The cyclical cascade of HIV care: Temporal care engagement trends within a population-wide cohort.

BACKGROUND: The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary "cyclical" cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting. METHODS AND FINDINGS: This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93% of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality. CONCLUSIONS: Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opportunities. While historical HIV cascades remain valuable for target setting and service monitoring, they can be complemented with insights from more detailed cyclical cascades.

Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: A comparative analysis between a multi-country tracing study and linkage to a health information exchange.

OBJECTIVES: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. METHODS: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correcting mortality estimates for all children, adolescents and young adults with HIV. RESULTS: We found substantial variations of mortality estimates among children, adolescents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI(asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. CONCLUSIONS: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out-of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.

Associations of inter-annual rainfall decreases with subsequent HIV outcomes for persons with HIV on antiretroviral therapy in Southern Africa: a collaborative analysis of cohort studies.

BACKGROUND: Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. METHODS: Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981-2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre's latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts < 200 cells/mm3, viral loads > 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. RESULTS: Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32-46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07-1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01-1.09]). Levels of rainfall were not strongly associated with CD4 counts < 200 cell/mm3 or > 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66-0.98] per 10 percentile rainfall rank decrease). CONCLUSIONS: Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.

Conceptualising engagement with HIV care for people on treatment: the Indicators of HIV Care and AntiRetroviral Engagement (InCARE) Framework.

BACKGROUND: As the crisis-based approach to HIV care evolves to chronic disease management, supporting ongoing engagement with HIV care is increasingly important to achieve long-term treatment success. However, 'engagement' is a complex concept and ambiguous definitions limit its evaluation. To guide engagement evaluation and development of interventions to improve HIV outcomes, we sought to identify critical, measurable dimensions of engagement with HIV care for people on treatment from a health service-delivery perspective. METHODS: We used a pragmatic, iterative approach to develop a framework, combining insights from researcher experience, a narrative literature review, framework mapping, expert stakeholder input and a formal scoping review of engagement measures. These inputs helped to refine the inclusion and definition of important elements of engagement behaviour that could be evaluated by the health system. RESULTS: The final framework presents engagement with HIV care as a dynamic behaviour that people practice rather than an individual characteristic or permanent state, so that people can be variably engaged at different points in their treatment journey. Engagement with HIV care for those on treatment is represented by three measurable dimensions: 'retention' (interaction with health services), 'adherence' (pill-taking behaviour), and 'active self-management' (ownership and self-management of care). Engagement is the product of wider contextual, health system and personal factors, and engagement in all dimensions facilitates successful treatment outcomes, such as virologic suppression and good health. While retention and adherence together may lead to treatment success at a particular point, this framework hypothesises that active self-management sustains treatment success over time. Thus, evaluation of all three core dimensions is crucial to realise the individual, societal and public health benefits of antiretroviral treatment programmes. CONCLUSIONS: This framework distils a complex concept into three core, measurable dimensions critical for the maintenance of engagement. It characterises elements that the system might assess to evaluate engagement more comprehensively at individual and programmatic levels, and suggests that active self-management is an important consideration to support lifelong optimal engagement. This framework could be helpful in practice to guide the development of more nuanced interventions that improve long-term treatment success and help maintain momentum in controlling a changing epidemic.

Contemporary disengagement from antiretroviral therapy in Khayelitsha, South Africa: A cohort study.

BACKGROUND: Retention in care is an essential component of meeting the UNAIDS "90-90-90" HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013-2014 and outcomes for those who disengaged. METHODS AND FINDINGS: We conducted a retrospective cohort study of all patients ≥10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013-2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4-63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47-1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11-22.4). As we included only patient follow-up from 2013-2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement. CONCLUSIONS: Twenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2-year period. Fifty-eight percent of these patients either subsequently returned to care (some "silently") or remained alive without hospitalization, suggesting that many who are considered "lost" actually return to care, and that misclassification of "lost" patients is likely common in similar urban populations. A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms.

The effect of care interruptions on mortality in adults resuming antiretroviral therapy.

OBJECTIVE: To estimate the relative rate of all-cause mortality amongst those on antiretroviral treatment (ART) with a history of interruptions compared with those with no previous interruptions in care. DESIGN: Retrospective cohort study. METHODS: We used data from four South African cohorts participating in the International epidemiology Databases to Evaluate AIDS Southern Africa collaboration. We included adults who started ART between 2004 and 2019. We defined a care interruption as a gap in contact longer than 180 days. Observation time prior to interruption was allocated to a 'no interruption' group. Observation time after interruption was allocated to one of two groups based on whether the first interruption started before 6 months of ART ('early interruption') or later ('late interruption'). We used Cox regression to estimate hazard ratios. RESULTS: Sixty-three thousand six hundred and ninety-two participants contributed 162 916 person-years of observation. There were 3469 deaths. Most participants were female individuals (67.4%) and the median age at ART initiation was 33.3 years (interquartile range: 27.5-40.7). Seventeen thousand and eleven (26.7%) participants experienced care interruptions. Those resuming ART experienced increased mortality compared with those with no interruptions: early interrupters had a hazard ratio of 4.37 (95% confidence interval (CI) 3.87-4.95) and late interrupters had a hazard ratio of 2.74 (95% CI 2.39-3.15). In sensitivity analyses, effect sizes were found to be proportional to the length of time used to define interruptions. CONCLUSION: Our findings highlight the need to improve retention in care, regardless of treatment duration. Programmes to encourage return to care also need to be strengthened.

Effects of the COVID-19 pandemic on early infant diagnosis of HIV in Cape Town, South Africa.

Background: In South Africa, infants who are HIV-exposed are tested for HIV at birth and 10 weeks of age. The COVID-19 pandemic lockdown restrictions resulted in reduced access to healthcare services and uncertain impact on early infant HIV testing. Objectives: To describe the effects of the COVID-19 pandemic lockdown restrictions on early infant HIV testing and diagnosis in Cape Town, South Africa. Method: This retrospective cohort study compares HIV-exposed infants born during the first COVID-19 pandemic lockdown (2020) to those born in the same period the year before (2019). Laboratory and other data were abstracted from the Provincial Health Data Centre. Results: A total of 2888 infants were included: 1474 born in 2020 and 1413 in 2019. Compared to 2019, there was an increase in the 10-week HIV polymerase chain reaction (PCR) uptake in 2020 (71% vs. 60%, P < 0.001). There was also an increase in the proportion of infants who demised without 10-week testing or were lost to follow-up in 2020 compared to 2019 (8% vs. 5%, P = 0.017). Differences detected in birth HIV PCR positivity rates between the two groups (1.1% vs. 0.5%, P = 0.17) did not reach statistical significance; however, a significant increase in vertical transmission of HIV by 10 weeks old was found in the 2020 cohort (1.2% vs. 0.5%. P = 0.046). Conclusion: Vertical transmission of HIV at 10 weeks increased in the Cape Town Metropolitan during the initial COVID-19 lockdown. There was also an increase in the proportion of deaths without testing by 10 weeks in the 2020 group.

Supporting re-engagement with HIV services after treatment interruption in South Africa: a mixed method program evaluation of MSF's Welcome Service.

Psychosocial challenges impact patients' ability to remain on antiretroviral therapy lifelong, magnified by disorganized health-systems and healthcare worker (HCW) attitudes. To address this, Médecins Sans Frontières and the Department of Health developed the Welcome Service intervention, to provide person-centered care at re-engagement after HIV treatment interruption. Implemented in Khayelitsha, South Africa, between August 2020 and February 2021, the intervention aimed to reorganize triage, optimize clinical and counselling services and address HCW attitudes. The study used a mixed-methods design, incorporating in-depth interviews, and analyses of programmatic and routine health data. Interviews demonstrated positive patient care experiences. HCWs understood the potential impact of attitudes on patient engagement, however, some continued to demonstrate judgmental attitude. Clinical objectives were variably met at re-engagement: 98% were re-initiated the same day, 50% had a CD4 done, and 45% received tuberculosis prevention. Nevertheless, 4-month retention was 66%, and 88% had a VL < 1000 c/mL. Despite HCWs' understanding of person-centered care not translating into supportive behaviors, patients had positive care experiences and the intervention ended with a high rate of VL suppression. More efforts are needed to design interventions building on Welcome Service principles to provide person-centered care and sustain retention after re-engagement.

ART history prior to conception: trends and association with postpartum disengagement from HIV care in Khayelitsha, South Africa (2013-2019): a retrospective cohort study.

INTRODUCTION: In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception. METHODS: We analysed data from people living with HIV (aged 15-49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan-Meier curves and proportional-hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum. RESULTS: Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25-27%) had disengaged from care by 1 year and 34% (95% CI 33-36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70-2.60), restarted (C: aHR 3.32, 95% CI 2.70-4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12-2.74) had increased hazards of postpartum disengagement compared to those on ART (A). CONCLUSIONS: There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care.

Transition to dolutegravir-based ART in 35 low- and middle-income countries: a global survey of HIV care clinics.

OBJECTIVE: We studied the transition to dolutegravir-containing antiretroviral therapy (ART) at HIV treatment clinics within the International epidemiology Databases to Evaluate AIDS (IeDEA). DESIGN: Site-level survey conducted in 2020-2021 among HIV clinics in low- and middle-income countries (LMICs). METHODS: We assessed the status of dolutegravir rollout and viral load and drug resistance testing practices for patients on ART switching to dolutegravir-based regimens. We used generalized estimating equations to assess associations between clinic rollout of both first- and second-line dolutegravir-based ART regimens (dual rollout) and site-level factors. RESULTS: Of 179 surveyed clinics, 175 (98%) participated; 137 (78%) from Africa, 30 (17%) from the Asia-Pacific, and 8 (5%) from Latin America. Most clinics (80%) were in low- or lower-middle-income countries, and there were a mix of primary-, secondary- and tertiary-level clinics. Ninety percent reported rollout of first-line dolutegravir, 59% of second-line, 94% of first- or second-line and 55% of dual rollout. The adjusted odds of dual rollout were higher among tertiary-level (aOR 4.00; 95% CI 1.39 to 11.47) and secondary-level clinics (aOR 3.66; 95% CI 2.19 to 6.11) than in primary-level clinics. Over half (59%) of clinics that introduced first- or second-line dolutegravir-based ART required recent viral load testing before switching to dolutegravir, and 15% performed genotypic resistance testing at switch. CONCLUSIONS: Dolutegravir-based ART was rolled out at nearly all IeDEA clinics in LMICs, yet many switched patients to dolutegravir without recent viral load testing and drug resistance testing was rarely performed. Without such testing, drug resistance among patient switching to dolutegravir may go undetected.

Ongoing High Prevalence of Severe Immune Suppression Among Children in South Africa.

BACKGROUND: Among children in Southern Africa severe immune suppression (SIS) has declined, but most continue to initiate antiretroviral therapy (ART) with SIS. SETTING: Using data from South Africa, we describe SIS at ART start and on ART between 2007 and 2020, among children <5 years with a CD4%/cell count at ART start and ≥1 subsequent measure. METHODS: Gap in care was defined as >9 months without a recorded visit. We defined SIS according to age and CD4%/cell count. A multistate model was used to estimate transition probabilities between 5 states: SIS on ART; Stable, not SIS; Early Gap, commencing <9 months from ART start; Late Gap, commencing ≥9 months on ART; and Death. RESULTS: Among 2536 children, 70% had SIS at ART start, and 36% experienced SIS on ART. An increasing proportion were age <1 year at ART initiation (2007-2009: 43% to 2013-2020: 55%). Increasingly, SIS on ART occurred after a gap, in those with SIS on ART for >1 year, and after a period of unknown immune status. Later year of ART initiation was associated with reduced transition from SIS on ART to Stable. Infants and those initiating ART with SIS were more likely to transition from Stable to SIS. Viremia strongly predicted death from both the on ART states. CONCLUSIONS: Increasingly SIS occurred among ART-experienced children. Those starting ART with SIS and during infancy remained especially vulnerable to SIS once on treatment. Managing ART in these children may be more complex and further reducing AIDS-related mortality is likely to remain challenging.

Advanced HIV disease and engagement in care among patients on antiretroviral therapy in South Africa: results from a multi-state model.

OBJECTIVE: Despite improved access to antiretroviral therapy (ART) for people with HIV (PWH), HIV continues to contribute considerably to morbidity and mortality. Increasingly, advanced HIV disease (AHD) is found among PWH who are ART-experienced. DESIGN: Using a multi-state model we examined associations between engagement with care and AHD on ART in South Africa. METHODS: Using data from IeDEA Southern Africa, we included PWH from South Africa, initiating ART from 2004 to 2017 aged more than 5 years with a CD4+ cell count at ART start and at least one subsequent measure. We defined a gap as no visit for at least 18 months. Five states were defined: 'AHD on ART' (CD4+ cell count <200 cells/µl), 'Clinically Stable on ART' (CD4+ cell count ≥200 or if no CD4+ cell count, viral load <1000 copies/ml), 'Early Gap' (commencing ≤18 months from ART start), 'Late Gap' (commencing >18 months from ART start) and 'Death'. RESULTS: Among 32 452 PWH, men and those aged 15-25 years were more likely to progress to unfavourable states. Later years of ART start were associated with a lower probability of transitioning from AHD to clinically stable, increasing the risk of death following AHD. In stratified analyses, those starting ART with AHD in later years were more likely to re-engage in care with AHD following a gap and to die following AHD on ART. CONCLUSION: In more recent years, those with AHD on ART were more likely to die, and AHD at re-engagement in care increased. To further reduce HIV-related mortality, efforts to address the challenges facing these more vulnerable patients are needed.

Measuring patient engagement with HIV care in sub-Saharan Africa: a scoping study.

INTRODUCTION: Engagement with HIV care is a multi-dimensional, dynamic process, critical to maintaining successful treatment outcomes. However, measures of engagement are not standardized nor comprehensive. This undermines our understanding of the scope of challenges with engagement and whether interventions have an impact, complicating patient and programme-level decision-making. This study identified and characterized measures of engagement to support more consistent and comprehensive evaluation. METHODS: We conducted a scoping study to systematically categorize measures the health system could use to evaluate engagement with HIV care for those on antiretroviral treatment. Key terms were used to search literature databases (Embase, PsychINFO, Ovid Global-Health, PubMed, Scopus, CINAHL, Cochrane and the World Health Organization Index Medicus), Google Scholar and stakeholder-identified manuscripts, ultimately including English evidence published from sub-Saharan Africa from 2014 to 2021. Measures were extracted, organized, then reviewed with key stakeholders. RESULTS AND DISCUSSION: We screened 14,885 titles/abstracts, included 118 full-texts and identified 110 measures of engagement, categorized into three engagement dimensions ("retention," "adherence" and "active self-management"), a combination category ("multi-dimensional engagement") and "treatment outcomes" category (e.g. viral load as an end-result reflecting that engagement occurred). Retention reflected status in care, continuity of attendance and visit timing. Adherence was assessed by a variety of measures categorized into primary (prescription not filled) and secondary measures (medication not taken as directed). Active self-management reflected involvement in care and self-management. Three overarching use cases were identified: research to make recommendations, routine monitoring for quality improvement and strategic decision-making and assessment of individual patients. CONCLUSIONS: Heterogeneity in conceptualizing engagement with HIV care is reflected by the broad range of measures identified and the lack of consensus on "gold-standard" indicators. This review organized metrics into five categories based on the dimensions of engagement; further work could identify a standardized, minimum set of measures useful for comprehensive evaluation of engagement for different use cases. In the interim, measurement of engagement could be advanced through the assessment of multiple categories for a more thorough evaluation, conducting sensitivity analyses with commonly used measures for more comparable outputs and using longitudinal measures to evaluate engagement patterns. This could improve research, programme evaluation and nuanced assessment of individual patient engagement in HIV care.

Virologic non-suppression and early loss to follow up among pregnant and non-pregnant adolescents aged 15-19 years initiating antiretroviral therapy in South Africa: a retrospective cohort study.

INTRODUCTION: Older adolescents aged 15-19 years continue to have high rates of loss to follow up (LTFU), and high rates of virologic non-suppression (VNS) compared to younger adolescents and adults. Adolescent females are at risk of pregnancy, which puts those living with HIV at a dual vulnerability. Our study assessed the factors associated with VNS and LTFU in older adolescents (including pregnant females) who initiated antiretroviral therapy (ART) in South Africa. METHODS: We included adolescents aged 15-19 years initiating ART between 2004 and 2019, with ≥ one viral load (VL) measurement between 4 and 24.5 months, and ≥ 6 months follow-up, from six South African cohorts of the International epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA). We defined VNS as VL ≥400 copies/ml and LTFU as not being in care for ≥180 days from ART start and not known as transferred out of the clinic or dead in the first 24 months on ART. We examined factors associated with VNS and LTFU using Fine&Gray competing risk models. RESULTS: We included a total of 2733 adolescents, 415 (15.2%) males, median (IQR) age at ART start of 18.6 (17.3, 19.4) years. Among females, 585/2318 (25.2%) were pregnant. Over the 24-month follow-up, 424 (15.5%) of all adolescents experienced VNS: range (11.1% pregnant females and 20.5% males). Over half of all adolescents were LTFU before any other event could occur. The hazard of VNS reduced with increasing age and CD4 count above 200 cells/µl at ART initiation among all adolescents having adjusted for all measured patient characteristics [adjusted sub-distribution hazard ratio (aSHR) 19 vs. 15 years: 0.50 (95% CI: 0.36, 0.68), aSHR: >500 vs. ≤200 cells/µl: 0.22 (95% CI: 0.16, 0.31)]. The effect of CD4 count persisted in pregnant females. Increasing age and CD4 count >200 cells/µl were risk factors for LTFU among all adolescents. CONCLUSIONS: Older adolescents had a high risk of LTFU shortly after ART start and a low risk of VNS, especially those initiating treatment during pregnancy. Interventions addressing adherence and retention should be incorporated into adolescent-friendly services to prevent VNS and LTFU and endeavour to trace lost adolescents as soon as they are identified.

Cohort profile: the Western Cape Pregnancy Exposure Registry (WCPER).

PURPOSE: The Western Cape Pregnancy Exposure Registry (PER) was established at two public sector healthcare sentinel sites in the Western Cape province, South Africa, to provide ongoing surveillance of drug exposures in pregnancy and associations with pregnancy outcomes. PARTICIPANTS: Established in 2016, all women attending their first antenatal visit at primary care obstetric facilities were enrolled and followed to pregnancy outcome regardless of the site (ie, primary, secondary, tertiary facility). Routine operational obstetric and medical data are digitised from the clinical stationery at the healthcare facilities. Data collection has been integrated into existing services and information platforms and supports routine operations. The PER is situated within the Provincial Health Data Centre, an information exchange that harmonises and consolidates all health-related electronic data in the province. Data are contributed via linkage across a unique identifier. This relationship limits the missing data in the PER, allows validation and avoids misclassification in the population-level data set. FINDINGS TO DATE: Approximately 5000 and 3500 pregnant women enter the data set annually at the urban and rural sites, respectively. As of August 2021, >30 000 pregnancies have been recorded and outcomes have been determined for 93%. Analysis of key obstetric and neonatal health indicators derived from the PER are consistent with the aggregate data in the District Health Information System. FUTURE PLANS: This represents significant infrastructure, able to address clinical and epidemiological concerns in a low/middle-income setting.

Virologic response of adolescents living with perinatally acquired HIV receiving antiretroviral therapy in the period of early adolescence (10-14 years) in South Africa.

BACKGROUND AND OBJECTIVES: Adolescents living with perinatally acquired HIV (ALPHIV) on antiretroviral therapy (ART) have been noted to have poorer adherence, retention and virologic control compared to adolescents with non-perinatally acquired HIV, children or adults. We aimed to describe and examine factors associated with longitudinal virologic response during early adolescence. DESIGN: A retrospective cohort study. METHODS: We included ALPHIV who initiated ART before age 9.5 years in South African cohorts of the International epidemiology Database to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration (2004-2016); with viral load (VL) values <400 copies/ml at age 10 years and at least one VL measurement after age 10 years. We used a log-linear quantile mixed model to assess factors associated with elevated (75th quantile) VLs. RESULTS: We included 4396 ALPHIV, 50.7% were male, with median (interquartile range) age at ART start of 6.5 (4.5, 8.1) years. Of these, 74.9% were on a non-nucleoside reverse transcriptase inhibitor (NNRTI) at age 10 years. After adjusting for other patient characteristics, the 75th quantile VLs increased with increasing age being 3.13-fold (95% CI 2.66, 3.68) higher at age 14 versus age 10, were 3.25-fold (95% CI 2.81, 3.75) higher for patients on second-line protease-inhibitor and 1.81-fold for second-line NNRTI-based regimens (versus first-line NNRTI-based regimens). There was no difference by sex. CONCLUSIONS: As adolescents age between 10 and 14 years, they are increasingly likely to experience higher VL values, particularly if receiving second-line protease inhibitor or NNRTI-based regimens, which warrant adherence support interventions.

Global estimates of viral suppression in children and adolescents and adults on antiretroviral therapy adjusted for missing viral load measurements: a multiregional, retrospective cohort study in 31 countries.

BACKGROUND: As countries move towards the UNAIDS's 95-95-95 targets and with strong evidence that undetectable equals untransmittable, it is increasingly important to assess whether those with HIV who are receiving antiretroviral therapy (ART) achieve viral suppression. We estimated the proportions of children and adolescents and adults with viral suppression at 1, 2, and 3 years after initiating ART. METHODS: In this retrospective cohort study, seven regional cohorts from the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium contributed data from individuals initiating ART between Jan 1, 2010, and Dec 31, 2019, at 148 sites in 31 countries with annual viral load monitoring. Only people with HIV who started ART after the time a site started routine viral load monitoring were included. Data up to March 31, 2020, were analysed. We estimated the proportions of children and adolescents (aged <18 years at ART initiation) and adults (aged ≥18 years at ART initiation) with viral suppression (viral load <1000 copies per mL) at 1, 2, and 3 years after ART initiation using an intention-to-treat approach and an adjusted approach that accounted for missing viral load measurements. FINDINGS: 21 594 children and adolescents (11 812 [55%] female, 9782 [45%] male) from 106 sites in 22 countries and 255 662 adults (163 831 [64%] female, 91 831 [36%] male) from 143 sites in 30 countries were included. Using the intention-to-treat approach, the proportion of children and adolescents with viral suppression was 7303 (36%) of 20 478 at 1 year, 5709 (30%) of 19 135 at 2 years, and 4287 (24%) of 17 589 at 3 years after ART initiation; the proportion of adults with viral suppression was 106 541 (44%) of 240 600 at 1 year, 79 141 (36%) of 220 925 at 2 years, and 57 970 (29%) of 201 124 at 3 years after ART initiation. After adjusting for missing viral load measurements among those who transferred, were lost to follow-up, or who were in follow-up without viral load testing, the proportion of children and adolescents with viral suppression was 12 048 (64% [plausible range 43-81]) of 18 835 at 1 year, 10 796 (62% [41-77]) of 17 553 at 2 years, and 9177 (59% [38-91]) of 15 667 at 3 years after ART initiation; the proportion of adults with viral suppression was 176 964 (79% [53-80]) of 225 418 at 1 year, 145 552 (72% [48-79]) of 201 238 at 2 years, and 115 260 (65% [43-69]) of 178 458 at 3 years after ART initiation. INTERPRETATION: Although adults with HIV are approaching the global target of 95% viral suppression, progress among children and adolescents is much slower. Substantial efforts are still needed to reach the viral suppression target for children and adolescents. FUNDING: US National Institutes of Health.

Long-term virologic responses to antiretroviral therapy among HIV-positive patients entering adherence clubs in Khayelitsha, Cape Town, South Africa: a longitudinal analysis.

INTRODUCTION: In South Africa, an estimated 4.6 million people were accessing antiretroviral therapy (ART) in 2018. As universal Test and Treat is implemented, these numbers will continue to increase. Given the need for lifelong care for millions of individuals, differentiated service delivery models for ART services such as adherence clubs (ACs) for stable patients are required. In this study, we describe long-term virologic outcomes of patients who have ever entered ACs in Khayelitsha, Cape Town. METHODS: We included adult patients enrolled in ACs in Khayelitsha between January 2011 and December 2016 with a recorded viral load (VL) before enrolment. Risk factors for an elevated VL (VL >1000 copies/mL) and confirmed virologic failure (two consecutive VLs >1000 copies/mL one year apart) were estimated using Cox proportional hazards models. VL completeness over time was assessed. RESULTS: Overall, 8058 patients were included in the analysis, contributing 16,047 person-years of follow-up from AC entry (median follow-up time 1.7 years, interquartile range [IQR]:0.9 to 2.9). At AC entry, 74% were female, 46% were aged between 35 and 44 years, and the median duration on ART was 4.8 years (IQR: 3.0 to 7.2). Among patients virologically suppressed at AC entry (n = 8058), 7136 (89%) had a subsequent VL test, of which 441 (6%) experienced an elevated VL (median time from AC entry 363 days, IQR: 170 to 728). Older age (adjusted hazard ratio [aHR] 0.64, 95% confidence interval [CI] 0.46 to 0.88), more recent year of AC entry (aHR 0.76, 95% CI 0.68 to 0.84) and higher CD4 count (aHR 0.67, 95% CI 0.54 to 0.84) were protective against experiencing an elevated VL. Among patients with an elevated VL, 52% (150/291) with a repeat VL test subsequently experienced confirmed virologic failure in a median time of 112 days (IQR: 56 to 168). Frequency of VL testing was constant over time (82 to 85%), with over 90% of patients remaining virologically suppressed. CONCLUSIONS: This study demonstrates low prevalence of elevated VLs and confirmed virologic failure among patients who entered ACs. Although ACs were expanded rapidly, most patients were well monitored and remained stable, supporting the continued rollout of this model.

A longitudinal analysis of the completeness of maternal HIV testing, including repeat testing in Cape Town, South Africa.

INTRODUCTION: The virtual elimination of mother-to-child transmission of HIV cannot be achieved without complete maternal HIV testing. The World Health Organization recommends that women in high HIV prevalent settings repeat HIV testing in the third trimester, and at delivery or directly thereafter. The Western Cape Province (South Africa) prevention of mother-to-child transmission (PMTCT) guidelines recommend a repeat maternal HIV test between 32 and 34 weeks gestation and at delivery in addition to testing at the first antenatal visit (ideally <20 weeks gestation). There are few published longitudinal studies on the uptake of initial and repeated maternal HIV testing programmes in sub-Saharan Africa. We aimed to investigate the implementation of initial and repeat maternal HIV testing guidelines in Cape Town, South Africa. METHODS: Between 2013 and 2016 we established an electronic PMTCT register that consolidated routine data from a primary healthcare facility and its secondary and tertiary referral sites in Cape Town. This provided a longitudinal record for each participant, from first antenatal visit to delivery. Utilizing these data, we conducted a retrospective analysis investigating the completeness of maternal HIV testing according to the PMTCT HIV testing guidelines in Cape Town, and predictors of complete testing, from 2014 to 2016. RESULTS: Among 8558 enrolled pregnant women, 7213 (84%) were not known to be HIV positive at their first visit and thus eligible for HIV testing; 91% of them received ≥1 HIV test during pregnancy/delivery. Testing at the first visit was 98% among the 85% of women who attended antenatal care. Among women eligible to receive all three recommended HIV tests, only 11% achieved all three tests. Delivery HIV testing completion among all women without an HIV-positive diagnosis was 23%. HIV prevalence at delivery was 21% and HIV incidence between first visit and delivery in those with ≥2 HIV tests was 0.2%. Women who enrolled after 2014 were more likely to receive the three recommended tests (aOR: 1.41; 95% CI: 1.10 to 1.81) and retest at delivery (aOR: 1.20; 95% CI: 1.05 to 1.39). CONCLUSIONS: Implementation of maternal HIV testing in Cape Town improved between 2014 and 2016 but major gaps remain, particularly at delivery.

Recording of HIV viral loads and viral suppression in South African patients receiving antiretroviral treatment: a multicentre cohort study.

BACKGROUND: Viral suppression in patients on antiretroviral treatment (ART) is critical to reducing HIV transmission and HIV-related mortality. Although many studies have evaluated factors associated with viral suppression, few have assessed the extent to which missing viral load data may bias results. METHODS: We included data on all patients starting ART from 2005 to 2019 in eight South African cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) collaboration. Multivariable logistic regression models were used to determine factors associated with having a viral load measurement within 2 months of a scheduled testing date and having a viral load <400 RNA copies/ml ('viral suppression'). In a sensitivity analysis, missing viral loads were imputed based on patients' clinical and demographic characteristics and outcomes. RESULTS: Viral load tests were scheduled in 603,549 and 77,423 intervals in adults and children, respectively, but test results were recorded in only 40.7% and 41.2%, respectively. The proportion of recorded results suppressed was 85.7% in adults and 72.4% in children. After imputation of missing viral load measurements, viral suppression reduced slightly in adults (85.3%) and increased in children (73.2%). Predictors of virological suppression in adults, which included female sex, older age, higher baseline CD4+ T-cell count and recent testing year, were similar in the main analysis and after imputing missing viral loads. CONCLUSIONS: Although viral load information was frequently missing in the South African setting, estimates of viral suppression and predictors of viral suppression did not change substantially after adjusting for missing data.