HIV Infections
Conditions
Keywords
Drug Therapy, Combination, HIV Non-Nucleoside Reverse Transcriptase Inhibitors, HIV Protease Inhibitors, Viral Load, Virologic Failure
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.
Interventions
DRUGLopinavir/ritonavir
Two tablets (200-mg lopinavir and 50 mg ritonavir in each tablet), taken orally twice daily
DRUGEmtricitabine/Tenofovir disoproxil fumarate
200-mg emtricitabine and 300 mg tenofovir disoproxil fumarate in each tablet, taken orally once daily
DRUGTenofovir disoproxil fumarate
300-mg tablet taken orally once daily
DRUGZidovudine
300-mg tablet taken orally twice daily
DRUGEmtricitabine
200-mg tablet taken orally once daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Virologic Failure at or Prior to Week 48 | 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
| Measure | Time frame | Description |
|---|---|---|
| CD4 Count at Follow-up Visits | At Weeks 4, 12, 24, 36, and 48 | CD4 cell count (median, inter-quartile range) |
| CD8 Count at Follow-up Visits | At week 4, 12, 24, 36, and 48 | CD8 cell count (median, inter-quartile range) |
| Time to First Grade 3 or 4 Lab Event | 52 weeks since randomization | 5th and 10th percentiles in weeks from randomization to first grade 3 or 4 lab event |
| Confirmed Virologic Failure at or Prior to Week 24 | 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. |
| Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 52 weeks since randomization | 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 | At weeks 4, 8, 12, 24, 36, 48 and 52 | Number of participants with self-reported 100% adherence over the week prior to study visit |
| Time to First Grade 3 or 4 Sign or Symptom | 52 weeks since randomization | 5th and 10th percentiles in weeks from randomization to first grade 3 or 4 sign or symptom |
Countries
Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, Zimbabwe
Participant flow
Recruitment details
Participants were recruited across 9 study sites (2 in Peru, one each in South Africa, Haiti, Uganda, Botswana, Zimbabwe, Brazil and Zambia) in the AIDS Clinical Trials Group system between April 2009 and September 2011.
Pre-assignment details
Five hundred twenty nine subjects including participants and partners entered the study. Among the 529 subjects, 259 were participants, which included two participants with eligibility violations. Only the 257 eligible participants were included in the analyses. All participants started TDF/FTC +LPV/rtv and stratified by screening HIV-1 RNA only.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 129 |
| 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. | 128 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 4 | 3 |
| Overall Study | Lost to Follow-up | 4 | 5 |
| Overall Study | Unable to adhere with study requirements | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Non-mDOT Arm | mDOT Arm |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 6 Participants | 5 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 250 Participants | 123 Participants | 127 Participants |
| Age, Continuous | 39.4 years STANDARD_DEVIATION 10.1 | 39.4 years STANDARD_DEVIATION 10.6 | 39.3 years STANDARD_DEVIATION 9.7 |
| CD4 Count Category 0-50 cells/mm3 | 31 participants | 14 participants | 17 participants |
| CD4 Count Category 101-200 cells/mm3 | 71 participants | 31 participants | 40 participants |
| CD4 Count Category 201-350 cells/mm3 | 82 participants | 47 participants | 35 participants |
| CD4 Count Category 351-500 cells/mm3 | 21 participants | 12 participants | 9 participants |
| CD4 Count Category >500 cells/mm3 | 13 participants | 5 participants | 8 participants |
| CD4 Count Category 51-100 cells/mm3 | 39 participants | 19 participants | 20 participants |
| CD4 Counts | 179 cells/mm3 | 201 cells/mm3 | 164 cells/mm3 |
| HIV-1 RNA Viral Load Category 100000-499999 copies/mL | 41 participants | 24 participants | 17 participants |
| HIV-1 RNA Viral Load Category 10000-99999 copies/mL | 109 participants | 55 participants | 54 participants |
| HIV-1 RNA Viral Load Category 1000-9999 copies/mL | 80 participants | 38 participants | 42 participants |
| HIV-1 RNA Viral Load Category <=400 copies/mL | 11 participants | 5 participants | 6 participants |
| HIV-1 RNA Viral Load Category 401-999 copies/mL | 6 participants | 2 participants | 4 participants |
| HIV-1 RNA Viral Load Category >=500000 copies/mL | 10 participants | 4 participants | 6 participants |
| Log10 HIV-1 RNA Viral Load | 4.3 log10 copies/mL | 4.3 log10 copies/mL | 4.2 log10 copies/mL |
| Race/Ethnicity, Customized Black Non-Hispanic | 204 participants | 103 participants | 101 participants |
| Race/Ethnicity, Customized Hispanic (regardless of race) | 52 participants | 25 participants | 27 participants |
| Race/Ethnicity, Customized More than one race | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Botswana | 8 participants | 4 participants | 4 participants |
| Region of Enrollment Brazil | 6 participants | 2 participants | 4 participants |
| Region of Enrollment Haiti | 73 participants | 36 participants | 37 participants |
| Region of Enrollment Peru | 46 participants | 23 participants | 23 participants |
| Region of Enrollment South Africa | 32 participants | 17 participants | 15 participants |
| Region of Enrollment Uganda | 50 participants | 25 participants | 25 participants |
| Region of Enrollment Zambia | 9 participants | 5 participants | 4 participants |
| Region of Enrollment Zimbabwe | 33 participants | 16 participants | 17 participants |
| Sex: Female, Male Female | 127 Participants | 65 Participants | 62 Participants |
| Sex: Female, Male Male | 130 Participants | 63 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 94 / 129 | 98 / 128 |
| serious Total, serious adverse events | 6 / 129 | 7 / 128 |
Outcome results
Primary
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.
Time frame: At or prior to Week 48
Population: Two hundred fifty seven eligible participants were included in the analysis. Intent to treat analysis was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Confirmed Virologic Failure at or Prior to Week 48 | No Failure | 95 participants |
| mDOT Arm | Confirmed Virologic Failure at or Prior to Week 48 | Experienced Failure | 34 participants |
| Non-mDOT Arm | Confirmed Virologic Failure at or Prior to Week 48 | No Failure | 105 participants |
| Non-mDOT Arm | Confirmed Virologic Failure at or Prior to Week 48 | Experienced Failure | 23 participants |
Comparison: Fisher exact test (unstratified)p-value: 0.133Fisher Exact
Secondary
Adherence to Second Line HAART Regimen
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
Population: Only the 257 eligible participants were included in the analysis. Self-reported adherence was collected face-to-face or by self-report on the Adherence/Quality of Life/Psychosocial Interview form. Only adherence to LPV/rtv was collected.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 24 | 107 participants |
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 4 | 105 participants |
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 48 | 103 participants |
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 12 | 114 participants |
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 52 | 104 participants |
| mDOT Arm | Adherence to Second Line HAART Regimen | Week 8 | 108 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 52 | 109 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 8 | 115 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 12 | 116 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 24 | 116 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 4 | 117 participants |
| Non-mDOT Arm | Adherence to Second Line HAART Regimen | Week 48 | 109 participants |
Secondary
CD4 Count at Follow-up Visits
CD4 cell count (median, inter-quartile range)
Time frame: At Weeks 4, 12, 24, 36, and 48
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| mDOT Arm | CD4 Count at Follow-up Visits | Week 12 | 225 cells/mm3 |
| mDOT Arm | CD4 Count at Follow-up Visits | Week 36 | 281 cells/mm3 |
| mDOT Arm | CD4 Count at Follow-up Visits | Week 24 | 268 cells/mm3 |
| mDOT Arm | CD4 Count at Follow-up Visits | Week 48 | 301 cells/mm3 |
| mDOT Arm | CD4 Count at Follow-up Visits | Week 4 | 212 cells/mm3 |
| Non-mDOT Arm | CD4 Count at Follow-up Visits | Week 48 | 347 cells/mm3 |
| Non-mDOT Arm | CD4 Count at Follow-up Visits | Week 4 | 219 cells/mm3 |
| Non-mDOT Arm | CD4 Count at Follow-up Visits | Week 12 | 235 cells/mm3 |
| Non-mDOT Arm | CD4 Count at Follow-up Visits | Week 24 | 266 cells/mm3 |
| Non-mDOT Arm | CD4 Count at Follow-up Visits | Week 36 | 294 cells/mm3 |
Secondary
CD8 Count at Follow-up Visits
CD8 cell count (median, inter-quartile range)
Time frame: At week 4, 12, 24, 36, and 48
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| mDOT Arm | CD8 Count at Follow-up Visits | Week 12 | 895 cells/mm3 |
| mDOT Arm | CD8 Count at Follow-up Visits | Week 36 | 787 cells/mm3 |
| mDOT Arm | CD8 Count at Follow-up Visits | Week 24 | 816 cells/mm3 |
| mDOT Arm | CD8 Count at Follow-up Visits | Week 48 | 815 cells/mm3 |
| mDOT Arm | CD8 Count at Follow-up Visits | Week 4 | 776 cells/mm3 |
| Non-mDOT Arm | CD8 Count at Follow-up Visits | Week 48 | 823 cells/mm3 |
| Non-mDOT Arm | CD8 Count at Follow-up Visits | Week 4 | 859 cells/mm3 |
| Non-mDOT Arm | CD8 Count at Follow-up Visits | Week 12 | 916 cells/mm3 |
| Non-mDOT Arm | CD8 Count at Follow-up Visits | Week 24 | 818 cells/mm3 |
| Non-mDOT Arm | CD8 Count at Follow-up Visits | Week 36 | 833 cells/mm3 |
Secondary
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.
Time frame: At or prior to Week 24
Population: Two hundred fifty seven eligible participants were included in the analysis. Intent to treat analysis was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Confirmed Virologic Failure at or Prior to Week 24 | No Failure | 105 participants |
| mDOT Arm | Confirmed Virologic Failure at or Prior to Week 24 | Experienced Failure | 24 participants |
| Non-mDOT Arm | Confirmed Virologic Failure at or Prior to Week 24 | No Failure | 111 participants |
| Non-mDOT Arm | Confirmed Virologic Failure at or Prior to Week 24 | Experienced Failure | 17 participants |
Secondary
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 frame: 52 weeks since randomization
Population: Two hundred fifty seven eligible participants were included in the analysis. As-treated analysis was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Time to First Grade 3 or 4 Lab Event | 5th percentile | 24 weeks |
| mDOT Arm | Time to First Grade 3 or 4 Lab Event | 10th percentile | NA weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Lab Event | 5th percentile | NA weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Lab Event | 10th percentile | NA weeks |
Secondary
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
Time frame: 52 weeks since randomization
Population: Two hundred fifty seven eligible participants were included in the analysis. As-treated analysis was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 5th percentile | 6.4 weeks |
| mDOT Arm | Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 10th percentile | 24 weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 5th percentile | 24 weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Lab or Sign/Symptom Event | 10th percentile | 32.6 weeks |
Secondary
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 frame: 52 weeks since randomization
Population: Two hundred fifty seven eligible participants were included in the analysis. As-treated analysis was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| mDOT Arm | Time to First Grade 3 or 4 Sign or Symptom | 5th percentile | 13.7 weeks |
| mDOT Arm | Time to First Grade 3 or 4 Sign or Symptom | 10th percentile | NA weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Sign or Symptom | 5th percentile | 26.7 weeks |
| Non-mDOT Arm | Time to First Grade 3 or 4 Sign or Symptom | 10th percentile | 48.9 weeks |