Determining the Effects of Observed and Self-Administered Drug Regimens in HIV Infected Adults

Study Overview
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Brief Summary
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Highly active antiretroviral therapy (HAART) has led to better health and survival rates among people with HIV/AIDS. The purpose of this study was to measure the effect of trained partner supervision when taking medication versus self-administered therapy in HIV infected participants. These participants have had their first virologic failure on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen and were starting a protease inhibitor (PI)-based HAART regimen at study entry.

Detailed Description
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Poor adherence to HAART is usually associated with resistant virus. Poor adherence to HAART can have serious consequences, including limited treatment options for HIV infected individuals if they become infected with resistant HIV. The purpose of this study was to examine the effectiveness of modified directly observed therapy (mDOT) and compare it with the effectiveness of self-administered therapy (non-mDOT) in HIV infected individuals with first virologic failure on an NNRTI-based HAART regimen who were starting a PI-based HAART regimen at study entry. mDOT was defined in this study as the daily observation of lopinavir/ritonavir (LPV/r) being taken on a regular basis. Observation consisted of an mDOT partner being present at the time the study participant took the observed dose. Half of the participants in this study were required to choose an mDOT partner to supervise adherence for the first 24 weeks of the study. Each mDOT partner completed the study-administered mDOT training program and was required to record all observed doses in an mDOT diary log. All participants and partners received health education through the study. Adherence was measured using Medication Event Monitoring System (MEMS) caps and self-report questionnaires. This study lasted 52 weeks. Per protocol, participants were to be stratified according to their screening viral load and the proposed study treatment. The study treatment each participant received was based on their treatment history. At entry, participants were to start one of the two PI-based HAART regimens, either FTC/Tenofovir Disoproxil Fumarate (TDF) 200/300 mg once daily (QD) and Lopinavir/Ritonavir (LPV/RTV) 400/100 mg twice a day (BID) or TDF 300 mg QD and zidovudine (ZDV) 300 mg BID and LPV/RTV 400/100 mg BID. mDOT was used for the first 24 weeks of the study, followed by self-administration of study medications from week 25 to week 52. ZDV was not provided by the study. All enrolled participants except one who did not start study regimen initiated FTC/TDF and LPV/rtv after randomization. No participants started ZDV containing regimen on study. Thus, participants in this study were stratified by screening HIV-1 RNA only. There were eight visits during the study. Medical and medication history, blood collection, and clinical assessment were required at all visits. A quality of life questionnaire and an adherence tools assessment were collected at most visits. For the mDOT arm, medication diary logs and mDOT partner monitoring were reviewed at most visits. An mDOT exit questionnaire and exit interview were required at the end of the study.

Official Title
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International Trial of Modified Directly Observed Therapy Versus Self-Administered Therapy for Participants With First Virologic Failure on a Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Antiretroviral Regimen

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Lopinavir/ritonavir
* Drug: Emtricitabine/Tenofovir disoproxil fumarate
* Drug: Tenofovir disoproxil fumarate
* Drug: Zidovudine
* Drug: Emtricitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Participants: HIV infected Have experienced or currently experiencing first baseline virologic failure on first NNRTI-based HAART regimen with no history of virologic failure on another regimen OR discontinued first NNRTI-based HAART regimen without the recommendations of clinicians and currently experiencing virologic failure with no history of virologic failure on another regimen. More information on this criterion can be found in the protocol. Confirmed virologic failure within 45 days of study entry Receiving one of the following NNRTI-based regimens for at least 16 weeks prior to study entry: ZDV+3TC+NVP, ZDV+3TC+EFV, d4T+3TC+NVP or d4T+3TC+EFV Able to identify a close friend, relative, or spouse who is willing to serve as a partner Intend to stay in current geographical area of residence for the duration of the study Agree to use LPV/rtv with MEMS caps and take the tablets out of the container only at dosing Willing to use acceptable forms of contraception Ability and willingness of participant or legal guardian/representative to give written informed consent. Required laboratory values obtained within 45 days prior to study entry. Negative serum or urine pregnancy test obtained within 48 hours prior to study entry for women of reproductive potential. Inclusion Criteria for Partners: Not a participant Friend, family member, or spouse who knows of the participant's HIV status. Partners do not have to live with participants. Willing to attend a 1- to 2-hour taped training session prior to study entry Willing to attend study visits with participant at study screening; entry; and Weeks 4, 8, 12, 24, and 52 Willing to directly observe participant taking at least one dose of LPV/rtv for at least 5 days per week for 24 weeks after stratification of participant Willing to act as a positive support for participant Willing to notify clinical staff of participant's nonadherence to study assigned regimen Willing to notify clinical staff if they are unable to provide mDOT for 2 weeks or more Willing to complete medication diary logs Willing to complete exit interview Agree to have their training session taped (if required). For mDOT arm, willing to discuss and decide with participants whether to continue mDOT after Week 24 At least 18 years old Understand that participants have agreed to use LPV/RTV with MEMS caps and take the tablets out of the container only at dosing Ability and willingness to give written informed consent. No intention to relocate away from current geographical area of residence for the duration of study participation. Exclusion Criteria for Participants: Use of any immunomodulator, HIV vaccine, or other investigational therapy within 45 days of study entry Prior treatment with any PI Previously diagnosed cancer other than basal cell carcinoma and cutaneous Kaposi's sarcoma Use of rifampin or rifabutin within 45 days of study entry or plan use of rifampin or rifabutin Requirement for taking any medications that are prohibited by this study. More information on this criterion can be found in the protocol. Known allergy to the study medications or their formulations Current drug or alcohol use that, in the opinion of the investigator, would interfere with the study Acute illness requiring hospitalization within 14 days of study entry Active tuberculosis (TB) infection Currently incarcerated Participation as a partner in this study Participation with no access to telephones Abnormal laboratory values Pregnant, breastfeeding, or intend to become pregnant Exclusion Criteria for Partners: A participant in this study Participation as a partner to any other participant No access to telephones Currently incarcerated

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mDOT arm<br>Oral FTC/TDF+LPV/rtv or TDF+ZDV+LPV/rtv for 52 weeks. Modified directly observed therapy (mDOT) for the first 24 weeks and self-administration for the remaining 28 weeks. | Drug: Lopinavir/ritonavir<br>* Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily<br>* Other names: Kaletra;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily<br>* Other names: Truvada;Drug: Tenofovir disoproxil fumarate<br>* 300-mg tablet taken orally once daily<br>* Other names: Viread;Drug: Zidovudine<br>* 300-mg tablet taken orally twice daily<br>* Other names: Retrovir;Drug: Emtricitabine<br>* 200-mg tablet taken orally once daily<br>* Other names: Emtriva;|
| Active Comparator: non-mDOT arm<br>Oral FTC/TDF+LPV/rtv or TDF+ZDV+LPV/rtv for 52 weeks. Self-administration of the study treatment (non-mDOT) for 52 weeks. | Drug: Lopinavir/ritonavir<br>* Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily<br>* Other names: Kaletra;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily<br>* Other names: Truvada;Drug: Tenofovir disoproxil fumarate<br>* 300-mg tablet taken orally once daily<br>* Other names: Viread;Drug: Zidovudine<br>* 300-mg tablet taken orally twice daily<br>* Other names: Retrovir;Drug: Emtricitabine<br>* 200-mg tablet taken orally once daily<br>* Other names: Emtriva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Virologic Failure at or Prior to Week 48 | Confirmed virologic failure was defined as two successive HIV-1 RNA measurements at least 24 hours apart that were either:1) <1 log10 copies/mL below the baseline level and >400 copies/mL at the week 12 HIV-1 RNA evaluation (obtained at least 11 weeks after the date of the randomization) 2) >400 copies/mL at or after the week 24 HIV-1 RNA evaluation (obtained at least 23 weeks after the date of randomization). 3) subjects who discontinued the study follow-up for any reason other than study completion, including death, and who did so ≤50 weeks after randomization was considered to be a virologic failure. Number of participants experiencing or not experiencing virologic failure at or prior to week 48 was reported. | At or prior to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Virologic Failure at or Prior to Week 24 | Confirmed virologic failure was defined as two successive HIV-1 RNA measurements at least 24 hours apart that were either:1) <1 log10 copies/mL below the baseline level and >400 copies/mL at the week 12 HIV-1 RNA evaluation (obtained at least 11 weeks after the date of the randomization) 2) >400 copies/mL at or after the week 24 HIV-1 RNA evaluation (obtained at least 23 weeks after the date of randomization). 3) subjects who discontinued the study follow-up for any reason other than study completion, including death, and who did so ≤30 weeks after randomization was considered to be a virologic failure. Number of participants experiencing or not experiencing virologic failure at or prior to week 24 was reported. | At or prior to Week 24 | 
| CD4 Count at Follow-up Visits | CD4 cell count (median, inter-quartile range) | At Weeks 4, 12, 24, 36, and 48 | 
| CD8 Count at Follow-up Visits | CD8 cell count (median, inter-quartile range) | At week 4, 12, 24, 36, and 48 | 
| Time to First Grade 3 or 4 Lab Event | 5th and 10th percentiles in weeks from randomization to first grade 3 or 4 lab event | 52 weeks since randomization | 
| Time to First Grade 3 or 4 Sign or Symptom | 5th and 10th percentiles in weeks from randomization to first grade 3 or 4 sign or symptom | 52 weeks since randomization | 
| Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 5th and 10th percentiles in weeks from randomization to first grade 3 or 4 lab or sign/ symptom event | 52 weeks since randomization | 
| Adherence to Second Line HAART Regimen | Number of participants with self-reported 100% adherence over the week prior to study visit | At weeks 4, 8, 12, 24, 36, 48 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Combination, HIV Non-Nucleoside Reverse Transcriptase Inhibitors, HIV Protease Inhibitors, Viral Load, Virologic Failure