HIV Infections
Conditions
Keywords
Treatment Experienced
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.
Interventions
DRUGEnfuvirtide
90mg subcutaneously twice daily
DRUGRaltegravir
400 mg twice daily
DRUGDarunavir
Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)
DRUGTipranavir
Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)
DRUGEtravirine
Two 100-mg tablets twice daily
DRUGMaraviroc
Dosage dependent on regimen in which maraviroc is included
Sponsors
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment | From study entry to end of Week 48 evaluation window | Virologic failure defined as confirmed plasma HIV-1 RNA meeting 1 of the following 4 criteria: \< 1.0 log10 copies/mL reduction from baseline level and \>= 200 copies/mL at or after week 12 evaluation; \>= 200 copies/mL after 1 measurement \< 200 copies/mL; absence of any values \< 200 copies/mL by and including week 24 evaluation; \>= 200 copies/mL at week 48 evaluation. Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for the discontinuation outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Results report percent of participants reaching regimen failure outcome by week 48 evaluation using Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | From treatment dispensation to week 96 study visit | First study ARV modification included any discontinuation or substitution of any chosen and initiated ARV for any reason. Events prompting study medication change could include protocol required (e.g. safety), protocol recommended but not required (e.g. virologic failure), or participant motivated (such as non-adherence, loss to follow-up or death; in other words, not protocol recommended or required). Event times were the exact weeks from treatment initiation to the time of qualifying regimen modification. Censoring times were the exact weeks from treatment initiation to the last date of study drugs. The week 96 (final study visit) could occur up through 110 weeks following randomization. |
| Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | From randomization to week 96 study visit | Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for meeting this outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Event times were scheduled study weeks when discontinuation events occurred. Censoring times were latest scheduled study visit weeks with evaluation. |
| Time From Randomization to Confirmed Virological Failure | From randomization to week 96 study visit | Virologic failure defined as confirmed (two consecutive) plasma HIV-1 RNA meeting 1 of the following 4 criteria: \< 1.0 log10 copies/mL reduction from baseline level and \>= 200 copies/mL at or after week 12 evaluation; \>= 200 copies/mL after 1 measurement \< 200 copies/mL; absence of any values \< 200 copies/mL by and including week 24 evaluation; \>= 200 copies/mL at week 48 evaluation. Event time was the scheduled study visit week when the initial plasma HIV-1 RNA specimen meeting the failure definition was collected. Censoring time was the latest scheduled study visit week when a plasma HIV-1 RNA specimen was collected and tested. |
| Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | At Weeks 24, 48, 96 | Number of participants with plasma HIV-1 Viral load \< 50 copies/mL at study visit weeks 24, 48, and 96. Closest observed result between 20 and up to 30 weeks (for week 24), between 42 and up to 54 (for week 48), and between 90 and up to 110 (for week 96) used if multiple results available. Missing values excluded. |
| Change in Plasma HIV-1 Viral Load From Baseline to Week 1 | From baseline to Week 1 evaluation | Method of Kaplan and Meier used to accommodate left-censoring for those whose week 1 levels \< 50 copies/mL. |
| Change in Summarized Quality of Life Score | At study entry and Weeks 24, 48, 96 | Quality-of-life score at each evaluation based upon a single question assessing participants' self-report of general health with a range of 0 (representing worst health status) to 100 (representing perfect health). |
| Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | From treatment dispensation to week 96 study visit | Events following permanent discontinuation of NRTI assignment are excluded (i.e. censoring at time of this event, if applicable). Week 96 study visit could occur up to 110 weeks following randomization. Censoring time was the latest study visit when participant was evaluated or when NRTI assignment was discontinued (when applicable). Event time was the exact number of weeks following treatment initiation when the qualifying sign/symptom started (for those safety events triggered by a sign/symptom), or exact number of weeks following treatment initiation when specimen from qualifying laboratory result was drawn (for those safety events triggered by a laboratory abnormality). |
| Change in Cardiovascular Risk Score From Baseline | At Weeks 24, 48, and 96 | Cardiovascular risk score defined by Framingham providing an estimate of the probability of developing cardiovascular disease over the next 10-year period. Persons with a historical cardiovascular event (CAD, cerebro- or peripheral- vascular disorder, MI or stroke), were excluded, and scores were not calculated at follow-up times after individuals had a cardiovascular event. Missing values for input data (e.g. smoking status) resulted in a missing value for Framingham score. |
| Change in CD4 Count From Baseline | From study entry to Weeks 48 and 96 | Baseline CD4 calculated as average of pre-entry and entry values. Closest observed result between 42 and up to 54 weeks (for week 48) or between 90 and up to 110 weeks (for week 96), used if multiple results available. Missing values excluded. |
| Time From Treatment Dispensation to Serious Non-AIDS-defining Events | From treatment initiation to week 96 study visit | Serious Non-AIDS defining Events were adjudicated by independent and blinded review and possible events included serious diagnoses in the following disease areas: liver, cardiovascular, end-stage renal, non-AIDS malignancy, and diabetes mellitus. Week 96 study visit could take place up to 110 weeks following randomization. Event times were the exact weeks following treatment initiation corresponding to the diagnosis dates of the qualifying serious non-AIDS defining events. Censoring times were the weeks following treatment initiation corresponding to the latest study visit. |
| Number of Participants With Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry | From study entry to time of confirmed virological failure (up to 96 weeks) | HIV Co-receptor tropism test result of either dual/mixed or evidence of X4 using virus from sample collected at confirmed virologic failure. |
| Change in Fasting Non-HDL Cholesterol From Baseline | From study entry to Weeks 24, 48 | Fasting non-HDL cholesterol calculated from difference between fasting total cholesterol and fasting HDL level. Missing values and non-fasting values excluded. |
| Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure | Between baseline and confirmed virologic failure (up to 96 weeks) | Defined among the subgroup of participants experiencing the outcome of confirmed virologic failure. Newly acquired HIV drug resistance is defined as one or more ARVs with partial resistance or resistance when pre-entry resistance was fully sensitive or resistant when pre-entry resistance was fully sensitive or partially sensitive. The ARVs included for resistance acquisition included the following: darunavir/ritonavir; etravirine, tipranavir, tenofovir, emtracitabine, lamivudine, zidovudine, abacavir. |
| Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) | At Weeks 24 and 48 | Results represent self-report of non-adherence during the 4-day period prior to the outcome evaluation visit. Participants in follow-up for whom these data are missing for any reason are inferred as not-adherent. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Subjects recruited between February 2008 and May 2011 from participating ACTG, IMPAACT, and ATN network sites located in the continental US and Puerto Rico.
Pre-assignment details
A total of 104 exclusions among 517 enrolled to active screening but prior to assignment and dispensation of study treatment were due to any of the following: no resistance/tropism test results, not willing to accept any ARV study regimens, changes to current PI based ARV regimen or non-adherence, or changes with respect to eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) Individualized ARV study regimen with antiretroviral potency defined as continuous phenotype sensitivity score (cPSS) greater than 2.0 recommended and chosen prior to randomization. To this regimen, an individualized NRTI combination of at least 2 drugs from this class, chosen prior to randomization, was also started. | 181 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) Individualized ARV study regimen with antiretroviral potency defined as continuous phenotype sensitivity score (cPSS) greater than 2.0 recommended and chosen prior to randomization. To this regimen, an individualized NRTI combination of at least 2 drugs from this class, chosen prior to randomization, was omitted, and any NRTIs the participant had been taking prior to randomization were to be permanently discontinued. | 179 |
| Non-randomized Group: Add NRTIs to Individual Regimen cPSS <=2 Among persons whose ARV resistance and history profile precluded any of the 20 possible ARV regimens having high enough potential potency (cPSS \<=2), treatment was assigned rather than being a randomized. To their regimen, individualized NRTI combination of at least 2 drugs from this class were added in order to form the most potent ARV regimen possible. | 53 |
| Total | 413 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 2nd Year of Follow-up | Clinic site closure | 1 | 0 | 0 |
| 2nd Year of Follow-up | Death | 4 | 1 | 2 |
| 2nd Year of Follow-up | Lost to Follow-up | 6 | 7 | 2 |
| 2nd Year of Follow-up | Withdrawal by Subject | 0 | 1 | 2 |
| First Year of Follow-up | Death | 7 | 0 | 0 |
| First Year of Follow-up | Lost to Follow-up | 1 | 5 | 1 |
| First Year of Follow-up | Severe debilitation | 1 | 0 | 1 |
| First Year of Follow-up | Withdrawal by Subject | 3 | 6 | 1 |
Baseline characteristics
| Characteristic | Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Non-randomized Group: Add NRTIs to Individual Regimen cPSS <=2 | Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 3 Participants | 6 Participants | 17 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 168 Participants | 50 Participants | 173 Participants | 391 Participants |
| Age, Continuous | 44.1 years STANDARD_DEVIATION 11.7 | 43.1 years STANDARD_DEVIATION 10.7 | 44.7 years STANDARD_DEVIATION 10.8 | 44.3 years STANDARD_DEVIATION 11.2 |
| CD4 count, continuous | 245.6 cells/mm^3 STANDARD_DEVIATION 195.1 | 154.8 cells/mm^3 STANDARD_DEVIATION 170.1 | 252.3 cells/mm^3 STANDARD_DEVIATION 194.9 | 236.9 cells/mm^3 STANDARD_DEVIATION 194.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 46 Participants | 14 Participants | 37 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 132 Participants | 38 Participants | 141 Participants | 311 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Plasma HIV-1 RNA, continuous | 4.2 log10 copies/mL | 4.4 log10 copies/mL | 4.2 log10 copies/mL | 4.2 log10 copies/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 72 Participants | 20 Participants | 81 Participants | 173 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 2 Participants | 8 Participants | 21 Participants |
| Race (NIH/OMB) White | 87 Participants | 29 Participants | 88 Participants | 204 Participants |
| Region of Enrollment United States | 179 participants | 53 participants | 181 participants | 413 participants |
| Sex: Female, Male Female | 47 Participants | 6 Participants | 46 Participants | 99 Participants |
| Sex: Female, Male Male | 132 Participants | 47 Participants | 135 Participants | 314 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 169 / 180 | 165 / 177 |
| serious Total, serious adverse events | 58 / 180 | 49 / 177 |
Outcome results
Primary
Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment
Virologic failure defined as confirmed plasma HIV-1 RNA meeting 1 of the following 4 criteria: \< 1.0 log10 copies/mL reduction from baseline level and \>= 200 copies/mL at or after week 12 evaluation; \>= 200 copies/mL after 1 measurement \< 200 copies/mL; absence of any values \< 200 copies/mL by and including week 24 evaluation; \>= 200 copies/mL at week 48 evaluation. Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for the discontinuation outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Results report percent of participants reaching regimen failure outcome by week 48 evaluation using Kaplan-Meier method.
Time frame: From study entry to end of Week 48 evaluation window
Population: Analysis uses intent to treat population, among the two randomized arms only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment | 26.0 percentage of participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment | 29.8 percentage of participants |
Comparison: Null Hypothesis was that omitting NRTIs is inferior to adding NRTIs for the outcome of regimen failure through 48 weeks.95% CI: [-6.1, 12.5]
Secondary
Change in Cardiovascular Risk Score From Baseline
Cardiovascular risk score defined by Framingham providing an estimate of the probability of developing cardiovascular disease over the next 10-year period. Persons with a historical cardiovascular event (CAD, cerebro- or peripheral- vascular disorder, MI or stroke), were excluded, and scores were not calculated at follow-up times after individuals had a cardiovascular event. Missing values for input data (e.g. smoking status) resulted in a missing value for Framingham score.
Time frame: At Weeks 24, 48, and 96
Population: Persons not starting treatment (N=1; N=2), who had cardiovascular disease prior to study entry (N=12; N=8), or were missing input values needed to calculate a baseline Framingham score (N= 6; N=4), were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Cardiovascular Risk Score From Baseline | Week 24 (N= 150; N=147) | -0.7 units on a scale | Standard Deviation 4.4 |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Cardiovascular Risk Score From Baseline | Week 48 (N=143; N=144) | 0.1 units on a scale | Standard Deviation 4.3 |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Cardiovascular Risk Score From Baseline | Week 96 (N=129; N=132) | 0.5 units on a scale | Standard Deviation 5.2 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Cardiovascular Risk Score From Baseline | Week 48 (N=143; N=144) | 0.8 units on a scale | Standard Deviation 4.9 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Cardiovascular Risk Score From Baseline | Week 24 (N= 150; N=147) | 0.3 units on a scale | Standard Deviation 4.9 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Cardiovascular Risk Score From Baseline | Week 96 (N=129; N=132) | 1.1 units on a scale | Standard Deviation 5 |
Secondary
Change in CD4 Count From Baseline
Baseline CD4 calculated as average of pre-entry and entry values. Closest observed result between 42 and up to 54 weeks (for week 48) or between 90 and up to 110 weeks (for week 96), used if multiple results available. Missing values excluded.
Time frame: From study entry to Weeks 48 and 96
Population: All subjects in the two randomized arms were assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in CD4 Count From Baseline | Change from entry to week 48 (N=166; N=163) | 105.5 cells/mm^3 |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in CD4 Count From Baseline | Change from entry to week 96 (N= 154; N=157) | 140.8 cells/mm^3 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in CD4 Count From Baseline | Change from entry to week 48 (N=166; N=163) | 89.5 cells/mm^3 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in CD4 Count From Baseline | Change from entry to week 96 (N= 154; N=157) | 115.5 cells/mm^3 |
Secondary
Change in Fasting Non-HDL Cholesterol From Baseline
Fasting non-HDL cholesterol calculated from difference between fasting total cholesterol and fasting HDL level. Missing values and non-fasting values excluded.
Time frame: From study entry to Weeks 24, 48
Population: All randomized participants who started study treatment. Non-fasting results and missing results excluded from analysis. Therefore, differences reported here represent a complete case analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Fasting Non-HDL Cholesterol From Baseline | Change from baseline to week 24 (N=131; N=121) | 4.1 mg/dL | Standard Deviation 35.8 |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Fasting Non-HDL Cholesterol From Baseline | Change from baseline to week 48 (N=125 ; N=117) | 7.6 mg/dL | Standard Deviation 35.5 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Fasting Non-HDL Cholesterol From Baseline | Change from baseline to week 24 (N=131; N=121) | 20.8 mg/dL | Standard Deviation 39.8 |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Fasting Non-HDL Cholesterol From Baseline | Change from baseline to week 48 (N=125 ; N=117) | 19.8 mg/dL | Standard Deviation 34.1 |
Secondary
Change in Plasma HIV-1 Viral Load From Baseline to Week 1
Method of Kaplan and Meier used to accommodate left-censoring for those whose week 1 levels \< 50 copies/mL.
Time frame: From baseline to Week 1 evaluation
Population: Modified intent to treat population among two randomized arms only: 2 participants (both in Omit NRTIs arm) were excluded because their baseline and week 1 RNA levels were both \< 50 copies/mL.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Plasma HIV-1 Viral Load From Baseline to Week 1 | 1.3 log10 copies/mL |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Plasma HIV-1 Viral Load From Baseline to Week 1 | 1.4 log10 copies/mL |
Secondary
Change in Summarized Quality of Life Score
Quality-of-life score at each evaluation based upon a single question assessing participants' self-report of general health with a range of 0 (representing worst health status) to 100 (representing perfect health).
Time frame: At study entry and Weeks 24, 48, 96
Population: Two randomized arms only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Summarized Quality of Life Score | Change from baseline to week 24 (N=165; N=165) | 0 units on a scale |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Summarized Quality of Life Score | Change from baseline to week 48 (N=161; N=158) | 0 units on a scale |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Change in Summarized Quality of Life Score | Change from baseline to week 96 (N=155; N=154) | 0 units on a scale |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Summarized Quality of Life Score | Change from baseline to week 96 (N=155; N=154) | 0.5 units on a scale |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Summarized Quality of Life Score | Change from baseline to week 24 (N=165; N=165) | 5 units on a scale |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Change in Summarized Quality of Life Score | Change from baseline to week 48 (N=161; N=158) | 0 units on a scale |
Secondary
Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable)
Results represent self-report of non-adherence during the 4-day period prior to the outcome evaluation visit. Participants in follow-up for whom these data are missing for any reason are inferred as not-adherent.
Time frame: At Weeks 24 and 48
Population: Persons not starting study treatment, or not receiving assigned study treatment by randomization were excluded from all analyses. If person no longer in study follow-up before beginning of week 24 or 48 evaluation window, additionally excluded as applicable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) | Week 24 (N=170; N=172) | 25 participants |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) | Week 48 (N=167; N=163) | 30 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) | Week 24 (N=170; N=172) | 26 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable) | Week 48 (N=167; N=163) | 26 participants |
Secondary
Number of Participants With Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry
HIV Co-receptor tropism test result of either dual/mixed or evidence of X4 using virus from sample collected at confirmed virologic failure.
Time frame: From study entry to time of confirmed virological failure (up to 96 weeks)
Population: Only randomized participants with R5-tropic virus at study entry (N=89; N=88), and who experienced confirmed virologic failure (N=27; N=22) during follow-up, and who had a tropism test following failure are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants With Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry | 3 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants With Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry | 2 participants |
Secondary
Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml
Number of participants with plasma HIV-1 Viral load \< 50 copies/mL at study visit weeks 24, 48, and 96. Closest observed result between 20 and up to 30 weeks (for week 24), between 42 and up to 54 (for week 48), and between 90 and up to 110 (for week 96) used if multiple results available. Missing values excluded.
Time frame: At Weeks 24, 48, 96
Population: ITT - among 2 randomized arms only; closest value to scheduled week used if multiple values available; missing values excluded. Numbers analyzed at each time point represent those with a valid RNA result.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 24: Number with RNA < 50 c/mL (N=170; N=171) | 122 participants |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 48: Number with RNA < 50 c/mL (N=169; N=165) | 112 participants |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 96: Number with RNA < 50 c/mL (N=158; N=158) | 107 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 24: Number with RNA < 50 c/mL (N=170; N=171) | 117 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 48: Number with RNA < 50 c/mL (N=169; N=165) | 106 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml | Week 96: Number with RNA < 50 c/mL (N=158; N=158) | 109 participants |
Secondary
Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure
Defined among the subgroup of participants experiencing the outcome of confirmed virologic failure. Newly acquired HIV drug resistance is defined as one or more ARVs with partial resistance or resistance when pre-entry resistance was fully sensitive or resistant when pre-entry resistance was fully sensitive or partially sensitive. The ARVs included for resistance acquisition included the following: darunavir/ritonavir; etravirine, tipranavir, tenofovir, emtracitabine, lamivudine, zidovudine, abacavir.
Time frame: Between baseline and confirmed virologic failure (up to 96 weeks)
Population: Those with confirmed virologic failure (N=54; N=50) among the randomized arms included; and those who were missing resistance information following virologic failure (N=2; N=4) are excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure | 18 participants |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure | 13 participants |
Secondary
Time From Randomization to Confirmed Virological Failure
Virologic failure defined as confirmed (two consecutive) plasma HIV-1 RNA meeting 1 of the following 4 criteria: \< 1.0 log10 copies/mL reduction from baseline level and \>= 200 copies/mL at or after week 12 evaluation; \>= 200 copies/mL after 1 measurement \< 200 copies/mL; absence of any values \< 200 copies/mL by and including week 24 evaluation; \>= 200 copies/mL at week 48 evaluation. Event time was the scheduled study visit week when the initial plasma HIV-1 RNA specimen meeting the failure definition was collected. Censoring time was the latest scheduled study visit week when a plasma HIV-1 RNA specimen was collected and tested.
Time frame: From randomization to week 96 study visit
Population: ITT (all randomized participants) included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Confirmed Virological Failure | 5th percentile | 12 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Confirmed Virological Failure | 10th percentile | 12 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Confirmed Virological Failure | 25th percentile | 48 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Confirmed Virological Failure | 5th percentile | 12 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Confirmed Virological Failure | 10th percentile | 12 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Confirmed Virological Failure | 25th percentile | 48 weeks |
Secondary
Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment
Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for meeting this outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Event times were scheduled study weeks when discontinuation events occurred. Censoring times were latest scheduled study visit weeks with evaluation.
Time frame: From randomization to week 96 study visit
Population: All randomized participants included (i.e. ITT analysis).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 1st percentile | 0 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 5th percentile | 36 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 10th percentile | NA weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 10th percentile | 48 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 1st percentile | 0 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment | 5th percentile | 36 weeks |
Secondary
Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality
Events following permanent discontinuation of NRTI assignment are excluded (i.e. censoring at time of this event, if applicable). Week 96 study visit could occur up to 110 weeks following randomization. Censoring time was the latest study visit when participant was evaluated or when NRTI assignment was discontinued (when applicable). Event time was the exact number of weeks following treatment initiation when the qualifying sign/symptom started (for those safety events triggered by a sign/symptom), or exact number of weeks following treatment initiation when specimen from qualifying laboratory result was drawn (for those safety events triggered by a laboratory abnormality).
Time frame: From treatment dispensation to week 96 study visit
Population: Only randomized participants included. Persons not starting study treatment excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 5th percentile | 3.1 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 25th percentile | 24.7 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 50th percentile | NA weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 5th percentile | 3.9 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 25th percentile | 25.3 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality | 50th percentile | 97.7 weeks |
Secondary
Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable)
First study ARV modification included any discontinuation or substitution of any chosen and initiated ARV for any reason. Events prompting study medication change could include protocol required (e.g. safety), protocol recommended but not required (e.g. virologic failure), or participant motivated (such as non-adherence, loss to follow-up or death; in other words, not protocol recommended or required). Event times were the exact weeks from treatment initiation to the time of qualifying regimen modification. Censoring times were the exact weeks from treatment initiation to the last date of study drugs. The week 96 (final study visit) could occur up through 110 weeks following randomization.
Time frame: From treatment dispensation to week 96 study visit
Population: Only randomized participants included, and those who never started study treatment were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 5th percentile | 9.0 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 10th percentile | 31.1 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 25th percentile | 98.0 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 5th percentile | 24.0 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 10th percentile | 38.0 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable) | 25th percentile | NA weeks |
Secondary
Time From Treatment Dispensation to Serious Non-AIDS-defining Events
Serious Non-AIDS defining Events were adjudicated by independent and blinded review and possible events included serious diagnoses in the following disease areas: liver, cardiovascular, end-stage renal, non-AIDS malignancy, and diabetes mellitus. Week 96 study visit could take place up to 110 weeks following randomization. Event times were the exact weeks following treatment initiation corresponding to the diagnosis dates of the qualifying serious non-AIDS defining events. Censoring times were the weeks following treatment initiation corresponding to the latest study visit.
Time frame: From treatment initiation to week 96 study visit
Population: Randomized participants were included, and those not starting study treatment were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to Serious Non-AIDS-defining Events | 1st percentile | 4.9 weeks |
| Add NRTIs (Randomized) to Individualized Regimen (cPSS > 2.0) | Time From Treatment Dispensation to Serious Non-AIDS-defining Events | 5th percentile | 60.0 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to Serious Non-AIDS-defining Events | 1st percentile | 29.3 weeks |
| Omit NRTIs (Randomized) From Individualized Regimen(cPSS > 2) | Time From Treatment Dispensation to Serious Non-AIDS-defining Events | 5th percentile | NA weeks |