Optimizing Treatment for Treatment-Experienced, HIV-Infected People

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.

Inclusion Criteria:

- HIV-1 infection

- Triple-class drug experience or resistance. More information on this criterion can be
found in the protocol.

- Currently on a failing PI-containing regimen that includes 2 other ARVs with no
regimen change for 8 weeks prior to study screening

- HIV viral load of 1000 copies/ml or more

- Hepatitis B surface antigen negative within 90 days of study entry

- Able to obtain NRTIs and ritonavir and have required ARVs at time of starting study
intervention

- Willing to use acceptable forms of contraception

- Parent or legal guardian willing to provide consent, if applicable

- CD4 count result from a specimen drawn within 120 days prior to study entry

- If any previous HIV-1 viral co-receptor tropism result is available, then most recent
specimen date and the tropism result of that specimen AND specimen date and tropism
result of any test with either X4 or D/M result, if different from the first
specimen, must be available

Inclusion Criteria continued:

- Receipt of successful phenotype/genotype resistance results within 105 days prior to
study treatment intervention assignment

- Study team identification of a study regimen and at least 2 NRTIs for participant to
take

- Certain abnormal laboratory values. More information on this criterion can be found
in the protocol.

Exclusion Criteria:

- Chronic, active hepatitis B virus infection (hepatitis B surface antigen positive or
HBV DNA positive)

- Taking certain medications. More information on this criterion can be found in the
protocol.

- Known allergy/sensitivity to components of two or more of the study-provided drugs or
their formulations. For maraviroc, this includes hypersensitivity or history of
allergy to soy lecithin or peanuts.

- Active drug or alcohol use that, in the opinion of the investigator, may interfere
with the study

- Pregnancy or breastfeeding

- Use of any immunomodulator (interferons, interleukins, systemic corticosteroids, or
cyclosporine), vaccine, or investigational therapy within 30 days prior to study
treatment allocation/assignment

- Require certain medications prohibited with study treatment

- Serious illness requiring systemic treatment or hospitalization. Participants who
complete therapy or are clinically stable on therapy for at least 14 days prior to
study treatment allocation are not excluded.