• Time to regimen failure [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  

• Toxicity, as defined as time to first Grade 3 or higher (and one grade higher than baseline) signs/symptom or laboratory abnormality [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  
• Tolerability, as defined as time to first dose modification, time to permanent discontinuation of all study drugs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Time to abandoning randomized NRTI strategy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Time to virological failure, as defined by the protocol [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  
• Binary variable indication if viral load is less than 50 copies/ml [ Time Frame: At Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
  
• Change in viral load [ Time Frame: From study entry to Week 1 ] [ Designated as safety issue: No ]
  
• Binary variable indicating acquisition of drug resistance mutations to any of the study agents [ Time Frame: At time of virologic failure ] [ Designated as safety issue: No ]
  
• Change in summarized quality of life score [ Time Frame: At study entry and Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
  
• Binomial indicator of "perfect" adherence to assigned ARVs [ Time Frame: At Weeks 24 and 48 ] [ Designated as safety issue: No ]
  
• Change in cardiovascular risk score and fasting lipid values [ Time Frame: At Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
  
• Change in CD4 count [ Time Frame: From study entry to Week 96 ] [ Designated as safety issue: No ]
  
• Time to serious non-AIDS events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  
• Change in virus coreceptor tropism among those with R5-only tropic virus in Step 1 [ Time Frame: From study entry to time of virological failure and Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
  
• HIV-1 co-receptor tropism [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Binary indicator of undetectable CSF HIV-1 RNA [ Time Frame: At or after Week 24 ] [ Designated as safety issue: No ]
  
• Summarized continuous neuro-cognitive performance Z-scores [ Time Frame: Through Week 96 ] [ Designated as safety issue: No ]
  
• Binary variable indicating whether CSF ARV drug concentrations are above the population median [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• CPE score (CNS penetration effectiveness) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  

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 is 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 will have treatment experience or resistance to NRTIs, nNRTIs, and PIs, and who are receiving novel agents.

This study will have 2 steps and 3 arms. It will last for at least 75 days for all participants and will last an additional 96 weeks for those who continue to Step 2. In Step 1, all participants will remain on their current drug regimen. During this time, phenotypic and genotypic HIV resistance tests will be performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team will determine the best new regimen options for each participant. Each clinician, along with the study participant, will then chose a new regimen based on the recommendations of the study team and the participant's preference.

Step 2 will begin when participants begin their new regimen. Stratification between Arms A and B or Arm C will be based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity will be randomly assigned to Arm A or B; those assigned a regimen predicted to have lower activity will be assigned to Arm C.

Participants in Arms A and C will take their new assigned study regimen plus at least 2 NRTIs for 96 weeks. Participants in Arm B will take their new assigned study regimen with no NRTIs for 96 weeks. Participants in Arms A and B who reach virologic failure before 96 weeks will discontinue the study.

Participants in Arm C who reach virologic failure before 96 weeks will remain in the study.

All participants will have 11 clinical visits. At each visit, blood collection will occur. At some visits, urine collection and quality of life and adherence questionnaires will occur. A neurocognitive assessment will occur for all participants who enter Step 2. Participants may also consent to have cerebrospinal fluid collected via lumbar puncture upon entering Step 2 and/or at Week 24. Those participants who consent to cerebrospinal fluid collection will also have neurocognitive assessments at the times of collections. Participants will be responsible for obtaining certain ARVs not provided by the study, including the ARVs they take in Step 1 and depending on which arm of Step 2 they are in.