstitution [3 Months] [ Time Frame: 3 months ]
   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.
2. Immune Reconstitution [6 Months] [ Time Frame: 6 months ]
   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.

Secondary Outcome Measures :

1. Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [3 Months] [ Time Frame: 3 months ]
   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.
2. Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [3 Months] [ Time Frame: 3 months ]
   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.
3. Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [6 Months] [ Time Frame: 6 months ]
4. Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [6 Months] [ Time Frame: 6 months ]
5. Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [3 Months] [ Time Frame: 3 months ]
6. Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [6 Months] [ Time Frame: 6 months ]
7. Clinical HIV-related Events [ Time Frame: 6 months ]
   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).
8. Rates of Virologic Failure [ Time Frame: 6 months ]
   Virologic failure defined as HIV RNA > 2,000 copies/mL

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Illinois

University of Illinois at Chicago

Chicago, Illinois, United States, 60607

Sponsors and Collaborators

University of Chicago

Abbott

Investigators

• Principal Investigator: David Pitrak, MD; University of Chicago

More Information

Publications of Results:

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.

• Responsible Party: David Pitrak, Professor, University of Chicago
• ClinicalTrials.gov Identifier: NCT00145795
• Other Study ID Numbers: 11711B
• First Posted: September 5, 2005
• Results First Posted: August 27, 2013
• Last Update Posted: August 27, 2013
• Last Verified: August 2013

Keywords provided by David Pitrak, University of Chicago:

HIV; HAART (Highly Active Anti-Retroviral Therapy) partial immune response; no immune response; Treatment Experienced

Additional relevant MeSH terms:

Infections; HIV Infections; Acquired Immunodeficiency Syndrome; Communicable Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Ritonavir; Lopinavir; HIV Protease Inhibitors; Viral 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