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

Primary Purpose

HIV Infections

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Lopinavir/ritonavir
Emtricitabine/Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate
Zidovudine
Emtricitabine
Sponsored by
AIDS Clinical Trials Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Infections focused on measuring Drug Therapy, Combination, HIV Non-Nucleoside Reverse Transcriptase Inhibitors, HIV Protease Inhibitors, Viral Load, Virologic Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Gaborone Prevention/Treatment Trials CRS
  • Instituto de Pesquisa Clinica Evandro Chagas (12101)
  • Les Centres GHESKIO CRS
  • San Miguel CRS
  • Barranco CRS
  • Wits HIV CRS
  • JCRC CRS
  • Kalingalinga Clinic CRS
  • UZ-Parirenyatwa CRS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

mDOT arm

non-mDOT arm

Arm Description

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.

Oral FTC/TDF+LPV/rtv or TDF+ZDV+LPV/rtv for 52 weeks. Self-administration of the study treatment (non-mDOT) for 52 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
CD4 Count at Follow-up Visits
CD4 cell count (median, inter-quartile range)
CD8 Count at Follow-up Visits
CD8 cell count (median, inter-quartile range)
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
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
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
Adherence to Second Line HAART Regimen
Number of participants with self-reported 100% adherence over the week prior to study visit

Full Information

First Posted
January 21, 2008
Last Updated
September 11, 2018
Sponsor
AIDS Clinical Trials Group
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00608569
Brief Title
Determining the Effects of Observed and Self-Administered Drug Regimens in HIV Infected Adults
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
March 2009 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AIDS Clinical Trials Group
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
Drug Therapy, Combination, HIV Non-Nucleoside Reverse Transcriptase Inhibitors, HIV Protease Inhibitors, Viral Load, Virologic Failure

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
529 (Actual)

8. Arms, Groups, and Interventions

Arm Title
mDOT arm
Arm Type
Experimental
Arm Description
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.
Arm Title
non-mDOT arm
Arm Type
Active Comparator
Arm Description
Oral FTC/TDF+LPV/rtv or TDF+ZDV+LPV/rtv for 52 weeks. Self-administration of the study treatment (non-mDOT) for 52 weeks.
Intervention Type
Drug
Intervention Name(s)
Lopinavir/ritonavir
Other Intervention Name(s)
LPV/RTV, LPV/r, Kaletra
Intervention Description
Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily
Intervention Type
Drug
Intervention Name(s)
Emtricitabine/Tenofovir disoproxil fumarate
Other Intervention Name(s)
FTC/TDF, Truvada
Intervention Description
200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily
Intervention Type
Drug
Intervention Name(s)
Tenofovir disoproxil fumarate
Other Intervention Name(s)
TDF, Viread
Intervention Description
300-mg tablet taken orally once daily
Intervention Type
Drug
Intervention Name(s)
Zidovudine
Other Intervention Name(s)
ZDV, Retrovir
Intervention Description
300-mg tablet taken orally twice daily
Intervention Type
Drug
Intervention Name(s)
Emtricitabine
Other Intervention Name(s)
FTC, Emtriva
Intervention Description
200-mg tablet taken orally once daily
Primary Outcome Measure Information:
Title
Confirmed Virologic Failure at or Prior to Week 48
Description
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.
Time Frame
At or prior to Week 48
Secondary Outcome Measure Information:
Title
Confirmed Virologic Failure at or Prior to Week 24
Description
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.
Time Frame
At or prior to Week 24
Title
CD4 Count at Follow-up Visits
Description
CD4 cell count (median, inter-quartile range)
Time Frame
At Weeks 4, 12, 24, 36, and 48
Title
CD8 Count at Follow-up Visits
Description
CD8 cell count (median, inter-quartile range)
Time Frame
At week 4, 12, 24, 36, and 48
Title
Time to First Grade 3 or 4 Lab Event
Description
5th and 10th percentiles in weeks from randomization to first grade 3 or 4 lab event
Time Frame
52 weeks since randomization
Title
Time to First Grade 3 or 4 Sign or Symptom
Description
5th and 10th percentiles in weeks from randomization to first grade 3 or 4 sign or symptom
Time Frame
52 weeks since randomization
Title
Time to First Grade 3 or 4 Lab or Sign/Symptom Event
Description
5th and 10th percentiles in weeks from randomization to first grade 3 or 4 lab or sign/ symptom event
Time Frame
52 weeks since randomization
Title
Adherence to Second Line HAART Regimen
Description
Number of participants with self-reported 100% adherence over the week prior to study visit
Time Frame
At weeks 4, 8, 12, 24, 36, 48 and 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Gross, MD, MSCE
Organizational Affiliation
University of Pennsylvania
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Alberto La Rosa, MD
Organizational Affiliation
Asociación Civil Impacta Salud y Educación, Peru
Official's Role
Study Chair
Facility Information:
Facility Name
Gaborone Prevention/Treatment Trials CRS
City
Gaborone
Country
Botswana
Facility Name
Instituto de Pesquisa Clinica Evandro Chagas (12101)
City
Rio de Janeiro
ZIP/Postal Code
21045
Country
Brazil
Facility Name
Les Centres GHESKIO CRS
City
Bicentenaire
State/Province
Port-au-Prince
ZIP/Postal Code
HT-6110
Country
Haiti
Facility Name
San Miguel CRS
City
San Miguel
State/Province
Lima
Country
Peru
Facility Name
Barranco CRS
City
Lima
ZIP/Postal Code
18
Country
Peru
Facility Name
Wits HIV CRS
City
Johannesburg
State/Province
Gauteng
Country
South Africa
Facility Name
JCRC CRS
City
Kampala
Country
Uganda
Facility Name
Kalingalinga Clinic CRS
City
Lusaka
Country
Zambia
Facility Name
UZ-Parirenyatwa CRS
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
17547827
Citation
Bangsberg DR, Kroetz DL, Deeks SG. Adherence-resistance relationships to combination HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2007 May;4(2):65-72. doi: 10.1007/s11904-007-0010-0.
Results Reference
background
PubMed Identifier
17525686
Citation
Conway B. The role of adherence to antiretroviral therapy in the management of HIV infection. J Acquir Immune Defic Syndr. 2007 Jun 1;45 Suppl 1:S14-8. doi: 10.1097/QAI.0b013e3180600766.
Results Reference
background
PubMed Identifier
17639650
Citation
Goggin K, Liston RJ, Mitty JA. Modified directly observed therapy for antiretroviral therapy: a primer from the field. Public Health Rep. 2007 Jul-Aug;122(4):472-81. doi: 10.1177/003335490712200408.
Results Reference
background
PubMed Identifier
17693890
Citation
Pearson CR, Micek MA, Simoni JM, Hoff PD, Matediana E, Martin DP, Gloyd SS. Randomized control trial of peer-delivered, modified directly observed therapy for HAART in Mozambique. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):238-44. doi: 10.1097/QAI.0b013e318153f7ba.
Results Reference
background
PubMed Identifier
34788110
Citation
Mantshonyane L, Roy J, Levy MZ, Wallis CL, Bar K, Godfrey C, Collier A, LaRosa A, Zheng L, Sun X, Gross R. Participants Switching to Second-Line Antiretroviral Therapy with Susceptible Virus Display Inferior Adherence and Worse Outcomes: An Observational Analysis. AIDS Patient Care STDS. 2021 Dec;35(12):467-473. doi: 10.1089/apc.2021.0115. Epub 2021 Nov 16.
Results Reference
derived
PubMed Identifier
26774947
Citation
De Boni RB, Zheng L, Rosenkranz SL, Sun X, Lavenberg J, Cardoso SW, Grinsztejn B, La Rosa A, Pierre S, Severe P, Cohn SE, Collier AC, Gross R. Binge drinking is associated with differences in weekday and weekend adherence in HIV-infected individuals. Drug Alcohol Depend. 2016 Feb 1;159:174-80. doi: 10.1016/j.drugalcdep.2015.12.013. Epub 2015 Dec 24.
Results Reference
derived
PubMed Identifier
26424232
Citation
Gross R, Zheng L, La Rosa A, Sun X, Rosenkranz SL, Cardoso SW, Ssali F, Camp R, Godfrey C, Cohn SE, Robbins GK, Chisada A, Wallis CL, Reynolds NR, Lu D, Safren SA, Hosey L, Severe P, Collier AC; ACTG 5234 team. Partner-based adherence intervention for second-line antiretroviral therapy (ACTG A5234): a multinational randomised trial. Lancet HIV. 2015 Jan;2(1):e12-9. doi: 10.1016/S2352-3018(14)00007-1. Epub 2014 Dec 11.
Results Reference
derived

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

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