HIV InfectionsPhase 4NCT00145795
A Research Study to See if a Change in Therapy for HIV Infection Can Improve the Immune Response to Treatment
A Phase 4 study testing Kaletra + Current Dual NRTI Backbone and Current Regimen in people with HIV Infections, run by University of Chicago at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- Kaletra + Current Dual NRTI Backbone and Current Regimen
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2004to Dec 2009
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Illinois at Chicago
Chicago, Illinois, 60607
About this study
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
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.
Read the 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.
- Conditions
- HIV Infections
- Being tested
- Kaletra + Current Dual NRTI Backbone, Current Regimen
- Keywords
- HIV, HAART (Highly Active Anti-Retroviral Therapy) partial immune response, no immune response, Treatment Experienced
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Kaletra + Current Dual NRTI BackboneDrug
Also called Lopinavir/ritonavir (LPV/r) + Current Dual NRTI Backbone
Current RegimenDrug
Also called Current HIV treatment regimen
| Study group | Role | What they receive |
|---|---|---|
| Kaletra + Current Dual NRTI Backbone | Experimental | Patients in this arm received Kaletra in addition to their current Dual NRTI Backbone. Receives: Drug: Kaletra + Current Dual NRTI Backbone |
| Current Regimen | Active comparator | Patients in this study arm continued their current regimen. Receives: Drug: Current Regimen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Immune Reconstitution [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.
Measured: 3 months
Immune Reconstitution [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.
Measured: 6 months
Secondary outcomes (8)
Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [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.
Measured: 3 months
Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [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.
Measured: 3 months
Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [6 Months]
Measured: 6 months
Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [6 Months]
Measured: 6 months
Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [3 Months]
Measured: 3 months
Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [6 Months]
Measured: 6 months
Clinical HIV-related Events
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).
Measured: 6 months
Rates of Virologic Failure
Virologic failure defined as HIV RNA > 2,000 copies/mL
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Sep 2005 (estimated)
- Study startApr 2004
- Primary completionJun 2009
- Study completionDec 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Collaborators
- Abbott
- Responsible party
- Sponsor
- Investigators
- David Pitrak, MD, Principal investigator, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00145795
- Sponsor's protocol ID
- 11711B
- Status last verified
- May 2022
- First submitted
- 1 Sep 2005
- Last updated
- 15 Jun 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 21054216
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00145795
- Acronym / sponsor ID
- 11711B
- Conditions
- HIV Infections
- Keywords
- HIV, HAART (Highly Active Anti-Retroviral Therapy) partial immune response, no immune response, Treatment Experienced
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Collaborators
- Abbott
- Study start
- Apr 2004
- Primary completion
- Jun 2009 (actual)
- Study completion
- Dec 2009 (actual)
- First posted
- 5 Sep 2005 (estimated)
- Results
- Posted 27 Aug 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Kaletra + Current Dual NRTI Backbone | Experimental | Drug: Kaletra + Current Dual NRTI BackbonePatients in this arm received Kaletra in addition to their current Dual NRTI Backbone. |
| Current Regimen | Active comparator | Drug: Current RegimenPatients in this study arm continued their current regimen. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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)
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Kaletra + Current Dual NRTI BackboneAlso: Lopinavir/ritonavir (LPV/r) + Current Dual NRTI Backbone | Drug | Kaletra + Current Dual NRTI Backbone |
| Current RegimenAlso: Current HIV treatment regimen | Drug | Current Regimen |
Primary outcome
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.
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.
8 secondary outcomes
Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [3 Months]
Time frame: 3 months
Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [3 Months]
Time frame: 3 months
Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [6 Months]
Time frame: 6 months
Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [6 Months]
Time frame: 6 months
Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [3 Months]
Time frame: 3 months
Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [6 Months]
Time frame: 6 months
Clinical HIV-related Events
Time frame: 6 months
Rates of Virologic Failure
Time frame: 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 21054216Pitrak 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Pitrak, MD principal investigator
University of Chicago
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Kaletra + Current Dual NRTI Backbone and Current Regimen in people with HIV Infections, run by University of Chicago at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Aug 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immune Reconstitution [3 Months] (time frame: 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00145795, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2022.