Effect of Delays in Pharmacy Art Pick Up on Adherence

• Periodical List
• PLoS Med
• v.17(7); 2020 Jul
• PMC7329062

PLoS Med. 2020 Jul; 17(7): e1003116.

Participation in adherence clubs and on-time drug pickup amidst HIV-infected adults in Republic of zambia: A matched-pair cluster randomized trial

Monika Roy, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing – original typhoon,^{i, *} Carolyn Bolton-Moore, Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing,^{2, 3} Izukanji Sikazwe, Conceptualization, Funding conquering, Project administration, Supervision, Writing – review & editing,² Mpande Mukumbwa-Mwenechanya, Project administration, Supervision, Writing – review & editing,² Emilie Efronson, Formal analysis, Investigation, Writing – review & editing,² Chanda Mwamba, Formal analysis, Investigation, Writing – review & editing,^two Paul Somwe, Data curation, Writing – review & editing,^two Estella Kalunkumya, Data curation, Writing – review & editing,ⁱⁱ Mwansa Lumpa, Conceptualization, Information curation, Project assistants, Software, Supervision, Writing – review & editing,² Anjali Sharma, Conceptualization, Projection assistants, Supervision, Writing – review & editing,ⁱⁱ Jake Pry, Conceptualization, Data curation, Investigation, Methodology, Project administration, Writing – review & editing,^{2, 4} Wilbroad Mutale, Conceptualization, Methodology, Supervision, Writing – review & editing,² Peter Ehrenkranz, Resources, Writing – review & editing,^v David Five. Glidden, Methodology, Writing – review & editing,¹ Nancy Padian, Conceptualization, Supervision, Writing – review & editing,^half-dozen Stephanie Topp, Data curation, Formal assay, Investigation, Methodology, Supervision, Writing – review & editing,^vii Elvin Geng, Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Writing – review & editing,¹ and Charles B. Holmes, Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – review & editing ^{8, 9}

Monika Roy

¹ Academy of California, San Francisco, San Fancisco, California, United states of america of America

Carolyn Bolton-Moore

² Centre for Communicable diseases Inquiry in Zambia, Lusaka, Zambia

³ University of Alabama, Tuscaloosa, Alabama, United states of america

Izukanji Sikazwe

^two Centre for Communicable diseases Research in Zambia, Lusaka, Zambia

Mpande Mukumbwa-Mwenechanya

^two Middle for Communicable diseases Research in Zambia, Lusaka, Zambia

Emilie Efronson

² Centre for Infectious Illness Research in Republic of zambia, Lusaka, Zambia

Chanda Mwamba

² Centre for Infectious Affliction Research in Zambia, Lusaka, Zambia

Paul Somwe

^two Centre for Infectious Disease Research in Republic of zambia, Lusaka, Zambia

Estella Kalunkumya

² Center for Infectious Affliction Research in Republic of zambia, Lusaka, Zambia

Mwansa Lumpa

² Centre for Communicable diseases Inquiry in Zambia, Lusaka, Zambia

Anjali Sharma

² Centre for Infectious Disease Inquiry in Republic of zambia, Lusaka, Zambia

Jake Pry

² Centre for Infectious Illness Enquiry in Zambia, Lusaka, Zambia

^four University of California, Davis, Davis, California, Usa of America

Wilbroad Mutale

² Center for Infectious disease Research in Zambia, Lusaka, Zambia

Peter Ehrenkranz

^five Bill and Melinda Gates Foundation, Seattle, Washington, Usa

David 5. Glidden

ⁱ University of California, San Francisco, San Fancisco, California, United states of america

Nancy Padian

^six Academy of California, Berkeley, Berkeley, California, U.s.a. of America

Stephanie Topp

⁷ James Cook University, Townsville, Queensland, Australia

Elvin Geng

¹ University of California, San Francisco, San Fancisco, California, U.s.a.

Charles B. Holmes

⁸ Johns Hopkins University, Baltimore, Maryland, U.s. of America

^ix Center for Global Health Practise and Touch on, Georgetown University Schoolhouse of Medicine, Washington, District of Columbia, United states of america of America

Matthew P. Play a joke on, Academic Editor

Received 2019 Jun iv; Accepted 2020 May 27.

Supplementary Materials

S1 Fig: Time to return to clinic afterwards outset missed drug pickup in intervention and control participants. (TIFF)

GUID: C9C73A09-01A4-4873-9C99-861E1C53A54B

S1 Table: Sample size calculation table. (DOCX)

GUID: 145D33C3-D3AE-40B4-9C2C-C8F1A1121FB6

S2 Tabular array: CONSORT checklist. (DOCX)

GUID: F2220814-BE3F-4CB2-943C-ACECE0C47636

S1 Text: Study protocol. (DOCX)

GUID: A43DD933-A4F2-4151-A8A2-74ECC1E50794

Information Availability Statement

The Government of Zambia allows data sharing when applicable local conditions are satisfied. To request information access, contact the CIDRZ Ethics and Compliance Commission chair/Chief Scientific Officer, Dr. Roma Chilengi (gro.zrdic@ignelihC.amoR) or the Secretary to the Committee/Head of Research Operations, Ms. Hope Mwanyungwi (gro.zrdic@iwgnuynawM.epoH) mentioning the intended use for the information.

Abstruse

Groundwork

Current models of HIV service commitment, with frequent facility visits, accept led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and retentivity in care. The Zambian urban adherence club (AC) is a health service innovation designed to meliorate on-time drug pickup and memory in HIV care through off-hours facility access and pharmacist-led grouping drug distribution. Similar models of differentiated service commitment (DSD) have shown hope in Southward Africa, but observational analyses of these models are prone to bias and misreckoning. Nosotros sought to evaluate the effectiveness and implementation of ACs in Republic of zambia using a more rigorous study design.

Methods and findings

Using a matched-pair cluster randomized report design (ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02776254","term_id":"NCT02776254"}}NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (five clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART >6 months, not acutely sick, CD4 count not <200 cells/mm³) and willingness to participate in an AC. Clinical and antiretroviral drug pickup data were obtained through the existing electronic medical record. AC coming together attendance data were collected at intervention facilities prospectively through October 28, 2017. The primary outcome was time to first late drug pickup (>7 days late). Intervention issue was estimated using unadjusted Kaplan–Meier survival curves and a Cox proportional hazards model to derive an adjusted take a chance ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female person), median time since Art initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mmⁱⁱⁱ), and baseline retentivity (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15–0.45, p < 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p < 0.001). Although 18% (683/3,734) of Ac group meeting visits were missed, on-fourth dimension drug pickup (within seven days) still occurred in 51% (350/683) of these missed visits through alternate means (apply of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and demand for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this report were the small number of clusters, lack of viral load data, and relatively curt follow-upwards period.

Conclusions

ACs were found to be an effective model of service commitment for reducing late Fine art drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to exist constructive.

Author summary

Why was this study done?

• The adherence society intervention was designed to decrease brunt on the health organisation and improve retention in care among handling-experienced, clinically stable HIV-infected adults past providing off-hours facility access and streamlined (grouping-based, chemist-led) drug delivery.

• To appointment, published data on adherence clubs have been primarily express to observational information from a similar intervention in South Africa.

• This study was done to larn about the effectiveness of the intervention and challenges with implementation in other settings in sub-Saharan Africa.

What did the researchers do and find?

• We conducted a matched-pair cluster randomized report to estimate the effect of participating in adherence clubs on on-fourth dimension drug pickup in Zambia.

• Nosotros additionally used a mixed-methods approach to evaluate the implementation of the intervention.

• Nosotros found that participation in the adherence club led to a reduction in the occurrence and rate of experiencing a late drug pickup. Even so, on-time drug pickups exterior of adherence club meetings were relatively common.

• Both patients and providers institute the intervention to be acceptable, but while patients embraced the patient-centered aspects of adherence clubs, some providers questioned the appropriateness and feasibility of the model.

What exercise these findings mean?

• The urban adherence society intervention decreased late drug pickup amid treatment-experienced adults living with HIV in Zambia.

• However, patients unremarkably missed their club meeting, seeking alternative ways to selection up their medication on time.

• While club participation was associated with greater retention in care, flexibility in drug pickup and patient-centeredness were likely important factors.

Introduction

Traditional facility-based models of HIV care in sub-Saharan Africa are marked by frequent clinic visits requiring considerable time investment, travel distance, and cost to the patient [1–four]. This has led to suboptimal downstream consequences for both patients and health systems, including poor long-term retention in care (less than 70% at 2 years afterwards ART initiation) [v] and exacerbation of existing infrastructure and human resource shortages, leading to clinic look times oftentimes exceeding 4 hours [vi–8]. The concept of differentiated service commitment (DSD) was developed in response to these challenges and to provide greater patient-centered care amid HIV-infected individuals accessing lifelong antiretroviral therapy (Fine art) [9,10]. DSD models, which seek to tailor the intensity, frequency, and location of HIV care to patient characteristics and needs, are currently being tested and scaled up throughout sub-Saharan Africa [ix,10].

The Fine art adherence club (AC) is one of several DSD models originally developed by Médecins Sans Frontières in South Africa with the aim of addressing HIV care commitment challenges through off-hours patient admission to the facility, group drug pickup and counseling, and pharmacy and clinical visit spacing. Studies of Air-conditioning outcomes in S Africa have reported high rates of memory in care (>90% at 24 months) and substantial reductions in loss to follow-upward and virological rebound [11–thirteen]. Although promising, the applicability of these findings or the models of intendance outside of South African written report settings is unclear, as data are based primarily on observational analyses in Southward Africa [xiv], where the implementation context can exist quite different than elsewhere in the region. Assessing the effectiveness of the Ac model has become increasingly critical as programs and policymakers throughout sub-Saharan Africa are making decisions regarding specific DSD models of care they wish to adopt at scale. Republic of zambia adapted South Africa'due south Air conditioning model from a nurse-led to a pharmacist-led intervention with distinct criteria for drug pickup past a buddy and club removal/referral back to facility-based care to address the needs of patients in decorated urban settings. There are to our knowledge no published data outside of S Africa evaluating the effectiveness of ACs, and much remains to exist understood about the implementability of the model in the region.

To address this gap, we conducted a matched-pair cluster randomized report to evaluate the implementation and effectiveness of ACs in Zambia, a country with a substantial burden of HIV disease (estimated developed prevalence 12.4% in 2017) and a large national HIV prevention, care, and treatment program, with over 750,000 patients estimated to be on treatment [15]. In add-on to evaluating retention, using time to showtime late drug pickup and medication possession ratio (MPR), nosotros employed mixed methods to evaluate key implementation outcomes including patient and healthcare worker acceptability, appropriateness, feasibility, and fidelity.

Methods

Description of the intervention

An AC is a group of approximately 30 HIV-positive individuals on Fine art who meet every 2 months in the first 6 months and every 3 months thereafter, during off-hours at the facility (evenings or weekends) to receive medication refills, symptom screening, and group psychosocial back up. Dissimilar nurse-led South African ACs, the Zambian ACs in this study were led by chemist's shop technologists, who were responsible for prepackaging Fine art medication prior to the coming together and dispensing the Art medication to the members. Groups were supported past ii community lay health workers who were responsible for conducting symptom screening and leading a group counseling session. In contrast to South African ACs, in which blood samples are taken for analysis at the meeting, and follow-up with a medical officer may occur only in one case a year, Zambian AC members continued to visit the facility every half-dozen months for both clinical follow-up and laboratory monitoring. Patients who were unable to attend the coming together in person were allowed to send a buddy for drug pickup on their behalf. In contrast to South African ACs, no restrictions were placed on the frequency of employ of the buddy organisation, and lack of meeting attendance was not considered a criterion for removal from the gild and referral back to facility-based intendance. Patients were up-referred from the AC to the facility in the case of acute illness or positive symptom screening and were transferred out of the AC if they became pregnant or considering of patient or clinician preference. The pharmacy technologist and lay healthcare workers were employed past the written report; however, the balance of the model components were supported by existing clinic staff to facilitate integration into routine clinical activities.

Description of the control

At the time of this written report, patients receiving standard of care were assigned render visits to the facility every one to three months. In addition to seeing the clinician, the patient had separate encounters with the pharmacist and adherence counselor on the twenty-four hours of their visit. Patients may look, on boilerplate, an additional i.5 hours for each of these encounters [16].

Setting

The Centre for Infectious Disease Research in Republic of zambia (CIDRZ) is an independent, Zambian non-governmental arrangement that supports a broad range of national wellness programs, provides public wellness and inquiry training, and conducts inquiry. CIDRZ, in collaboration with the Ministry of Health, supports HIV prevention, care, and treatment services in public sector clinics across 4 of ten provinces in Zambia, using PEPFAR/CDC funding.

Report blueprint and site selection

All CIDRZ-supported urban clinics in 3 provinces (Lusaka, Southern, and Eastern) that were not part of a large ongoing randomized trial (HPTN 071 [11865]), were considered for inclusion in this report. Clinics were pair-matched on several criteria (clinic province, population size, and baseline patient retention in care) to maximize efficiency and ability with a small sample size of clusters. Sample size was derived using formulae for matched-pair cluster randomized trials as specified past Hayes and Moulton [17] and programmed in R 3.two.2 [18]:

c = two + ( z α / 2 + z β ) 2 π 0 ( 1 − π 0 ) / 1000 + π i ( 1 − π one ) / m + k yard 2 ( π 0 2 + π 1 2 ) ( π 0 − π i ) two

k ₁₀₀₀ refers to the matched-pair coefficient of variation. Matched-pair coefficient, number of clinics, and number of patients per clinic were varied to estimate their effect on power (S1 Table). Existing program data suggest that 65% of patients are >seven days late for a pharmacy refill visit at least in one case during their first year later on starting ART, and that 95% of clinics autumn within xv% of this gauge (65% ± 15% = 50%–80%). Thus, nosotros assumed a bourgeois matched-pair coefficient of variation of 0.10. We besides causeless a fifty% relative reduction in missed pharmacy visits due to Air conditioning participation. Under these assumptions, our option of 5 pairs of clinics and 120 patients per clinic yields a ability of 96%.

V matched pairs of clinics were purposively selected, and then clinics were randomized within each pair (using Stata 14.0) by report investigators to either receive the intervention or serve every bit a control facility. A systematic random sample of patients (every northwardth patient based on clinic population size) meeting eligibility criteria at intervention and control facilities were assessed for willingness to participate in an Air conditioning and, if willing, underwent private informed consent. The cosmos of a counterfactual (i.e., comparison of patients who agreed to be in the model at both intervention and command sites) was employed to minimize selection bias. Target enrollment at each clinic was 120 individuals. Individuals at intervention clinics were allocated to 1 of 4 Ac groups (30 individuals per group) at that dispensary based on patient preference for meeting time. Individuals at control clinics were informed, at the fourth dimension of informed consent, that the intervention was not currently being offered at their site but may be offered in the future. Qualitative data drove consisted of focus groups and in-depth interviews with patients, healthcare workers, and study staff at all intervention sites.

Patient recruitment and eligibility

Inside both intervention and control facilities, a systematic random sample of eligible patients (HIV positive, age ≥ 14 years, on ART >6 months, not acutely ill, and CD4 count non <200 cells/mm³) were assessed for willingness to participate in an AC. Every sixth patient (clinic population greater than 4,000) or every patient (clinic population less than four,000) who presented for a routine HIV clinical visit was evaluated for eligibility by the HIV clinician. If eligible, the patient was approached by study staff to assess for willingness to join an AC, using an infographic to draw the intervention. Patients who expressed interest subsequently underwent individual written informed consent. Participants were recruited between May xix and Oct 27, 2016, and followed until October 28, 2017 (minimum 12 months of follow-up).

Qualitative information were obtained at intervention sites using in-depth interviews and focus groups that were conducted at the midline (January to April 2017) and endline (August to November 2017) of study implementation. A full of 15 focus groups (iii per site) and 16 interviews were conducted at midline, and 20 focus groups (4 per site) and xiii interviews were conducted at endline. Study patients and healthcare workers were invited to participate in focus group discussions via open up invitation (during Ac meetings or drug pickup for patients and during staff announcements for report staff). For in-depth interviews, facility and written report staff were invited to participate either in person or past phone utilizing existing contact data held at the facilities. In-depth interviews were conducted with a purposive sample of ART clinic in-charges, pharmacy technologists, study customs liaison officers, report lay healthcare workers, and banana study coordinators.

Measurements

We extracted sociodemographic, laboratory, clinical, and drug pickup data for all participants from Smartcare, an existing national electronic medical record used in routine clinical intendance. Disease at care enrollment was defined every bit the presence of either WHO stage III or 4 illness at HIV care enrollment or an initial CD4 count < 200 cells/mmⁱⁱⁱ. For all participants, drug pickup date and next assigned drug pickup appointment in Smartcare were utilized to measure out late drug pickup and medication possession. To ensure complete information drove, manual review of paper charts was conducted for all participants, and any data missing from Smartcare were entered into the electronic medical record organisation by study staff. Additionally, for intervention participants, group meeting omnipresence and symptom screening data were obtained through coming together attendance registers that were later entered electronically into a written report database. Consequence ascertainment occurred 12 months mail-enrollment and was accompanied by administration of a patient go out survey.

Qualitative interviews lasted approximately 45 minutes, while focus groups lasted 1–ii hours, and all were conducted in English or a local linguistic communication (Nyanja, Bemba, or Tonga) co-ordinate to the preference of the participants. At midline, semi-structured guides included questions about the introduction, enrollment, and implementation of the Ac model. At endline, guides included questions on patient, provider, and study staff experiences with model implementation and the practicality of integration of these models into the current wellness system.

Analysis

All patients who accustomed Air conditioning participation at intervention and control facilities were analyzed independently of receiving the allocated treatment (Fig 1). The primary consequence was time to first late drug pickup (defined as greater than seven days late) (S1 Text). Kaplan–Meier survival analyses were conducted to summarize fourth dimension to beginning late drug pickup. The adapted effect was estimated using a Cox proportional hazards model with a random upshot for center [xix]. Covariate choice for the model was based on inclusion of variables that were a priori considered to be potential confounders. These included historic period, sexual activity, illness at care enrollment (divers equally WHO stage Iii or IV or CD4 < 200 cells/mm³ at care enrollment), time since ART initiation, and MPR at study enrollment. In secondary analyses of the primary outcome, we explored longer intervals of lateness to ascertain a missed pharmacy visit (14 and thirty days). All analyses were conducted with Stata version xv.0 (StataCorp, College Station, Texas, US).

Participant flowchart.

Eligible patients at intervention and command clinics were offered the intervention (i.e., assessed for willingness to participate in an adherence social club), simply only participants at intervention clinics received the intervention. ^aneTwo patients who did not ultimately receive the intervention were even so included in the intervention arm of the analysis as patients were analyzed independently of receiving the allocated treatment. ²Reasons for intervention discontinuation: pregnancy (northward = x), unable to be located >thirty days after a missed adherence club coming together (northward = six), patient preference for facility-based care (northward = iv), dismissed considering of inability to follow adherence club rules (n = four), diagnosed with tuberculosis (n = 4), and other (north = 4).

Secondary outcomes included MPR and implementation outcomes equally outlined by Proctor et al. [xx]. MPR is defined as the proportion of time that a patient has ART in their possession over 12 months. Drug possession (assessed either via delays in drug pickup or MPR) is recognized every bit a reliable measure out of adherence, with previous studies showing a stiff negative clan between MPR and viral load, handling failure, and poor clinical outcomes [21–26]. For MPR adding, we used drug pickup information in Smartcare to ascertain the number of days of ART not-possession in the year after study enrollment; MPR was calculated as 365 minus the number of days of ART non-possession, divided by 365, multiplied past 100 (to express MPR equally a percentage). Approximately 2 to 3 extra days of medication are given at each drug pickup; therefore, in our analysis patients began to accumulate medication non-possession 3 days after a missed drug pickup. Patients who died or transferred to another clinic were censored at the date of decease or date of transfer, respectively.

Five principal implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were analyzed quantitatively and qualitatively. Adoption (divers every bit "the intention, initial decision, or action to effort or employ an innovation or evidence-based exercise" [20]) was assessed quantitatively past describing the proportion of patients who accepted, joined, and attended AC meetings amongst those offered participation. Patient acceptability (divers as "the perception among implementation stakeholders that a given handling, service, practice, or innovation is agreeable, palatable, or satisfactory" [xx]), feasibility (defined every bit "the extent to which a new treatment, or an innovation, can be successfully used or carried out" [20]), and appropriateness (defined equally "the perceived fit, relevance, or compatibility of the innovation for a given setting and to address a item issue or problem" [20]) were assessed qualitatively. Fidelity of implementation (defined equally "the caste to which an intervention was implemented equally information technology was prescribed in the original protocol or as it was intended by the programme developers" [twenty]) has 5 dimensions including "adherence, quality of delivery, plan component differentiation, exposure to the intervention, and participant responsiveness or involvement" [xx]. We analyzed the final 2 dimensions past examining the proportion of scheduled AC visits attended.

For qualitative analysis, a codebook was adult per a thematic framework [27] to evaluate acceptability, appropriateness, and feasibility. The concept of acceptability was used to synthesize private stakeholders' full general experiences of, and feelings about, ACs. The concept of appropriateness was used to capture more than specific assessments of the psychosocial or clinical implications of the Air conditioning, in particular the model's ability to better engagement in HIV care. The concept of feasibility was used to capture stakeholders' perceptions regarding the material capacity (due east.grand., human resourcing, logistical capacity, drug availability, infrastructure) and organizational chapters (east.g., work culture and oversight) of the health centers and broader wellness system to support, scale up, and sustain the model. The lead qualitative investigator transformed transcripts into projects for coding in NVivo (QSR International, Doncaster, Australia). V coders independently coded the same 2 transcripts to refine and validate an initial, deductively constructed codebook. Codes were then used to refine themes through inductive reasoning. In a second round, three coders independently coded iii additional transcripts to attain and ostend consistency in coding. With loftier inter-coder understanding these 3 coders subsequently coded the remaining transcripts independently.

Viral load suppression at 12 months was a planned secondary outcome but could non be evaluated due to unexpected inaccuracy of test results from dried blood spot (DBS) specimens (nerveless during study enrollment and exit procedures on all patients) and lack of availability of plasma viral load tests (collected in routine clinical intendance merely available for less than 50% of study participants). Despite employ of a validated DBS analysis (COBAS AmpliPrep/COBAS TaqMan, Roche Diagnostics, Indianapolis, Indiana, US) [28–30] and detailed laboratory investigation, a clear cause for the assay fault could not be determined, as was reported to the institutional review boards at the Academy of Zambia and University of California, San Francisco. Other secondary outcomes (S1 Text), including costs and cost-effectiveness, are planned for separate publication.

This trial is registered at ClinicalTrials.gov ({"blazon":"clinical-trial","attrs":{"text":"NCT02776254","term_id":"NCT02776254"}}NCT02776254). The trial protocol (S1 Text) and CONSORT checklist (S2 Tabular array) are included for reference. Written informed consent was obtained from participants, and ethical approval was obtained from the institutional review boards at the Academy of Zambia and University of California, San Francisco.

Results

Patient characteristics

Among 571 intervention patients, median age was 42 years (IQR 35–48), 356 (62%) were female, median CD4 count at study enrollment was 512 cells/mm³ (IQR 327–653), and median time since Art initiation was four.viii years (IQR ii.2–7.2) (Tabular array ane). Baseline demographic characteristics were similar for the 489 control patients with respect to age, sex, time since ART initiation, CD4 at study enrollment, and baseline metrics of retention.

Table i

Baseline characteristics of intervention and control participants.

Characteristics	Intervention n = 571	Control northward = 489
Female sexual activity	356 (62%)	322 (66%)
Median historic period (years)	42.0 (34.9–48.0)	xl.8 (34.0–47.7)
Initial CD4 countone (cells/mmthree)	441 (271–565)	475 (306–631)
WHO phase at HIV intendance enrollment2
Stage 1	215 (42%)	215 (50%)
Stage two	129 (25%)	95 (22%)
Stage three	153 (xxx%)	109 (25%)
Phase 4	thirteen (three%)	11 (three%)
WHO stage III or IV or CD4 < 200 cells/mm3 at HIV care enrollmentthree	159 (30%)	118 (27%)
Time since enrollment in HIV intendance (years)	5.2 (2.6–7.6)	5.half dozen (3.0–vii.half-dozen)
Time since Fine art initiationiv (years)	4.viii (two.2–vii.two)	5.0 (2.3–6.9)
CD4 count at report enrollment5 (cells/mm3)	506 (327–649)	533 (371–682)
0–100	17 (iv%)	4 (1%)
101–200	14 (3%)	3 (1%)
201–350	98 (22%)	51 (17%)
351–500	100 (23%)	86 (29%)
>500	209 (48%)	148 (51%)
Medication possession ratio at study enrollment6 (%)	83 (76–95)	83 (78–91)
Belatedly drug pickup (>7 days belatedly) in year prior to study enrollment	305 (53%)	271 (55%)

Retention in care: Time to first late drug pickup

Kaplan–Meier survival data for first late drug pickup (>7 days belatedly) (Fig 2A) was examined at diverse time points. There was a statistically pregnant difference in time to offset late drug pickup betwixt the intervention and control groups (log rank test: p <0.001). Twelve-month cumulative incidence of first missed drug pickup was 0.24 (95% CI 0.20–0.27) in the intervention group and 0.67 (95% CI 0.63–0.72) in the control grouping (Fig 2A). The divergence between groups persisted even when the interval of lateness was increased to thirty days (Fig 2B). Accounting for competing risk due to death gave similar results owing to the small number of deaths. In adjusted survival analyses, the rate of tardily drug pickup was lower in intervention participants compared to control participants (adjusted run a risk ratio [aHR] 0.26, 95% CI 0.15–0.45, p < 0.001) (Tabular array 2).

Fourth dimension to first late drug pickup.

Late drug pickup defined as >seven days late (A) or >xxx days tardily (B).

Table 2

Unadjusted and adjusted Cox proportional hazards model results of late drug pickup in intervention compared to control participants.

Predictor	Unadjusted hazard ratio (95% CI)	p-Value	Adjusted adventure ratio (95% CI)	p-Value
Intervention	0.26 (0.21–0.32)	<0.001	0.26 (0.xv–0.45)	<0.001
Male person sex activity	1.34 (1.xi–1.61)	0.002	one.53 (i.24–1.88)	<0.001
Age at enrollment (per yr)	0.99 (0.98–1.00)	0.019	1.00 (0.98–ane.01)	0.41
Fourth dimension since Fine art initiation (per year)	0.98 (0.95–1.00)	0.107	0.99 (0.95–1.03)	0.46
WHO stage III or IV or CD4 < 200 cells/mmiii at HIV intendance enrollment	0.87 (0.70–1.07)	0.193	0.96 (0.76–1.22)	0.76
Medication possession ratio (%) at study enrollment	0.99 (0.99–i.00)	0.016	1.00 (0.99–1.00)	0.31

Late drug pickups were more frequent in the control group. Amongst 489 control participants, 205 (42%) were more than 7 days belatedly only 1 time, while 126 (25%) were tardily ii or more times during the report period. In comparison, among the 569 patients who received the Air conditioning intervention, 105 (eighteen%) were late just i time, and 81 (14%) were tardily two or more than times. Although tardily drug pickups were more frequent in the control group, among those who did miss a drug pickup, time to render after showtime late drug pickup was like in both groups: median of 25 days (IQR 5–63) in the intervention arm and 15 days (IQR 3–84) in the control arm (S1 Fig). This difference was not statistically significant (log rank examination: p = 0.25).

Adherence: MPR

Baseline MPR at report enrollment was similar between handling groups, at 83% (Table 1). Median MPR at 12 months post-enrollment was 100% (mean 95%; IQR 96%–100%) in the intervention arm compared to 96% (mean 89%; IQR eighty%–100%) in the control arm (p < 0.001) (Fig 3).

Twelve-month medication possession ratio (%) in intervention and command participants.

Adoption

Of 597 patients offered AC participation, 594 (99%) accustomed; 508 (85%) attended their first meeting (Fig iv), and 237 (40%) attended all AC meetings, with 194 (33%) missing 2 or more than grouping meetings.

Individual patient uptake of adherence club model in Zambia.

UAC, urban adherence order.

Acceptability

Table 3 summarizes fundamental qualitative themes relating to acceptability, ceremoniousness, and feasibility synthesized from the data. Patients who participated in focus group discussions described ACs equally existence highly acceptable equally a outcome of more fourth dimension during normal working hours to address livelihood concerns regardless of employment status ("We spend less fourth dimension here and within a short time we become back, that is very beneficial."—female person participant, Petauke); reduced concerns about stigma due to decreased exposure during the facilities' busiest hours; and reduced self-stigma and improved access to data and group support ("We encourage each other when we sit and nosotros also teach others how to accept drugs…If we have seen that our friends are in problems, nosotros try past all means to encourage each other."—male participant, Petauke). Healthcare workers too found the model highly acceptable due to perceptions of reduced clinic congestion and, in select cases, workload; every bit one participant described: "Before the model, the congestion [was high]…Maybe the doc was tired and stopped doing clinical work; even adherence counseling…was hectic. But because of this model…it was less."

Table 3

Key qualitative research findings evaluating patient and healthcare worker perspectives on intervention acceptability, appropriateness, and feasibility.

Issue	Patient perspectives	HCW perspectives
Acceptability	• More fourth dimension during normal working hours to address livelihood and other family responsibilities (described variously by patients regardless of employment status) • Reduced concerns almost stigma due to reduced and more user-friendly time being spent at dispensary (less visibility at clinic) • Reduced self-stigma • Improved admission to data and group support	• Reduced clinic congestion and, in select cases, workload
Appropriateness	• Reduced stress and logistics in accessing medication • Preference for group counseling over ane-on-one adherence counseling due to having more time to ask questions, sharing own experiences, and learning from others' experiences • Patient-centered approach afforded respect and responsiveness • Mixed gender groups felt to exist appropriate • Lack of inclusion of children in ACs felt inappropriate for some mothers as they still had to back-trail their children to the facility for all their visits	• Intervention aligns with existing clinical guidelines • One-on-one counseling more constructive and appropriate • Members should be required to exist on Fine art for 12 months (instead of six) and/or they should accept more than frequent clinical checks
Feasibility	• Patients were offered a variety of time slots (more patients opted for weekend meetings; fourth dimension conflicts with church were not an outcome as previously predictable) • Supportive attitude and responsiveness of AC coordinators should be maintained if government takes over Air-conditioning services	• Lay HCW of import resource, and government employment of lay HCW needed • Increased human resources for wellness needed in central areas, most notably chemist's shop

Appropriateness

Qualitative findings (Table 3) highlighted that ACs were felt to be advisable by patients considering of reduced stress and logistics in accessing medication, preference for group counseling over one-on-one counseling, and strengthened patient-centered approach, where patients had "an opportunity to interact with the staff" without fright that wellness workers would be tired, moody, or disrespectful. Group size and mixed gender groups were generally felt to exist advisable; however, several mothers felt that children should exist included in AC groups as parents were otherwise required to accompany their children to all facility visits. Wellness workers were more equivocal, with some acknowledging the businesslike advantages of ACs but others expressing concern most the importance of retaining "more personalized" (one-on-one) counseling and more frequent clinical checks.

Feasibility

Both patients and healthcare workers described the Air-conditioning model as beingness feasible bold sufficient staff and funding were bachelor. Nigh all participants stressed that ACs would only be successfully integrated and scaled in the electric current health system if (1) government-employed Air conditioning group leaders were selected and trained to be respectful and patient-centered past being "friendly" and "helpful" and to "talk nicely," instead of "ever chatting" and "shouting at us"; (two) in that location is formal employment of lay healthcare workers, who play a fundamental role in Air-conditioning functions ("These lay counsellors or community health workers play a major role…The government should even employ them."—healthcare worker, Lusaka); and (iii) there are increased homo resource for wellness, particularly to come across pharmacy needs ("If it is to be handed to government health workers, I think they should only increase human being ability so that there are enough workers at the facility."—male participant, Lusaka).

Fidelity

Assigned appointment frequency for drug pickup in the intervention group coincided with Air-conditioning meetings and was every 2 months in the offset half-dozen months of the report period then every 3 months in the 2d 6 months of the report period. In comparison, the median drug pickup engagement interval was ninety days (IQR 60–92 days) over the 12-month study period in the control group. Overall, of 3,734 scheduled AC meeting visits, 683 (18%) were non attended. However, drug pickup inside seven days nonetheless occurred for 350 (51%) of these missed visits, either via buddy pickup or early on return for drug pickup at the facility (Fig 5). Intervention discontinuation occurred among 32 participants, with pregnancy being the about mutual reason for discontinuation (due north = ten) (Fig ane).

Meeting attendance and on-time versus delayed drug pickup.

UAC, urban adherence society.

Discussion

Nosotros found that participation in an Air-conditioning model was associated with a 74% reduction in risk of experiencing a late drug pickup, which is strongly associated with retention and is a key driver of virological rebound [22]. Like effects were observed when the definition of lateness was extended from 7 to xxx days. These effects were observed despite the fact that nearly 20% of scheduled group meeting visits were non attended. Our findings advise that although participants did not e'er adhere to group-based ART commitment, model participation did facilitate culling methods of on-time drug pickup (via buddy system or early return to clinic later on a missed Air-conditioning visit). Although intervention and control participants returned to the clinic at similar rates after missing a drug pickup, fewer overall missed drug pickups, combined with early return, accounted for a median MPR of 100% (no gaps in medication possession) among intervention participants.

Our study findings are consistent with those of earlier published observational studies showing high memory in ART care among patients enrolled in ACs and is the first to our knowledge to provide non-observational effectiveness data that back up this intervention. Previously published observational studies in South Africa [11,13] reported loftier retention in ART care, divers as any contact with club or facility, equally their principal written report event. While they did not item club coming together omnipresence, ane of the studies did note that 27% of patients sent a buddy to at least 1 club visit. More than recently, a businesslike trial conducted in South Africa (comparing 24-calendar month retention in clinic-based versus community-based ACs) found that missing a club visit was common regardless of club type [31]. Twenty-six percentage of patients in the South African cohort missed drug pickup completely afterward missing a order visit; however, only 10% were lost from ART care. In our written report, although nearly twenty% of scheduled lodge visits were missed, missing drug pickup completely (no buddy pickup and no clinic return inside 7 days of a missed club visit) occurred in merely 10% of scheduled visits overall. Thus, collectively, these studies appear to share several findings: Retention in Art intendance is high amid patients who initially accept society participation (even after club discontinuation), individual gild meeting attendance is not uniformly high, and patients commonly utilize the flexibility afforded past the buddy system and drug pickup at the facility.

Frequent alternative drug pickup, every bit found in our written report, underscores two key points of public wellness significance: the demand for DSD models to remain flexible and patient-centered if they are to be effective and the need to reconsider the settings in which ACs afford greater benefits compared to other pop forms of DSD such as visit spacing and streamlined facility-based drug delivery alone. In the businesslike trial conducted by Hanrahan et al. [31], patients were removed from the lodge and referred back to facility-based care if they sent a buddy to ii consecutive meetings, had two late medication pickups at the facility, or missed a medication pickup entirely (no buddy and no late medication pickup). Loss to club-based care was high in both community- and clinic-based clubs (nearly fifty%), and involuntary discontinuation for missed/late visits was the most common reason. Similar policies exist in Western Cape Province in South Africa, where ACs take been broadly scaled upward, with greater than 50%–seventy% of eligible patients enrolled in clubs to appointment [12,32]. Qualitative piece of work from this setting revealed that social club expulsion for missed society meetings was seen as an unfair punishment and was associated with a breakdown of trust between the patient and healthcare system [33]. In patients for whom access issues limit on-time attendance to club meetings, requiring increased contact with the facility may only make the situation worse [34]. Given that a key chemical element of DSD is increased patient-centeredness, rigid and "one size fits all" requirements within DSD models are unlikely to be successful, just as they proved to exist suboptimal in maintaining long-term intendance appointment in facility-based care models [35]. Rather, individual reasons for missed order visits should exist elicited and patient-specific responses developed prior to considering order expulsion. It is likewise evident, given the number of patients that became significant during study follow-upwardly, that flexibility for pregnant patients or others with changing clinical needs who may temporarily require more facility contact (i.due east., for tuberculosis treatment) is likewise necessary.

Given the theoretical complexities and resources required to get together and maintain ACs and the relatively common occurrence of missed guild visits, program developers and policymakers may appropriately question what benefits a group-based ART commitment model affords over improved individual models of care (visit spacing and streamlined drug pickup at the facility). ACs exist on a continuum between other models such every bit community adherence groups (in which small groups [e.g., half-dozen] of patients meet monthly in their homes and rotate drug pickup responsibilities for the entire group) and fast-track drug pickup (in which individuals receive longer elapsing drug refills and expedited drug pickup at the facility) [36]. However, the mechanism of effect for each of these models is poorly understood and likely multifactorial [37,38]. Theoretical behavioral mechanisms by which ACs improve retentivity in ART care include greater self-efficacy, perceived social back up, empowerment, and perceived benefits [38]. The group format of urban ACs theoretically affords greater peer social support than fast-rail drug commitment alone. ACs may likewise offer relative advantages over fast-rails refills for patients who are unable to visit the clinic during regular working hours due to employment. Both of these mechanisms were supported by our qualitative research results but need to be elucidated further. Information technology is unclear if these establish important mechanisms of effect or whether expedited drug refills and/or "VIP treatment" at the facility due to club participation played a larger role in retaining patients in care. Comparative effectiveness studies, comparing more complex interventions (i.e., urban ACs and customs adherence groups) to visit spacing and fast-track refills alone, and seeking in-depth agreement of contextual influences on efficacy, are urgently needed.

In that location were several limitations to our study. While matching of clusters (in this case, facilities) helped amend the similarity between treatment arms at baseline (particularly given the small-scale number of clusters), comparability is limited to the characteristics that were matched upon. The principle of intention to care for is also challenged in cluster RCTs because of the lack of a statistical method to handle non-recruited participants. Furthermore, patients within each facility were invited to participate through a systematic pick process, which falls short of actual randomization. Despite these limitations, we attempted to minimize bias and misreckoning by matching on the baseline value of the endpoint of interest, performing additional adjustment during analysis, and analyzing patients independently of receipt of the allocated treatment [39]. Additionally, we lacked accurate viral load data in over 50% of the patients and were therefore unable to include these data in our secondary analyses. Duration of follow-up in our study was relatively short (12 months), and therefore we have limited ability to comment on sustainability and long-term outcomes of the intervention.

As DSD models are beingness scaled up throughout sub-Saharan Africa, our study provides timely and robust evidence of the effectiveness of the Ac intervention. Although visit spacing and grouping-based ART drug pickup and counseling are cadre components of the Ac intervention, our study highlighted that flexible drug pickup by a buddy and/or late drug pickup at the facility without punitive repercussions was also an essential part of the intervention. However, more than piece of work needs to be washed to understand the causal impact and resource cost of the Ac intervention compared to simpler non-grouping-based DSD interventions (e.g., visit spacing and fast-track refills) to optimize the quality and efficiency of a DSD-based health organization that could somewhen provide not just Art, but medicines for other chronic diseases.

Supporting information

S1 Fig

Fourth dimension to return to clinic later on first missed drug pickup in intervention and control participants.

(TIFF)

S1 Table

Sample size adding table.

(DOCX)

S2 Table

CONSORT checklist.

(DOCX)

S1 Text

Written report protocol.

(DOCX)

Abbreviations

Ac	adherence club
aHR	adjusted hazard ratio
Art	antiretroviral therapy
DSD	differentiated service delivery
MPR	medication possession ratio

Funding Argument

Bill and Melinda Gates Foundation: awarded to C.H. National Institutes of Health: awarded to Due east.G.; Grant numbers: K24 AI134413, P30 AI027763. The funders had no role in study pattern, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

The Authorities of Zambia allows data sharing when applicative local conditions are satisfied. To request data access, contact the CIDRZ Ethics and Compliance Committee chair/Chief Scientific Officer, Dr. Roma Chilengi (gro.zrdic@ignelihC.amoR) or the Secretary to the Committee/Head of Research Operations, Ms. Hope Mwanyungwi (gro.zrdic@iwgnuynawM.epoH) mentioning the intended use for the data.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329062/

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