Temporal changes in paediatric and adolescent HIV outcomes across the care continuum in Zambia: an interrupted time-series analysis.

BACKGROUND: Paediatric and adolescent HIV treatment programmes in sub-Saharan Africa have rapidly expanded and evolved over the past decade. Real-world evidence of how the implementation of new policies over time has affected treatment outcomes is inadequate, but is crucial for guiding the implementation of the next phases of the HIV treatment response for children. We examined how treatment outcomes in Zambia's national paediatric and adolescent HIV treatment programmes have changed over time as new policies were implemented. METHODS: We used data from Zambia's routine electronic health record to analyse children and adolescents living with HIV who were antiretroviral therapy (ART) naive between the ages of 0 and 19 years who were newly enrolled in care between Jan 1, 2011, and March 31, 2019, at 102 health facilities in Lusaka and Western provinces supported by the Centre for Infectious Disease Research in Zambia. Sociodemographic factors, clinical data, facility-level data, and visit history were obtained from the national electronic health record and laboratory systems used in routine HIV care in Zambia. We aimed to characterise the changes in the distribution of the age and sex of new enrolees over time. We used an interrupted time-series design to examine the rates of ART initiation, retention in care, time to ART initiation, and first-line ART regimens among new enrolees across different age strata as they changed over time with the adoption of new ART guidelines in 2014 and 2017. FINDINGS: Between Jan 1, 2011, and March 31, 2019, 26 214 children and adolescents living with HIV who were ART naïve were newly enrolled at one of 102 ART facilities in two provinces in Zambia. Rates of new enrolees increased by 25-35% among children younger than 15 years over time, but by 92·3% between 2011 and 2017 among adolescents, with the largest absolute increase among adolescent girls. Rates of ART initiation increased steadily and in parallel across all age groups from before the implementation of the 2014 guidelines to after the implementation of the 2017 guidelines (<2 years, 42·4% for 2014 and 81·6% for 2017; 2 to <5 years, 39·3% for 2014 and 82·8% for 2017; 5 to <15 years, 49·2% for 2014 and 86·6% for 2017; 15 to 19 years, 52·4% for 2014 and 86·2% for 2017); median time to ART initiation went from 2-3 months to same-day initiation during this same time period. Rates of retention on ART 6 months after linkage saw much smaller improvements over time (<2 years, 35·4% for 2014 and 52·0% for 2017; 2 to <5 years, 40·2% for 2014 and 54·4% for 2017; 5 to <15 years, 46·7% for 2014 and 63·4% for 2017; 15 to 19 years, 40·1% for 2014 and 52·7% for 2017). INTERPRETATION: Improvements in ART initiation occurred largely in parallel across age groups over time, despite universal treatment being implemented at different timepoints for different ages. Although the rates of ART initiation reach high levels, retention on ART was low. This analysis provides a comprehensive examination of how paediatric and adolescent outcomes have evolved over the past decade in Zambia and identifies where more targeted efforts will be needed over the next decade. FUNDING: National Institutes of Health.

Mitigating the effects of COVID-19 on HIV treatment and care in Lusaka, Zambia: a before-after cohort study using mixed effects regression.

INTRODUCTION: The Zambian Ministry of Health (MoH) issued COVID-19 mitigation guidance for HIV care immediately after the first COVID-19 case was confirmed in Zambia on 18 March 2020. The Centre for Infectious Disease Research in Zambia implemented MoH guidance by: 1) extending antiretroviral therapy (ART) refill duration to 6 multi-month dispensation (6MMD) and 2) task-shifting communication and mobilisation of those in HIV care to collect their next ART refill early. We assessed the impact of COVID-19 mitigation guidance on HIV care 3 months before and after guidance implementation. METHODS: We reviewed all ART pharmacy visit data in the national HIV medical record for PLHIV in care having ≥1 visit between 1 January-30 June 2020 at 59 HIV care facilities in Lusaka Province, Zambia. We undertook a before-after evaluation using mixed-effects Poisson regression to examine predictors and marginal probability of early clinic return (pharmacy visit >7 days before next appointment), proportion of late visit (>7 days late for next appointment) and probability of receiving a 6MMD ART refill. RESULTS: A total of 101 371 individuals (64% female, median age 39) with 130 486 pharmacy visits were included in the analysis. We observed a significant increase in the adjusted prevalence ratio (4.63; 95% CI 4.45 to 4.82) of early return before compared with after guidance implementation. Receipt of 6MMD increased from a weekly mean of 47.9% (95% CI 46.6% to 49.2%) before to 73.4% (95% CI 72.0% to 74.9%) after guidance implementation. The proportion of late visits (8-89 days late) was significantly higher before (18.8%, 95% CI17.2%to20.2%) compared with after (15.1%, 95% CI13.8%to16.4%) guidance implementation . CONCLUSIONS: Timely issuance and implementation of COVID-19 mitigation guidance involving task-shifted patient communication and mobilisation alongside 6MMD significantly increased early return to ART clinic, potentially reducing interruptions in HIV care during a global public health emergency.

Effects of implementing universal and rapid HIV treatment on initiation of antiretroviral therapy and retention in care in Zambia: a natural experiment using regression discontinuity.

BACKGROUND: Universal testing and treatment (UTT) for all people living with HIV has only been assessed under experimental conditions in cluster-randomised trials. The public health effectiveness of UTT policies on the HIV care cascade under real-world conditions is not known. We assessed the real-world effectiveness of universal HIV treatment policies that were implemented in Zambia on Jan 1, 2017. METHODS: We used data from Zambia's routine electronic health record system to analyse antiretroviral therapy (ART)-naive adults who newly enrolled in HIV care up to 1 year before and after the implementation of universal treatment (ie, Jan 1, 2016, to Jan 1, 2018) at 117 clinics supported by the Centre for Infectious Disease Research in Zambia. We used a regression discontinuity design to estimate the effects of implementing UTT on same-day ART initiation, ART initiation within 1 month, and retention on ART at 12 months (defined as clinic attendance 9-15 months after enrolment and at least 6 months on ART), under the assumption that patients presenting immediately before and after UTT implementation were balanced on both measured and unmeasured characteristics. We did an instrumental variable analysis to estimate the effect of same-day ART initiation under routine conditions on 12-month retention on ART. FINDINGS: 65 673 newly enrolled patients with HIV (40 858 [62·2%] female, median age 32 years [IQR 26-39], median CD4 count 287 cells per µL [IQR 147-466]) were eligible for inclusion in the analyses; 31 145 enrolled before implementation of UTT, and 34 528 enrolled after UTT. Implementation of universal treatment increased same-day ART initiation from 41·7% to 74·8% (risk difference [RD] 33·1%, 95% CI 30·5-35·7), ART initiation by 1 month from 69·6% to 87·0% (RD 17·4%, 15·5-19·3), and 12-month retention on ART from 56·2% to 63·3% (RD 7·1%, 4·3-9·9). ART initiation rates became more uniform across patient subgroups after implementation of universal treatment, but heterogeneity in 12-month retention on ART between subgroups was unchanged. Instrumental variable analyses indicated that same-day ART initiation in routine settings led to a 15·8% increase (95% CI 12·1-19·5) in 12-month retention on ART. INTERPRETATION: UTT policies implemented in Zambia increased the rapidity and uptake of ART, as well as retention on ART at 12 months, although overall retention on ART remained suboptimal. UTT policies reduced disparities in treatment initiation, but not 12-month retention on ART. Natural experiments reveal both the anticipated and unanticipated effects of real-world implementation and indicate the need for new strategies leveraging the short-term effects of UTT to cultivate long-term treatment success. FUNDING: National Institutes of Health.

Understanding patient transfers across multiple clinics in Zambia among HIV infected adults.

Many patients in HIV care in Africa considered lost to follow up (LTFU) at one facility are reportedly accessing care in another. The success of these unofficial transfers as measured by time to re-entry at the new-facility, prevalence of treatment interruptions, speed of ART-initiation, and overall continuity of care is not well characterized but may reveal opportunities for improvement. We traced a random sample of LTFU HIV-infected patients in Zambia. Among those found alive and reported in care at a new-facility, we reviewed records at the receiving facility to verify transfer; and when verified, documented the transfer experience. We used Kaplan-Meier methods to examine incidence of ART-initiation after transfer to new clinic. We assessed demographic and clinical characteristics, official and cross-provincial transfer for associations with HIV treatment re-engagement using Poisson regression models and associations between official-transfer and same-day ART initiation at the new-facility. Among 350 LTFU-patients, 178 (51%) were successfully verified through chart review at the new-facility. 132 (74.2%) were female, 72 (40.4%) aged 25-35, and 51% were ever recorded as previously being on ART. 110 patients (61.8%) were registered under new ART-IDs and 97 (54.5%) received a new HIV test. 54% of those previously on ART-initiated on the same-day. Using the same ART-ID was associated with same-day initiation compared to those receiving a new ART-ID (p = 0.07). 80% (n = 91) of those ever on ART had evidence of medication initiation at new clinic. Among these, initiation reached 66% (95% CI: 56-75) by 30 days, 77.5% (95% CI: 68-86) by 90 days after new-facility presentation. Many patients use new identifiers at new facilities, indicative of inefficiencies. Re-entry into new facilities among the unofficial-transfer population is often delayed and timely treatment initiation is inconsistent, suggesting interruptions in treatment. Health systems innovations to ensure smooth and safe transfers are needed to maintain quality HIV care.

Care Continuum and Postdischarge Outcomes Among HIV-Infected Adults Admitted to the Hospital in Zambia.

BACKGROUND: We characterized the extent of antiretroviral therapy (ART) experience and postdischarge mortality among hospitalized HIV-infected adults in Zambia. METHODS: At a central hospital with an opt-out HIV testing program, we enrolled HIV-infected adults (18+ years) admitted to internal medicine using a population-based sampling frame. Critically ill patients were excluded. Participants underwent a questionnaire regarding their HIV care history and CD4 count and viral load (VL) testing. We followed participants to 3 months after discharge. We analyzed prior awareness of HIV-positive status, antiretroviral therapy (ART) use, and VL suppression (VS; <1000 copies/mL). Using Cox proportional hazards regression, we assessed risk factors for mortality. RESULTS: Among 1283 adults, HIV status was available for 1132 (88.2%), and 762 (67.3%) were HIV-positive. In the 239 who enrolled, the median age was 36 years, 59.7% were women, and the median CD4 count was 183 cells/mm3. Active tuberculosis or Cryptococcus coinfection was diagnosed in 82 (34.3%); 93.3% reported prior awareness of HIV status, and 86.2% had ever started ART. In the 64.0% with >6 months on ART, 74.4% had VS. The majority (92.5%) were discharged, and by 3 months, 48 (21.7%) had died. Risk of postdischarge mortality increased with decreasing CD4, and there was a trend toward reduced risk in those treated for active tuberculosis. CONCLUSIONS: Most HIV-related hospitalizations and deaths may now occur among ART-experienced vs -naïve individuals in Zambia. Development and evaluation of inpatient interventions are needed to mitigate the high risk of death in the postdischarge period.

Estimating the real-world effects of expanding antiretroviral treatment eligibility: Evidence from a regression discontinuity analysis in Zambia.

BACKGROUND: Although randomized trials have established the clinical efficacy of treating all persons living with HIV (PLWHs), expanding treatment eligibility in the real world may have additional behavioral effects (e.g., changes in retention) or lead to unintended consequences (e.g., crowding out sicker patients owing to increased patient volume). Using a regression discontinuity design, we sought to assess the effects of a previous change to Zambia's HIV treatment guidelines increasing the threshold for treatment eligibility from 350 to 500 cells/µL to anticipate effects of current global efforts to treat all PLWHs. METHODS AND FINDINGS: We analyzed antiretroviral therapy (ART)-naïve adults who newly enrolled in HIV care in a network of 64 clinics operated by the Zambian Ministry of Health and supported by the Centre for Infectious Disease Research in Zambia (CIDRZ). Patients were restricted to those enrolling in a narrow window around the April 1, 2014 change to Zambian HIV treatment guidelines that raised the CD4 threshold for treatment from 350 to 500 cells/µL (i.e., August 1, 2013, to November 1, 2014). Clinical and sociodemographic data were obtained from an electronic medical record system used in routine care. We used a regression discontinuity design to estimate the effects of this change in treatment eligibility on ART initiation within 3 months of enrollment, retention in care at 6 months (defined as clinic attendance between 3 and 9 months after enrollment), and a composite of both ART initiation by 3 months and retention in care at 6 months in all new enrollees. We also performed an instrumental variable (IV) analysis to quantify the effect of actually initiating ART because of this guideline change on retention. Overall, 34,857 ART-naïve patients (39.1% male, median age 34 years [IQR 28-41], median CD4 268 cells/µL [IQR 134-430]) newly enrolled in HIV care during this period; 23,036 were analyzed after excluding patients around the threshold to allow for clinic-to-clinic variations in actual guideline uptake. In all newly enrolling patients, expanding the CD4 threshold for treatment from 350 to 500 cells/µL was associated with a 13.6% absolute increase in ART initiation within 3 months of enrollment (95% CI, 11.1%-16.2%), a 4.1% absolute increase in retention at 6 months (95% CI, 1.6%-6.7%), and a 10.8% absolute increase in the percentage of patients who initiated ART by 3 months and were retained at six months (95% CI, 8.1%-13.5%). These effects were greatest in patients who would have become newly eligible for ART with the change in guidelines: a 43.7% increase in ART initiation by 3 months (95% CI, 37.5%-49.9%), 13.6% increase in retention at six months (95% CI, 7.3%-20.0%), and a 35.5% increase in the percentage of patients on ART at 3 months and still in care at 6 months [95% CI, 29.2%-41.9%). We did not observe decreases in ART initiation or retention in patients not directly targeted by the guideline change. An IV analysis found that initiating ART in response to the guideline change led to a 37.9% (95% CI, 28.8%-46.9%) absolute increase in retention in care. Limitations of this study include uncertain generalizability under newer models of care, lack of laboratory data (e.g., viral load), inability to account for earlier stages in the HIV care cascade (e.g., HIV testing and linkage), and potential for misclassification of eligibility status or outcome. CONCLUSIONS: In this study, guidelines raising the CD4 threshold for treatment from 350 to 500 cells/µL were associated with a rapid rise in ART initiation as well as enhanced retention among newly treatment-eligible patients, without negatively impacting patients with lower CD4 levels. These data suggest that health systems in Zambia and other high-prevalence settings could substantially enhance engagement even among those with high CD4 levels (i.e., above 500 cells/µL) by expanding treatment without undermining existing care standards.

Awareness and management of elevated blood pressure among human immunodeficiency virus-infected adults receiving antiretroviral therapy in urban Zambia: a call to action.

The prevalence of high blood pressure (HBP) and hypertension (HTN), awareness of the diagnoses, and use of anti-hypertensive drugs were examined among human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy (ART) in Zambia's capital Lusaka. Within a prospective cohort based at two public sector ART clinics, BP was measured at ART initiation and every 6 months thereafter as a routine clinic procedure. Predictors of HBP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) during one year on ART were analyzed using logistic regression, and the proportion with HTN (2+ episodes of HBP >3 months apart) described. A phone survey was used to understand patient awareness of HBP, use of anti-hypertensive drugs, and history of cardiovascular events (CVE; myocardial infarction or stroke). Among 896 cohort participants, 887 (99.0%) had at least one BP measurement, 98 (10.9%) had HBP, and 57 (6.4%) had HTN. Increasing age (10-year increase in age: adjusted odds ratio [AOR] = 1.50; 95% confidence interval [CI] 1.20-1.93), male sex (AOR = 2.33, 95% CI 1.43-3.80), and overweight/obesity (AOR = 4.07; 95% CI 1.94-8.53) were associated with HBP. Among 66 patients with HBP, 35 (53.0%) reported awareness of the condition, and nine (25.7%) of these reported having had a CVE. Only 14 (21.2%) of those reached reported ever taking an anti-hypertensive drug, and one (1.5%) was currently on treatment. These data suggest that major improvements are needed in the management of HBP among HIV-infected individuals in settings such as Zambia.

Nonadherence to antiretroviral therapy among HIV-infected patients in Zambia is concentrated among a minority of patients and is highly variable across clinics.

OBJECTIVES: The distribution of adherence to antiretroviral therapy (ART) can indicates whether barriers are concentrated or more distributed. We quantified the medication possession ratio (MPR) and characterized the distribution of medication nonpossession in a network of clinics in Zambia to identify 'hotspots' and predictors of poorer adherence. METHODS: We analyzed a population of adults on ART for more than 3 months who made at least one clinic visit between 1 January 2013 and 28 February 2015. Pharmacy refill and clinical information were obtained through the electronic medical record system used in routine care. We constructed a Lorenz curve to visualize the distribution of poor adherence and used a multilevel logistic regression model to examine factors associated with MPR. RESULTS: Among 131 767 patients in 56 clinics [64% women, median age 34 years (interquartile range (IQR) 29-41), median CD4 cell count at ART initiation 351 cells/µl (IQR 220-517)], the median MPR was 85.8% (IQR 70.8-96.8). During months 7-12 on ART, 45.6% of patients had 100% MPR and 10.5% accounted for 50% of medication nonpossession. Across clinics, median MPR ranged from 49.1 to 98.5, and clinic accounted for 12% of the variability in adherence after adjusting for individual and clinic-level characteristics. CONCLUSION: A small fraction of patients account for the majority of days of medication nonpossession. Further characterization of these subpopulations is needed to target interventions. Clinic also accounted for much variability in MPR. Health systems interventions targeting clinic 'hot spots' may represent an efficient use of resources to improve ART adherence.