Kaletra-isentress Treatment Evaluation

RATIONALE: Virologic failure and adverse effects associated with current highly active antiretroviral therapy (HAART) warrant continuing search for novel combination therapeutic options. Raltegravir's (RAL) was recently shown to be a potent antiretroviral (ARV) agent with a favorable safety profile. If future reports continue to show positive data on this first-in-class integrase inhibitor, there may be a paradigm shift in the currently recommended first line HAART to regimens that will include integrase inhibitors.

Combining RAL with a drug that has a high genetic barrier to resistance, such as lopinavir/ritonavir (LPV/r) may offer a number of advantages. Both agents are potent and should produce durable virologic suppression. Because their combination is reverse transcriptase inhibitor (RTI) class sparing, its tolerability might be superior. In addition, RAL is not metabolized by the cytochrome P-450 enzymes, therefore, a compatible pharmacokinetic profile is expected with this combination. Pairing LPV/r with RAL in early ARV regimens as is proposed in this application may provide a HAART regimen that is highly efficacious and durable, with less resistance and adverse drug events.

DESIGN: This is single center, open label, randomized, controlled, study designed to assess the tolerability, pharmacokinetic compatibility, and the durability of virologic suppression of the RTI sparing combination therapy of LPV/r + RAL. HIV-infected subjects who are virologically suppressed (HIV-RNA PCR < 50 copies/ml) on current HAART regimen will be randomized in a 2:1 fashion to be switched to a regimen consisting of LPV/r + RAL, intervention arm A (n=40), or to be continued on their pre-study HAART regimen, control arm B (n=20). The primary endpoint will be proportion of subjects with sustained virologic suppression (HIV-1 RNA PCR < 50 copies/ml) through week 48. The immunoreconstitution, toxicity profile, and pharmacokinetic profile of the RAL and LPV/r in this novel combination therapy will be evaluated.

DURATION: 48 weeks after the enrollment of the last participant. Enrollment is expected to take about 10 months.

SAMPLE SIZE: 60 subjects.

POPULATION: HIV-infected individuals (male and female), Age > 18 years, who are virologically suppressed (HIV-RNA PCR < 50 copies/ml) on their current HAART regimen for > 6 months.

REGIMEN: For Arm A= LPV/r 400/100 mg (2 tablets) twice daily + RAL 400 mg (1 tablet) twice daily taken by mouth. For Arm B=Pre-study HAART regimen.

Inclusion criteria

• HIV-1-infected individuals receiving HAART regimen (if on PI-based regimen, must be 1st PI-containing HAART).
• They must have been on and tolerating current HAART regimen for > 6-months.
• Plasma HIV-1 viral load < 50 copies/ml at study entry.
• Men and women age > 18 years (sex is defined as sex at birth).
• Laboratory values obtained within 30 days prior to study entry:

• Hemoglobin > 9.4 g/dl
• Creatinine < 2 mg/dl
• AST (SGOT) < 2 x ULN
• ALT (SGPT) < 2 x ULN
• Ability and willingness of subject or legal guardian/representative to give written informed consent.
• No CD4 T-cell counts requirement

Exclusion criteria

• Subjects with a history of previous intolerance to or virological failure to LPV/r
• Concomitant drugs (including alternative therapies) that may affect PI or RAL plasma concentrations (inducers or inhibitors of the CYP 3A4 or UDP-glucuronosyltransferase iso-enzymes).
• A known history of noncompliance with medications or a known history of noncompliance with scheduled physician and clinic visits.
• Investigational ARV drug.
• Pregnancy/Breast feeding.
• HBV-coinfected patients receiving nucleoside analogue for both HIV and HBV suppression.
• Active drug or alcohol use or dependence which, in the Investigator's opinion, may interfere with adherence to study requirements or endanger subject's health while on the study.
• Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to the screening visit.