Safety and Effectiveness of Lopinavir/Ritonavir in Individuals Who Have Failed Prior HIV Therapy

Most anti-HIV regimens include a non-nucleoside reverse transcriptase inhibitor (NNRTI); however, some individuals fail on these regimens. The purpose of this study is to evaluate the safety and effectiveness of the protease inhibitor (PI) lopinavir/ritonavir (LPV/r) in HIV infected individuals who are failing an anti-HIV regimen that includes an NNRTI.

Standard effective antiretroviral therapy for HIV infected individuals includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a PI or an NNRTI. However, three-drug regimens may not be ideal in resource-limited settings, where viral load and resistance testing may not be readily available. The purpose of this study is to evaluate the safety and efficacy of the PI LPV/r alone in treatment-experienced, PI-naive HIV infected individuals who are experiencing virologic failure on three-drug regimens.

This study will last 104 weeks. All participants will receive LPV/r twice daily for up to 104 weeks. Participants who experience virologic failure will receive emtricitabine/tenofovir disoproxil fumarate once daily in addition to LPV/r twice daily for the remainder of the study.

There will be 16 study visits for participants on LPV/r monotherapy and 12 study visits for participants who have intensified LPV/r with emtricitabine/tenofovir disoproxil fumarate. Blood collection and clinical assessment will occur at all visits; urine collection and resistance testing will occur at selected visits.

Eligibility Criteria:
Inclusion Criteria for Step 1 Participants:

* HIV infected
* Continuous treatment with a three-drug, NNRTI-containing regimen for at least 6 months prior to study entry
* Viral load of 1,000 copies/ml or greater and less or equal to 200,000 copies/ml obtained within 30 days of study entry
* Negative pregnancy test within 48 hours of study entry
* Willing to use acceptable forms of contraception for the duration of the study
* Laboratory values obtained within 30 days of study entry:

  * Hemoglobin greater or equal to 8.0 g/dL
  * Platelet count greater or equal to 50,000/mm3
  * Estimated Creatinine Clearance greater or equal to 60 mL/min x ULN
  * AST (SGOT), ALT (SGPT) and alkaline phosphatase \< 3 x ULN
  * Total bilirubin less or equal to 2.5 x ULN
* Ability and willingness of participant or legal guardian/representative to give informed consent

Inclusion Criteria for Step 2 Participants:

* Virologic failure on LPV/r monotherapy defined as viral load of 400 copies/ml or greater after 24 consecutive weeks on LPV/r monotherapy OR virologic failure after initial viral suppression on LPV/r monotherapy
* Estimated creatinine clearance of 60 ml/min or greater
* Negative pregnancy test within 48 hours of entry into Step 2
* Willing to use acceptable forms of contraception for the duration of the study

Exclusion Criteria for All Participants:

* Breastfeeding
* Known allergy or sensitivity to study drugs
* Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with study adherence to study requirements
* History of chronic hepatitis B infection

Exclusion Criteria for Step I Participants:

* Prior use of any protease inhibitor treatment
* Acute therapy for any serious medical condition within 14 days of study entry. For ongoing or chronic therapy, the participant must be on the treatment regimen for at least 14 days, and clinically stable prior to entry. If a potential participant has TB and has received treatment for more than 2 weeks, the TB treatment would have to be modified to include a rifabutin-containing regimen. TB compatible syndromes will also be carefully evaluated prior to entry.

Exclusion Criteria for Step 2 Participants:

- Active opportunistic infection, including tuberculosis (TB)