Optimizing Treatment for Treatment-Experienced, HIV-Infected People

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Optimized Treatment That Includes or Omits NRTIs Trial: A Randomized Strategy Study for HIV-1-Infected Treatment-Experienced Subjects Using the cPSS to Select an Effective Regimen

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Enfuvirtide
* Drug: Raltegravir
* Drug: Darunavir
* Drug: Tipranavir
* Drug: Etravirine
* Drug: Maraviroc


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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. | Drug: Enfuvirtide<br>* 90mg subcutaneously twice daily<br>Drug: Raltegravir<br>* 400 mg twice daily<br>Drug: Darunavir<br>* Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Tipranavir<br>* Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Etravirine<br>* Two 100-mg tablets twice daily<br>Drug: Maraviroc<br>* Dosage dependent on regimen in which maraviroc is included<br>|
| Experimental: B<br>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. | Drug: Enfuvirtide<br>* 90mg subcutaneously twice daily<br>Drug: Raltegravir<br>* 400 mg twice daily<br>Drug: Darunavir<br>* Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Tipranavir<br>* Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Etravirine<br>* Two 100-mg tablets twice daily<br>Drug: Maraviroc<br>* Dosage dependent on regimen in which maraviroc is included<br>|
| Other: C<br>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. | Drug: Enfuvirtide<br>* 90mg subcutaneously twice daily<br>Drug: Raltegravir<br>* 400 mg twice daily<br>Drug: Darunavir<br>* Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Tipranavir<br>* Two 250-mg capsules twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)<br>Drug: Etravirine<br>* Two 100-mg tablets twice daily<br>Drug: Maraviroc<br>* Dosage dependent on regimen in which maraviroc is included<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From study entry to end of Week 48 evaluation window | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From treatment dispensation to week 96 study visit | 
| 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. | From treatment dispensation to week 96 study visit | 
| 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. | From randomization to week 96 study visit | 
| 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. | From randomization to week 96 study visit | 
| 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. | At Weeks 24, 48, 96 | 
| 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. | From baseline to Week 1 evaluation | 
| 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). | At study entry and Weeks 24, 48, 96 | 
| 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. | At Weeks 24 and 48 | 
| 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. | At Weeks 24, 48, and 96 | 
| 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. | From study entry to Weeks 48 and 96 | 
| 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. | From treatment initiation to week 96 study visit | 
| 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. | From study entry to time of confirmed virological failure (up to 96 weeks) | 
| 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. | From study entry to Weeks 24, 48 | 
| 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. | Between baseline and confirmed virologic failure (up to 96 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced