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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Lopinavir/ritonavir; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Tenofovir disoproxil fumarate; Drug: Zidovudine; Drug: Emtricitabine

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.

• Study Type: Interventional
• Enrollment (Actual): 529
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Gaborone Prevention/Treatment Trials CRS
• Brazil
  • Rio de Janeiro, Brazil, 21045
    • Instituto de Pesquisa Clinica Evandro Chagas (12101)
• Haiti
  • Port-au-Prince
    • Bicentenaire, Port-au-Prince, Haiti, HT-6110
      • Les Centres GHESKIO CRS
• Peru
  • Lima, Peru, 18
    • Barranco CRS
  • Lima
    • San Miguel, Lima, Peru
      • San Miguel CRS
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa
      • Wits HIV CRS
• Uganda
  • Kampala, Uganda
    • JCRC CRS
• Zambia
  • Lusaka, Zambia
    • Kalingalinga Clinic CRS
• Zimbabwe
  • Harare, Zimbabwe
    • UZ-Parirenyatwa CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mDOT arm; 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; Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily; Other Names: Kaletra; LPV/r; LPV/RTV; Drug: Emtricitabine/Tenofovir disoproxil fumarate; 200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily; Other Names: Truvada; FTC/TDF; Drug: Tenofovir disoproxil fumarate; 300-mg tablet taken orally once daily; Other Names: TDF; Viread; Drug: Zidovudine; 300-mg tablet taken orally twice daily; Other Names: ZDV; Retrovir; Drug: Emtricitabine; 200-mg tablet taken orally once daily; Other Names: FTC; Emtriva
Active Comparator: non-mDOT arm; 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; Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily; Other Names: Kaletra; LPV/r; LPV/RTV; Drug: Emtricitabine/Tenofovir disoproxil fumarate; 200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily; Other Names: Truvada; FTC/TDF; Drug: Tenofovir disoproxil fumarate; 300-mg tablet taken orally once daily; Other Names: TDF; Viread; Drug: Zidovudine; 300-mg tablet taken orally twice daily; Other Names: ZDV; Retrovir; Drug: Emtricitabine; 200-mg tablet taken orally once daily; Other Names: FTC; Emtriva

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Robert Gross, MD, MSCE, University of Pennsylvania; Study Chair: Alberto La Rosa, MD, Asociación Civil Impacta Salud y Educación, Peru

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: January 21, 2008
• First Submitted That Met QC Criteria: January 23, 2008
• First Posted (Estimate): February 6, 2008

Study Record Updates

• Last Update Posted (Actual): October 12, 2018
• Last Update Submitted That Met QC Criteria: September 11, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Viral Load; HIV Protease Inhibitors; Virologic Failure; HIV Non-Nucleoside Reverse Transcriptase Inhibitors
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Tenofovir; Emtricitabine; Ritonavir; Lopinavir; Zidovudine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: ACTG A5234; 1U01AI068636 (U.S. NIH Grant/Contract)