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

• Confirmed virologic failure [ Time Frame: At or prior to Week 24 ] [ Designated as safety issue: Yes ]
• CD4 count [ Time Frame: At Weeks 4, 12, 14, 36, and 48 ] [ Designated as safety issue: Yes ]
• Occurence of adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Grade 2, 3, or 4 signs and symptoms; Grade 3 or 4 laboratory test abnormal values; new diagnoses [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Acceptability and feasibility of mDot [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Adherence and resistance to second line HAART regimen [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

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

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 is to examine the effectiveness of modified directly observed therapy (mDOT) and compare it with the effectiveness of self-administered therapy in HIV infected individuals with first virologic failure on an NNRTI-based HAART regimen who are starting a PI-based HAART regimen.

mDOT is defined in this study as the daily observation of lopinavir/ritonavir (LPV/r) being taken on a regular basis. Observation consists of an mDOT partner being present at the time the study participant takes the observed dose. Half of the participants in this study will be required to choose an mDOT partner to supervise adherence for the first 28 weeks of the study. Each mDOT partner will complete the study-administered mDOT training program and must record all observed doses in an mDOT diary log. All participants and partners will receive health education through the study. Adherence will be measured using Medication Event Monitoring System (MEMS) caps and self-report questionnaires.

This study will last approximately 52 weeks. Participants will be stratified according to their viral load into one of four arms. The arm in which each participant is placed by the clinician is based on the treatment history of the participant. Participants in Arms 1 and 3 will receive emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and lopinavir/ritonavir (LPV/r) for the duration of the study. Participants in Arms 2 and 4 will receive LPV/r, TDF, and zidovudine (ZDF) for the duration of the study. mDOT will be used for the first 24 weeks of the study. For the remaining 28 weeks, participants in Arms 1 and 2 will use self-administration without mDOT. Participants in Arms 3 and 4 will self-administer study medications without mDOT for all 52 weeks. ZDV will not be provided by the study.

There will be eight visits during the study. Medical and medication history, blood collection, and adherence monitoring will occur at all visits. A quality of life questionnaire and an adherence tools assessment will occur at most visits. For Arms 1 and 2, medication diary logs and mDOT partner monitoring will be reviewed at most visits. An mDOT exit questionnaire and exit interview will occur at the end of the study for each partner.

• Drug: Lopinavir/ritonavir
  200-mg lopinavir and 50 mg ritonavir in each tablet, taken orally twice daily
  Other Names:

  • LPV/RTV
  • LPV/r
  • Kaletra
• Drug: Emtricitabine/Tenofovir disoproxil fumarate
  200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily
  Other Names:

  • FTC/TDF
  • Truvada
• Drug: Tenofovir disoproxil fumarate
  200-mg tablet taken orally once daily
  Other Names:

  • TDF
  • Viread
• Drug: Zidovudine
  300-mg tablet taken orally twice daily
  Other Names:

  • ZDV
  • Retrovir

• Experimental: 1
  Oral FTC/TDF and LPV/r for 52 weeks. Modified directly observed therapy (mDOT) for the first 24 weeks and self-administration for the remaining 28 weeks.
  Interventions:

  • Drug: Lopinavir/ritonavir
  • Drug: Emtricitabine/Tenofovir disoproxil fumarate
• Experimental: 2
  Oral TDF, ZDV, and LPV/r for 52 weeks. Modified directly observed therapy (mDOT) for the first 24 weeks and self-administration for the remaining 28 weeks.
  Interventions:

  • Drug: Lopinavir/ritonavir
  • Drug: Tenofovir disoproxil fumarate
  • Drug: Zidovudine
• Experimental: 3
  Self-administration of oral FTC/TDF and LPV/r for 52 weeks
  Interventions:

  • Drug: Lopinavir/ritonavir
  • Drug: Emtricitabine/Tenofovir disoproxil fumarate
• Experimental: 4
  Self-administered oral TDF, ZDV, and LPV/r for 52 weeks
  Interventions:

  • Drug: Lopinavir/ritonavir
  • Drug: Tenofovir disoproxil fumarate
  • Drug: Zidovudine

• Bangsberg DR, Kroetz DL, Deeks SG. Adherence-resistance relationships to combination HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2007 May;4(2):65-72. Review.
• 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. Review.
• 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.
• 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.

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, and NVP; ZDV, 3TC, and EFV; d4T, 3TC, and NVP; OR d4T, 3TC, and EFV
• Able to identify a close friend, relative, or spouse who is willing to serve as a partner (for Arms 1 and 2 only)
• Intend to stay in current geographical area of residence for the duration of the study
• Agree to use LPV/r with MEMS caps and take the tablets out of the container only at dosing
• Willing to use acceptable forms of contraception

Inclusion Criteria for Partners:

• 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 observe participant taking at least one dose of LPV/r 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
• In Arms 3 and 4, 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

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
• Require certain 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 abuse 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
• 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