Clinical trial NCT00145795: A Research Study to See if a Change in Therapy for HIV Infection Can Improve the Immune Response to 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: HIV
HAART (Highly Active Anti-Retroviral Therapy) partial immune response
no immune response
Treatment Experienced
Lead sponsor: University of Chicago
Sponsor class: OTHER
Collaborators: name: Abbott
First posted: 2005-09-05
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Immune Reconstitution [3 Months]
timeFrame: 3 months
measure: Immune Reconstitution [6 Months]
timeFrame: 6 months
Secondary outcomes:
measure: Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [3 Months]
timeFrame: 3 months
measure: Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [3 Months]
timeFrame: 3 months
measure: Rates of ex Vivo T Cell Apoptosis: CD4+ Memory Cell Population [6 Months]
timeFrame: 6 months
measure: Rates of ex Vivo T Cell Apoptosis: CD4+ naïve Cell Population [6 Months]
timeFrame: 6 months
measure: Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [3 Months]
timeFrame: 3 months
measure: Rates of ex Vivo T Cell Apoptosis: CD8+ Cell Population [6 Months]
timeFrame: 6 months
measure: Clinical HIV-related Events
timeFrame: 6 months
measure: Rates of Virologic Failure
timeFrame: 6 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
Study officials:
affiliation: University of Chicago
name: David Pitrak, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.