HIV-1-infection
Conditions
Keywords
antiretroviral therapy, retention, ART, cost-effectiveness, virologic suppression
Brief summary
This is an unblinded cluster-randomized study to evaluate the effectiveness of two strategies for scripting/dispensing of antiretroviral therapy (ART) on retention, virologic suppression, and cost compared to the standard of care. The study will be conducted in Malawi and Zambia among approximately 8,200 HIV-1-infected adults (18 years or older) who are stable on ART. Clusters will be randomized to one of three study arms: (1) standard of care (SOC) ART scripting (varies by country, region, clinic, and/or provider), (2) three-month ART scripting, and (3) six-month ART scripting. 30 clusters will be selected for the study, 15 in Malawi and 15 in Zambia, and will be randomized to a study arm.
Detailed description
This study will be conducted among approximately 8,200 HIV-infected individuals age 18 years or older who are stable on antiretroviral therapy (ART) in 30 clusters in Malawi and Zambia. Individuals will be screened at routine clinic visits and enrolled if they meet inclusion criteria. Enrolled individuals will receive standard of care at their site with the exception of their ART dispensing interval based on the assigned randomization. Outcomes will be assessed after 12 months, but all participants will be under observational follow-up for 36 months, with annual re-assessment of retention, virologic suppression, and cost-effectiveness. There will be no contact with study participants during the period of follow-up. Endpoints will be determined by chart review after the primary endpoint is reached (12 months). Endpoint data collection will include: 1. Retention in care on strategy 2. Suppressed viral load of \<1,000 copies done as part of standard of care viral load monitoring In a subset of participants in Malawi (n=1,500), we will perform a review of participants' health passports, a record of patient clinic visits, general health information, and medications that is possessed by patients in Malawi, after the 12-month endpoint has been completed. Data will be collected on interim clinic visits, such as reason for visit/services received (sick, family planning, non-communicable disease treatment), frequency of visits, and location of clinic services. In a subset of participants (\ 240), we will perform a post intervention study visit after the 12-month endpoint is completed. Qualitative interviews will be performed with a subset of participants and will focus on patient experience with assigned dispensing interval, including challenges/barriers and facilitators towards adherence and retention. Focused questions around endpoints (if default, reasons; if virologic failure, reasons including adherence) will also be addressed in the post-intervention visit.
Interventions
OTHERThree-month ART dispensing
Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART from their provider for the duration of the study.
OTHERSix-month ART dispensing
Patients enrolled in the six-month ART dispensing arm will receive a 180-day supply of ART from their provider for the duration of the study.
Sponsors
Boston University
Equip, Lesotho
Ministry of Health, Malawi
Ministry of Health, Zambia
Partners in Hope, Inc.
Right to Care
United States Agency for International Development (USAID)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Intervention model description
The study will be a cluster randomized trial comparing three different antiretroviral therapy (ART) dispensing strategies. Clusters will be comprised of individual clinics in Malawi and Zambia. Enrolled individuals will receive standard of care at their site with the exception of the ART dispensing interval based on the assigned randomization. Outcomes will be assessed after 12 months.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age. * Willing and able to provide written informed consent for participation in this study. * Confirmed HIV-1 infection based on country standard of care for testing. * On antiretroviral treatment (ART) for at least six months. * On a first-line ART regimen as defined by country-specific guidelines. * No drug toxicity/tolerability issues with ART regimen within the prior six months. * No period of more than one month without ART medication possession within the last six months. * No active opportunistic infection suspected (including tuberculosis) and not treated for an opportunistic infection in the last 30 days. * No active comorbidity (including hypertension) and not treated for a comorbidity in the last 30 days. * No viral load of more than 1000 copies/ml (using standard assay) within the last six months. * Not currently pregnant. * At least six months postpartum if recently delivered a baby. * Not currently breastfeeding or planning to breastfeed.
Exclusion criteria
* Under 18 years of age. * Viral load of 1000 copies/ml or greater (using standard assay) within the last six months. * On alternative first-line or second-line ART regimen. * One month or more without medication possession within the last six months. * Experienced an ART toxicity/tolerability issue within the last six months. * Currently receiving treatment for tuberculosis or receiving treatment for any other opportunistic infection or comorbidity (including hypertension). * Pregnant or less than six months postpartum. * Women who are breastfeeding. * Unwilling or unable to provide informed consent. * Previously enrolled in the study. * Currently enrolled in any other research study at the site that involves adherence/retention or alters delivery of HIV care.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Retention in Care at 12 Months | 12 months | The primary outcome to be studied is whether scripting/dispensing of ART for intervals of six months is non-inferior to three months with respect to retention in care. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virologic Suppression at 12 Months | 12 months | The secondary outcome to be studied is whether scripting/dispensing of ART for intervals of six months is non-inferior to three months with respect to a viral load outcome of \<1,000 copies/ml (undetectable) at 12 months. |
| Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | 12 months | The secondary outcome to be studied is the cost-effectiveness of scripting/dispensing of ART for intervals of six months compared to three months and SOC. Cost-effectiveness will be estimated as the average cost per successful outcome (patient retained at 12 months). |
Countries
Malawi, Zambia
Participant flow
Recruitment details
Recruitment relied on active identification and referral of stable patients by clinic staff. Clinics were randomized to a study arm, and enrolled individuals initiated the study drug dispensing interval to which the clinic had been randomly assigned. A total of 14,430 individuals were screened from May 2017- April 2018 across 30 study sites.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care ART Dispensing (SOC) The standard of care arm will allow ART dispensing based on usual practice at the clinic. Standard of care is anticipated to have variability in how ART is dispensed, although the approach should be consistent with applicable country guidelines at the time of study. | 3,012 |
| Standard of Care ART Dispensing (SOC) The standard of care arm will allow ART dispensing based on usual practice at the clinic. Standard of care is anticipated to have variability in how ART is dispensed, although the approach should be consistent with applicable country guidelines at the time of study. | 10 |
| Three-month ART Dispensing (3MD) Providers at facilities randomized to three-month ART dispensing will be expected to provide all enrolled patients with a 90-day supply of ART and associated HIV medications (cotrimoxazole and isoniazid if part of country guidelines). All other aspects of care will be as per standard of care for the enrolling clinic.
Three-month ART dispensing: Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART from their provider for the duration of the study. | 2,726 |
| Three-month ART Dispensing (3MD) Providers at facilities randomized to three-month ART dispensing will be expected to provide all enrolled patients with a 90-day supply of ART and associated HIV medications (cotrimoxazole and isoniazid if part of country guidelines). All other aspects of care will be as per standard of care for the enrolling clinic.
Three-month ART dispensing: Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART from their provider for the duration of the study. | 10 |
| Six-month ART Dispensing (6MD) Providers at facilities randomized to six-month ART dispensing will be expected to provide all enrolled patients with a 180-day supply of ART and associated HIV medications (cotrimoxazole and isoniazid if part of country guidelines). All other aspects of care will be as per standard of care for the enrolling clinic.
Six-month ART dispensing: Patients enrolled in the six-month ART dispensing arm will receive a 180-day supply of ART from their provider for the duration of the study. | 2,981 |
| Six-month ART Dispensing (6MD) Providers at facilities randomized to six-month ART dispensing will be expected to provide all enrolled patients with a 180-day supply of ART and associated HIV medications (cotrimoxazole and isoniazid if part of country guidelines). All other aspects of care will be as per standard of care for the enrolling clinic.
Six-month ART dispensing: Patients enrolled in the six-month ART dispensing arm will receive a 180-day supply of ART from their provider for the duration of the study. | 10 |
| Total | 8,749 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | participant files could not be located | 111 | 170 | 118 |
Baseline characteristics
| Characteristic | Standard of Care ART Dispensing (SOC) | Total | Six-month ART Dispensing (6MD) | Three-month ART Dispensing (3MD) |
|---|---|---|---|---|
| Age, Continuous | 42.9 years | 42.6 years | 42.6 years | 42.7 years |
| Among reproductive age women, received contraception in last three months | 139 Participants | 508 Participants | 214 Participants | 155 Participants |
| Average monthly earnings | 48.02 USD | 60.00 USD | 72.45 USD | 66.24 USD |
| Disclosure of HIV status to primary partner No | 161 Participants | 551 Participants | 166 Participants | 224 Participants |
| Disclosure of HIV status to primary partner Yes | 2054 Participants | 5973 Participants | 2100 Participants | 1819 Participants |
| For those incurring transport costs, median one-way cost | 0.69 USD | 0.69 USD | 0.69 USD | 0.55 USD |
| Marital status Married or long-term partner | 1889 Participants | 5516 Participants | 1977 Participants | 1650 Participants |
| Marital status Single or no long-term partner | 247 Participants | 762 Participants | 267 Participants | 248 Participants |
| Marital status Widowed, divorced, or separated | 876 Participants | 2439 Participants | 736 Participants | 827 Participants |
| Median ART dispensing interval in year prior | 60.0 days | 75.0 days | 78.0 days | 80.0 days |
| Median household size | 4 People in household | 4 People in household | 5 People in household | 5 People in household |
| Median one-way travel time to clinic | 40.2 minutes | 40.3 minutes | 40.2 minutes | 45.0 minutes |
| Median time spent at ART clinic | 120.0 minutes | 150.0 minutes | 180.0 minutes | 180.0 minutes |
| Median years on ART | 4.9 years | 5.0 years | 4.9 years | 5.4 years |
| Missed work to attend current ART clinic visit | 1490 Participants | 4191 Participants | 1600 Participants | 1101 Participants |
| Proportion of patients incurring transport costs to clinic | 917 Participants | 2994 Participants | 1265 Participants | 812 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — | — |
| Region of Enrollment Malawi | 1532 participants | 4550 participants | 1588 participants | 1430 participants |
| Region of Enrollment Zambia | 1480 participants | 4169 participants | 1393 participants | 1296 participants |
| School (highest level completed) No education or less than primary school | 574 Participants | 1401 Participants | 347 Participants | 480 Participants |
| School (highest level completed) Primary school | 1453 Participants | 4118 Participants | 1372 Participants | 1293 Participants |
| School (highest level completed) Secondary school | 841 Participants | 2630 Participants | 978 Participants | 811 Participants |
| School (highest level completed) University/Graduate | 137 Participants | 542 Participants | 267 Participants | 138 Participants |
| Sex: Female, Male Female | 2020 Participants | 5774 Participants | 1913 Participants | 1841 Participants |
| Sex: Female, Male Male | 991 Participants | 2944 Participants | 1068 Participants | 885 Participants |
| Transport method to ART clinic Bicycle | 339 Participants | 1028 Participants | 385 Participants | 304 Participants |
| Transport method to ART clinic Bicycle taxi | 65 Participants | 398 Participants | 237 Participants | 96 Participants |
| Transport method to ART clinic Bus or minibus | 770 Participants | 2329 Participants | 925 Participants | 634 Participants |
| Transport method to ART clinic Other | 10 Participants | 38 Participants | 9 Participants | 19 Participants |
| Transport method to ART clinic Personal or friend's vehicle | 42 Participants | 216 Participants | 119 Participants | 55 Participants |
| Transport method to ART clinic Walk | 1786 Participants | 4710 Participants | 1306 Participants | 1618 Participants |
| Work status Formal employment | 450 Participants | 1477 Participants | 629 Participants | 398 Participants |
| Work status Informal employment | 1435 Participants | 4007 Participants | 1545 Participants | 1027 Participants |
| Work status Not working | 1121 Participants | 3221 Participants | 803 Participants | 1297 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 3,012 | 8 / 2,726 | 8 / 2,981 |
| other Total, other adverse events | 0 / 3,012 | 0 / 2,726 | 0 / 2,981 |
| serious Total, serious adverse events | 0 / 3,012 | 0 / 2,726 | 0 / 2,981 |
Outcome results
Primary
Retention in Care at 12 Months
The primary outcome to be studied is whether scripting/dispensing of ART for intervals of six months is non-inferior to three months with respect to retention in care.
Time frame: 12 months
Population: The sample includes only those participants for whom outcome data was available (n=8719). As described in the participant flow, 399 participant files could not be located to analyze final outcome data at the endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard of Care ART Dispensing (SOC) | Retention in Care at 12 Months | Retention | 2478 Participants |
| Standard of Care ART Dispensing (SOC) | Retention in Care at 12 Months | Transfer | 60 Participants |
| Standard of Care ART Dispensing (SOC) | Retention in Care at 12 Months | Death | 11 Participants |
| Standard of Care ART Dispensing (SOC) | Retention in Care at 12 Months | Lost to follow-up | 463 Participants |
| Three-month ART Dispensing (3MD) | Retention in Care at 12 Months | Lost to follow-up | 296 Participants |
| Three-month ART Dispensing (3MD) | Retention in Care at 12 Months | Retention | 2356 Participants |
| Three-month ART Dispensing (3MD) | Retention in Care at 12 Months | Death | 8 Participants |
| Three-month ART Dispensing (3MD) | Retention in Care at 12 Months | Transfer | 66 Participants |
| Six-month ART Dispensing (6MD) | Retention in Care at 12 Months | Lost to follow-up | 186 Participants |
| Six-month ART Dispensing (6MD) | Retention in Care at 12 Months | Transfer | 58 Participants |
| Six-month ART Dispensing (6MD) | Retention in Care at 12 Months | Death | 8 Participants |
| Six-month ART Dispensing (6MD) | Retention in Care at 12 Months | Retention | 2729 Participants |
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-4.3, 12.3]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [0.9, 17.2]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [1, 9.1]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-0.8, 1.6]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-0.9, 0.8]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-1.7, 0.7]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-0.4, 0.2]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-0.9, 0.8]
Comparison: Our sample size was estimated for a cluster-randomized non-inferiority trial. We had 30 clusters available for randomization and assumed a fixed number of clusters (k), an equal number of clusters per arm, and an equal number of subjects per cluster.95% CI: [-0.3, 0.3]
Secondary
Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI)
The secondary outcome to be studied is the cost-effectiveness of scripting/dispensing of ART for intervals of six months compared to three months and SOC. Cost-effectiveness will be estimated as the average cost per successful outcome (patient retained at 12 months).
Time frame: 12 months
Population: For the cost analysis, we excluded 179 participants whose visit data were unclear, leaving an analytic sample of 8,540 patients.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard of Care ART Dispensing (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 63.40 US Dollars |
| Standard of Care ART Dispensing (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 89.00 US Dollars |
| Standard of Care ART Dispensing (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 86.50 US Dollars |
| Three-month ART Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 62.30 US Dollars |
| Three-month ART Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 88.40 US Dollars |
| Three-month ART Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 86.00 US Dollars |
| Six-month ART Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 84.60 US Dollars |
| Six-month ART Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 85.92 US Dollars |
| Six-month ART Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 66.10 US Dollars |
| Zambia: Standard of Care (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 132.00 US Dollars |
| Zambia: Standard of Care (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 99.00 US Dollars |
| Zambia: Standard of Care (SOC) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 143.60 US Dollars |
| Zambia: 3 Month Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 134.00 US Dollars |
| Zambia: 3 Month Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 99.00 US Dollars |
| Zambia: 3 Month Dispensing (3MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 141.60 US Dollars |
| Zambia: 6 Month Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Achieved primary outcome | 131.13 US Dollars |
| Zambia: 6 Month Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | Did not achieve primary outcome | 99.00 US Dollars |
| Zambia: 6 Month Dispensing (6MD) | Provider Cost Per Patient by Outcome (USD) (Mean, 95% CI) | All patients | 128.00 US Dollars |
Secondary
Virologic Suppression at 12 Months
The secondary outcome to be studied is whether scripting/dispensing of ART for intervals of six months is non-inferior to three months with respect to a viral load outcome of \<1,000 copies/ml (undetectable) at 12 months.
Time frame: 12 months
Population: Viral load was originally listed as a secondary outcome. However, given the nature of this implementation science project, and under real world conditions, Viral Load testing was not done due to the early state of viral load scale-up in both Malawi and Zambia.