Article and Study Summary:
Outcomes of Three- Versus Six-Monthly Dispensing of Antiretroviral Treatment (ART) for Stable HIV Patients in Community ART Refill Groups: A Cluster-Randomized Trial in Zimbabwe
J Acquir Immune Defic Syndr. 2020;84(2):162-172. doi:10.1097/QAI.0000000000002333
Fatti G, Ngorima-Mabhena N, Mothibi E, et al.
This three-arm, cluster-randomized, non-inferiority trial compared clinical outcomes of clients receiving antiretroviral therapy (ART) through community-based differentiated service delivery (DSD) models, to clients receiving standard-of-care facility-based ART services in Zimbabwe. Thirty public health facilities were randomized to provide one of three DSD models for stable participants: 1) ART refills every three months through community ART refill groups (CARGs), 2) ART refills every six months through CARGs, or 3) ART refills every three months at the facility (standard-of-care). The primary outcome was retention in care after 12 months, and secondary outcomes were retention in assigned DSD model and viral load suppression (VLS) after 12 months. Retention in care after 12 months was high for participants receiving ART through CARGs and found to be non-inferior to the standard-of-care. Similarly, there was high retention of participants in their assigned DSD model after 12 months, but variability in the availability of routine viral load (VL) testing by district limited interpretation of VL results. Of those with VL results available, all groups had VLS above 90%, with high VLS among participants receiving three-monthly refills through CARGs and slightly lower VLS in those receiving six-monthly refills through CARGs. This trial suggests that providing ART through community-based DSD models is an effective way to provide ART services, with good retention in care after 12 months, but more information is required before drawing conclusions about VLS in these models.
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This three-arm, cluster-randomized, non-inferiority trial compared clinical outcomes of clients receiving antiretroviral therapy (ART) through community-based differentiated service delivery (DSD) models, with three and six multi-month dispensing (MMD) of ART through groups, to clients receiving standard-of-care facility-based ART services.
- Thirty public health facilities in rural and urban settings in Zimbabwe.
- Facilities were considered eligible for the study if they had supply-chain procedures for implementation of MMD, community ART refill groups (CARGs) recently implemented or deemed feasible, adequate routine data collection systems, and at least 430 adults enrolled in ART services.
- Eligible facilities were stratified into urban facilities, rural hospitals, and rural clinics, and then randomized into one of three arms:
- Control arm: Participants received ART at three-monthly intervals at the facility (arm 3MF).
- Intervention arm 1: Participants received ART at three-monthly intervals in CARGs with annual clinic visits and clinical consultations (arm 3MC).
- Intervention arm 2: Participants received ART at six-monthly intervals in CARGs with annual clinic visits and clinical consultations (arm 6MC).
- All enrolled participants at a particular facility received the same model of care based on the facility arm assignment.
- CARGs consisted of 6–12 people, with participants living in a similar geographic location and attending the same health facility. Each CARG met at least once every three months at a venue of their choice in the community.
- In the 3MC arm, a single alternating CARG representative collected ART from the facility every three months and distributed the medicines to all other members at the CARG meeting.
- In the 6MC arm, a single CARG representative collected ART from the facility six months after enrollment and distributed to all members at the CARG meeting.
- After 12 months, stable 3MC and 6MC participants were scheduled to receive a clinical consultation, viral load (VL) testing and ART supply from the clinic, with all members from a CARG scheduled to attend the clinic on the same day.
- Participants in the 3MF arm received clinical consultations and collected their own ART at the facility every three months.
- Participant eligibility criteria were in line with routine criteria for stable ART patients in Zimbabwe:
- Inclusion criteria were: aged >18 years, received standard first-line ART for >six months, VL <1000 copies/milliliter, weight >35 kilograms, and willing to join a CARG.
- Exclusion criteria were: recent ART tolerability issues; active or suspected tuberculosis; recent, active, or suspected opportunistic infection; received an alternative first-line or second-line ART regimen, active co-morbidities requiring visits to the facility more frequently than six-monthly, confirmed pregnancy, or <18 months postpartum.
- Participants in 3MC and 6MC arms were recruited from newly formed CARGs (<3 months), which had not yet had their first CARG refill meeting.
- The primary outcome was the proportion of participants remaining in ART care 12 months after enrollment. Participants were not considered retained in the case of death (all-cause) or loss to follow-up (LTFU), defined as no ART collection for 90 days after the last missed collection date.
- Secondary outcomes were the proportion of participants retained in their assigned study arm after 12 months and the proportion achieving viral load suppression (VLS) after 12 months. Participants were considered not retained if they transitioned off the study arm for any reason including death, LTFU, transfer to another clinic, or requiring increased ART dispensing frequency. VLS was defined as VL <1000 copies/milliliter.
- LTFU tracking was per routine site procedures, with no additional tracking for study participants, and VL testing was conducted on an annual basis as per routine national guidelines.
- Study staff extracted data from patient files, the routine electronic Patient Monitoring System for HIV patients, and routine CARG data collection forms.
- All analyses were done by intention-to-treat (ITT) and a non-inferiority threshold of -3.25% (risk difference [RD]) was set for both intervention arms compared to the control arm and to each other.
- Two pre-specified VLS analyses were conducted: (1) ITT analysis including all enrolled participants, irrespective of whether they had available VL results; and (2) an analysis restricted to participants who had available VL results 12 months after study enrollment (+/- 3 months from target date).
Study Population and Follow-up
- Between August 2017 and February 2018, 9,018 ART patients were screened for inclusion and in total 1,919, 1,335, and 1,546 participants were enrolled in arms 3MF, 3MC, and 6MC, respectively.
- The most common reason for ineligibility was unavailability of VL results (20.5%), followed by having an unsuppressed VL (15.6%).
- The target sample size of 1,920 participants was not met in the 3MC and 6MC arms, as formation of CARGs during the enrollment period was slower than expected, especially in rural areas.
- Participants in the three arms had similar median ages (44.8 years in 3MF, 46.5 years in 3MC and 44.8 years in 6MC) and the majority were female (71.8% female in 3MF, 73.7% in 3MC and 71.2% in 6MC).
- After 12 months, 1,784 (93.0%), 1,265 (94.8%), and 1,477 (95.5%) participants enrolled in 3MF, 3MC, and 6MC, respectively, remained in ART care.
- The non-inferiority limit was met for all comparisons of the primary outcome in both unadjusted and adjusted analyses.
- In the pooled analysis of both intervention arms vs. control, retention was marginally higher in the CARG arms without reaching statistical significance (95.2% vs. 93.0%, adjusted RD = 1.3%; 95% confidence interval [CI] -0.2% to 2.7%; p = 0.086).
- Retention was lower in those aged 18–24 years (87.3%) and at rural hospitals (90.9%) in unadjusted analyses, and variation in retention was seen by district.
- After 12 months, 1,746 (91.0%), 1,245 (93.3%), and 1,447 (93.6%) participants continued receiving ART through their initial randomized strategy in 3MF, 3MC, and 6MC, respectively. No statistical differences between arms were found in retention in the study arm.
- The number of participants who transitioned off their arms because they required more frequent ART dispensing was relatively small and similar between arms: 20 (1.0%), 18 (1.4%), and 28 (1.8%) in 3MF, 3MC, and 6MC, respectively.
- At 12 months, 865 (49.0%), 566 (44.8%), and 113 (7.7%) had recorded VL results in 3MF, 3MC, and 6MC, respectively. VL result availability varied dramatically between facilities (range: 0%–97%) and by district due to variable VL testing infrastructure.
- Among participants with available VL results at 12 months, 857 (99.1%), 564 (99.7%), and 105 (92.9%) achieved VLS in the 3MF, 3MC, and 6MC arms, respectively.
- In both ITT analyses and analyses limited to those with available VL results, the probability of VLS was not different in the 3MC arm compared to the 3MF arm.
- Among participants with available VL results, VLS was slightly reduced in the 6MC arm vs. the 3MF arm (relative risk [RR] = 0.9; 95% CI 0.9 to 1.0; p = 0.070) and vs. the 3MC arm (RR = 0.9; 95% CI 0.9 to 1.0; p = 0.083).
- When comparing both intervention arms combined to 3MF, VLS in the CARG arms was not different in analyses by ITT or among those with VL results available.
This cluster-randomized, non-inferiority trial found that 12-month retention was similar among participants receiving three and six MMD of ART through community-based group models, compared to standard-of-care facility-based ART delivery. A high level of VLS was found in the 3MC arm among participants with available VL results; however, variability in the availability of VL results limited the interpretation of VLS outcomes in the 6MC arm.
The following points should be considered when interpreting the study findings:
- Facilities were not stratified by district prior to randomization, which led to notable variability in the availability of VL results by arm. VL completion was highest in the Chitungwiza district (96%), but substantially lower in all other districts (range: 14%–32%), and no Chitungwiza facilities were allocated to 6MC. This made it difficult to draw conclusions about VLS, especially in the 6MC arm.
- Given low VL completion at some sites, it is possible that VL testing was not random and that targeted VL testing occurred for higher-risk participants, which further limits the interpretation of VLS results.
- Enrollment targets were not met in the intervention arms as CARG formation was slower than anticipated during the study period, resulting in fewer patients available for screening. Therefore, this trial was underpowered, and marginally significant findings may have been significant if powered as originally planned.
- The proportion of participants aged 18–24 years was <3% in all arms; therefore, conclusions about this age group cannot be drawn.
- The study design did not allow for patient choice regarding DSD models, which is often part of DSD implementation in routine settings. Allowing patients to choose a model that best fits their needs could result in further improvement in clinical outcomes.
- Participant outcomes were evaluated one year after enrollment, making the durability of these findings unclear as retention and VLS may decline over time.
This large-scale, cluster-randomized, non-inferiority trial in Zimbabwe is among the first to evaluate clinical outcomes of three and six MMD of ART in community-based DSD models. Retention at 12 months among participants in the CARG arms was high and non-inferior to standard-of-care facility-based ART delivery every three months. Varying availability of routine VL testing by district limited the interpretation of VLS results, but among participants who received a VL test, VLS after 12 months was similar between those receiving three MMD through CARGs and those in the control arm. This trial suggests that implementation of MMD through community-based groups can be an effective way to provide ART services. However, VL uptake should be closely monitored and further evidence is needed before drawing conclusions about VLS.
This article synopsis was written by Cassia Wells. Share your thoughts on this article or suggest an article for Journal Club by emailing her at firstname.lastname@example.org
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