Clinical trial NCT00537394
Conditions: HIV Infections
Keywords: Treatment Experienced
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2008-01-01; Completion date: 2013-04-01
Enrollment: 517 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of anti-HIV therapy is to prevent HIV from replicating. Long-term control of HIV requires at least two anti-HIV drugs that are active against the virus. Drug resistance is a problem for many treatment-experienced, HIV-infected people. The purpose of this study was to determine the benefit of adding a nucleoside reverse transcriptase inhibitor (NRTI) to a new anti-HIV drug regimen for the suppression of HIV.

Detailed description:
Two or more fully active antiretrovirals (ARVs) are recommended for successful suppression of HIV. In people infected with resistant HIV virus, finding two drugs that are fully active against HIV can be a challenge. However, the new generation of anti-HIV drugs has been designed to suppress drug-resistant HIV. These drugs include the FDA-approved protease inhibitors (PIs) darunavir and tipranavir, the investigational non-nucleoside transcriptase inhibitor (nNRTI) etravirine, the FDA-approved fusion inhibitor enfuvirtide, the recently FDA-approved CCR5 inhibitor maraviroc, and the investigational integrase inhibitor raltegravir. Also, it is not yet known whether multiple, partially-active drugs have the same rate of success in suppressing HIV. The purpose of this study was to use HIV resistance testing to predict the potency of a suggested ARV regimen using second generation ARVs and determine if the benefits of adding NRTIs to this new drug regimen outweigh the risks of drug toxicity and pill burden. All participants had treatment experience or resistance to NRTIs, nNRTIs, and PIs, and received novel agents.

An active screening period (after enrollment but before randomization or treatment dispensation), occurred for up to 75 days for all participants, and study participation lasted an additional 96 weeks for those who qualified for either randomization or assignment (i.e. not randomized), to the study intervention. During active screening, all participants remained on their current drug regimen. During screening, phenotypic and genotypic HIV resistance tests were performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team determined the best new regimen options for each participant. Each clinician, along with the study participant, then chose a new regimen based on the recommendations of the study team and the participant's preference.

Evaluation for study outcomes began when participants started their new regimen as assigned by either randomization or determined assignment. Stratification between Arms A (Add NRTIs) and B (Omit NRTIs) or Arm C (Non-randomized to Add NRTIs) was based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity were randomly assigned to Arm A (Add NRTIs) or B (Omit NRTIs); those assigned a regimen predicted to have lower activity were not randomized, but were assigned to Arm C (Add NRTIs).

Participants in Arms A and C were instructed to take their newly assigned study regimen plus at least 2 NRTIs (personalized from expert recommendation and choice by local provider and participant) for 96 weeks. Participants in Arm B were instructed to take their newly assigned study regimen with no NRTIs for 96 weeks. Participants in all arms who met the primary efficacy outcome of regimen failure remained in the study in order to be followed for important secondary outcomes.

All participants were scheduled to have 13 clinical visits, which included blood collection. At some visits, urine collection and quality of life and adherence questionnaires occurred. A neurocognitive assessment was performed for all participants at time of starting the new study regimen. Participants may also have consented to have cerebrospinal fluid collected via lumbar puncture following study treatment assignment and/or at Week 24. Those participants who consented to cerebrospinal fluid collection also had neurocognitive assessments at the times of collections. Participants were responsible for obtaining certain ARVs not provided by the study, including the ARVs they during the active screening period.

The primary and secondary study objectives and comparisons relate to the randomized arms, and therefore, results are not provided for the non-randomized arm (C). The purpose of the non-randomized arm (C) was to include persons higher baseline resistance (and thus, lower activity scores) in order to address an exploratory objective related to the predictive power of these activity scores (and thus a larger range of scores by inclusion of arm C), on certain, virologic outcomes.

Arms: arm 1: Regimen with higher predicted activity assigned by the study plus at least 2 NRTIs (personalized choice from expert recommendation) for 96 weeks. A 3-4 drug regimen was selected from the drugs listed to the right. arm 2: Regimen with higher predicted activity assigned by the study without NRTIs for 96 weeks. A 3-4 drug regimen was selected from the drugs listed to the right. arm 3: Regimen with lower predicted activity assigned plus at least 2 NRTIs (personalized choice from expert recommendation) for 96 weeks. A 3-4 drug regimen was selected from the drugs listed to the right.
Interventions: intervention 1: Enfuvirtide intervention 2: Raltegravir intervention 3: Darunavir intervention 4: Tipranavir intervention 5: Etravirine intervention 6: Maraviroc
Intervention descriptions: intervention 1: 90mg subcutaneously twice daily intervention 2: 400 mg twice daily intervention 3: Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study) intervention 4: Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study) intervention 5: Two 100-mg tablets twice daily intervention 6: Dosage dependent on regimen in which maraviroc is included

Protocol documents: