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.

Person-centred interventions to improve patient-provider relationships for HIV services in low- and middle-income countries: a systematic review.

INTRODUCTION: Person-centred care (PCC) has been recognized as a critical element in delivering quality and responsive health services. The patient-provider relationship, conceptualized at the core of PCC in multiple models, remains largely unexamined in HIV care. We conducted a systematic review to better understand the types of PCC interventions implemented to improve patient-provider interactions and how these interventions have improved HIV care continuum outcomes and person-reported outcomes (PROs) among people living with HIV in low- and middle-income countries. METHODS: We searched databases, conference proceedings and conducted manual targeted searches to identify randomized trials and observational studies published up to January 2023. The PCC search terms were guided by the Integrative Model of Patient-Centeredness by Scholl. We included person-centred interventions aiming to enhance the patient-provider interactions. We included HIV care continuum outcomes and PROs. RESULTS: We included 28 unique studies: 18 (64.3%) were quantitative, eight (28.6.%) were mixed methods and two (7.1%) were qualitative. Within PCC patient-provider interventions, we inductively identified five categories of PCC interventions: (1) providing friendly and welcoming services; (2) patient empowerment and improved communication skills (e.g. supporting patient-led skills such as health literacy and approaches when communicating with a provider); (3) improved individualized counselling and patient-centred communication (e.g. supporting provider skills such as training on motivational interviewing); (4) audit and feedback; and (5) provider sensitisation to patient experiences and identities. Among the included studies with a comparison arm and effect size reported, 62.5% reported a significant positive effect of the intervention on at least one HIV care continuum outcome, and 100% reported a positive effect of the intervention on at least one of the included PROs. DISCUSSION: Among published HIV PCC interventions, there is heterogeneity in the components of PCC addressed, the actors involved and the expected outcomes. While results are also heterogeneous across clinical and PROs, there is more evidence for significant improvement in PROs. Further research is necessary to better understand the clinical implications of PCC, with fewer studies measuring linkage or long-term retention or viral suppression. CONCLUSIONS: Improved understanding of PCC domains, mechanisms and consistency of measurement will advance PCC research and implementation.

Decision to self-isolate during the COVID-19 pandemic in the UK: a rapid scoping review.

OBJECTIVE: Testing for COVID-19 was a key component of the UK's response to the COVID-19 pandemic. This strategy relied on positive individuals self-isolating to reduce transmission, making isolation the lynchpin in the public health approach. Therefore, we scoped evidence to systematically identify and categorise barriers and facilitators to compliance with self-isolation guidance during the COVID-19 pandemic in the UK, to inform public health strategies in future pandemics. DESIGN: A rapid scoping review was conducted. SEARCH STRATEGY: Key terms were used to search literature databases (PubMed, Scopus and the WHO COVID-19 Research Database, on 7 November 2022), Google Scholar and stakeholder-identified manuscripts, ultimately including evidence published in English from UK-based studies conducted between 2020 and 2022. DATA EXTRACTION AND SYNTHESIS: Data were extracted and synthesised into themes, organised broadly into capability, opportunity and motivation, and reviewed with key stakeholders from the UK Health Security Agency (UKHSA). RESULTS: We included 105 sources, with 63 identified from UKHSA and used to inform their decision-making during the pandemic. Influences on the decision to comply with isolation guidance were categorised into six themes: perceived ability to isolate; information and guidance; logistics; social influences, including trust; perceived value; and perceived consequences. Individuals continuously assessed these factors in deciding whether or not to comply with guidance and self-isolate. CONCLUSIONS: Decisions to self-isolate after a positive test were influenced by multiple factors, including individuals' beliefs, concerns, priorities and personal circumstances. Future testing strategies must facilitate meaningful financial, practical and mental health support to allow individuals to overcome the perceived and actual negative consequences of isolating. Clear, consistent communication of the purpose and procedures of isolating will also be critical to support compliance with self-isolation guidance, and should leverage people's perceived value in protecting others. Building public trust is also essential, but requires investment before the next pandemic starts.

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.

Relationship Between Tenofovir Diphosphate Concentrations in Dried Blood Spots and Virological Outcomes After Initiating Tenofovir-Lamivudine-Dolutegravir as First-Line or Second-Line Antiretroviral Therapy.

BACKGROUND: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir-lamivudine-dolutegravir (TLD) as first-line or second-line antiretroviral therapy. SETTING: Three primary care clinics in Khayelitsha, Cape Town, South Africa. METHODS: We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories. RESULTS: We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes. CONCLUSION: TFV-DP concentrations in dried blood spots exhibit a dose-response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.

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.

Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial.

BACKGROUND: The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. METHODS: RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per µL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588. FINDINGS: Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per µL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). INTERPRETATION: Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. FUNDING: Wellcome Trust.

Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial.

BACKGROUND: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms. RESULTS: One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% [95% confidence interval {CI}: 75%-93%]) in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%-90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. CONCLUSIONS: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. CLINICAL TRIALS REGISTRATION: NCT03991013.

Between empathy and anger: healthcare workers' perspectives on patient disengagement from antiretroviral treatment in Khayelitsha, South Africa - a qualitative study.

BACKGROUND & OBJECTIVES: The benefits of long-term adherence to antiretroviral therapy (ART) are countered by interruptions in care or disengagement from care. Healthcare workers (HCWs) play an important role in patient engagement and negative or authoritarian attitudes can drive patients to disengage. However, little is known about HCWs' perspectives on disengagement. We explored HCWs' perspectives on ART disengagement in Khayelitsha, a peri-urban area in South Africa with a high HIV burden. METHOD: Semi-structured interviews were conducted with 30 HCWs in a primary care HIV clinic to explore their perspectives of patients who disengage from ART. HCWs interviewed included clinical (doctors and nurses) and support staff (counsellors, social workers, data clerks, security guards, and occupational therapists). The interview guide asked HCWs about their experience working with patients who interrupt treatment and return to care. Transcripts were audio-recorded, transcribed, and analysed using an inductive thematic analysis approach. RESULTS: Most participants were knowledgeable about the complexities of disengagement and barriers to sustaining engagement with ART, raising their concerns that disengagement poses a significant public health problem. Participants expressed empathy for patients who interrupted treatment, particularly when the challenges that led to their disengagement were considered reasonable by the HCWs. However, many also expressed feelings of anger and frustration towards these patients, partly because they reported an increase in workload as a result. Some staff, mainly those taking chronic medication themselves, perceived patients who disengage from ART as not taking adequate responsibility for their own health. CONCLUSION: Lifelong engagement with HIV care is influenced by many factors including disclosure, family support, and HCW interactions. Findings from this study show that HCWs had contradictory feelings towards disengaged patients, experiencing both empathy and anger. Understanding this could contribute to the development of more nuanced interventions to support staff and encourage true person-centred care, to improve patient outcomes.

Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks.

BACKGROUND: Recycling tenofovir and lamivudine/emtricitabine with dolutegravir (TLD) after failure of non-nucleoside transcriptase inhibitor first-line antiretroviral therapy is more tolerable and scalable than dolutegravir plus optimized nucleoside reverse transcriptase inhibitors. Studies have demonstrated TLD's efficacy as second line, but long-term follow-up is limited. METHODS: ARTIST is a single arm, prospective, interventional study conducted in Khayelitsha, South Africa, which switched 62 adults with 2 viral loads >1000 copies/mL from tenofovir, lamivudine/emtricitabine, and an non-nucleoside transcriptase inhibitor to TLD. We report efficacy to 72 weeks and, in a post hoc analysis, evaluated viral load trajectories of individuals with viremic episodes. RESULTS: Virologic suppression was 86% [95% confidence interval (CI) 74 to 93], 74% (95% CI: 61 to 84), and 75% (95% CI: 63 to 86) <50 copies/mL and 95%, 84%, and 77% <400 copies/mL at week 24, 48, and 72, respectively, with 89% (50/56) resistant (Stanford score ≥15) to tenofovir and/or lamivudine preswitch. No participants developed integrase-inhibitor resistance. Of the 20 participants not suppressed at week 24 and/or 48, 2 developed virologic failure, 1 switched regimen (adverse event), 2 were lost to follow-up, 1 missed the visit, 1 transferred out, 9 resuppressed <50 copies/mL with enhanced adherence counseling, and 4 remained viremic (3 with <200 copies/mL) at week 72. CONCLUSIONS: Recycling NRTIs with dolutegravir was effective for most participants to 72 weeks. Most with viremia did not develop virologic failure and subsequently suppressed with enhanced adherence counseling or continued to have low-level viremia. No integrase-inhibitor resistance was detected despite low-level viremia in a minority of participants.

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.

Social determinants of health and the double burden of disease in Nepal: a secondary analysis.

BACKGROUND: As the global burden of disease evolves, lower-resource countries like Nepal face a double burden of non-communicable and infectious disease. Rapid adaptation is required for Nepal's health system to provide life-long, person-centred care while simultaneously improving quality of infectious disease services. Social determinants of health be key in addressing health disparities and could direct policy decisions to promote health and manage the disease burden. Thus, we explore the association of social determinants with the double burden of disease in Nepal. METHODS: This is a retrospective, ecological, cross-sectional analysis of infectious and non-communicable disease outcome data (2017 to 2019) and data on social determinants of health (2011 to 2013) for 753 municipalities in Nepal. Multinomial logistic regression was conducted to evaluate the associations between social determinants and disease burden. RESULTS: The 'high-burden' combined double burden (non-communicable and infectious disease) outcome was associated with more accessible municipalities, (adjOR3.94[95%CI2.94-5.28]), municipalities with higher proportions of vaccine coverage (adjOR12.49[95%CI3.05-51.09]) and malnutrition (adjOR9.19E103[95%CI19.68E42-8.72E164]), lower average number of people per household (adjOR0.32[95%CI0.22-0.47]) and lower indigenous population (adjOR0.20[95%CI0.06-0.65]) compared to the 'low-burden' category on multivariable analysis. 'High-burden' of non-communicable disease was associated with more accessible municipalities (adjOR1.93[95%CI1.45-2.57]), higher female proportion within the municipality (adjOR1.69E8[95%CI3227.74-8.82E12]), nutritional deficiency (adjOR1.39E17[95%CI11799.83-1.64E30]) and malnutrition (adjOR2.17E131[95%CI4.41E79-1.07E183]) and lower proportions of population under five years (adjOR1.05E-10[95%CI9.95E-18-0.001]), indigenous population (adjOR0.32[95%CI0.11-0.91]), average people per household (adjOR0.44[95%CI0.26-0.73]) and households with no piped water (adjOR0.21[95%CI0.09-0.49]), compared to the 'low-burden' category on adjusted analysis. 'High burden' of infectious disease was also associated with more accessible municipalities (adjOR4.29[95%CI3.05-6.05]), higher proportions of population under five years (adjOR3.78E9[95%CI9418.25-1.51E15]), vaccine coverage (adjOR25.42[95%CI7.85-82.29]) and malnutrition (adjOR4.29E41[95%CI12408.29-1.48E79]) and lower proportions of households using firewood as fuel (adjOR0.39[95%CI0.20-0.79]) ('moderate-burden' category only) compared to 'low-burden'. CONCLUSIONS: While this study produced imprecise estimates and cannot be interpreted for individual risk, more accessible municipalities were consistently associated with higher disease burden than remote areas. Female sex, lower average number per household, non-indigenous population and poor nutrition were also associated with higher burden of disease and offer targets to direct interventions to reduce the burden of infectious and non-communicable disease and manage the double burden of disease in Nepal.

Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen.

OBJECTIVE: Recycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine. DESIGN: Single arm, prospective, interventional study. SETTING: Two primary care clinics in Khayelitsha, South Africa. PARTICIPANTS: Sixty adult patients with two viral loads greater than 1000 copies/ml. INTERVENTION: Participants were switched to TLD with additional dolutegravir (50 mg) for 2 weeks to overcome efavirenz induction. PRIMARY OUTCOME: Proportion achieving viral load less than 50 copies/ml at week 24 using the FDA snapshot algorithm. RESULTS: Baseline median CD4+ cell count was 248 cells/µl, viral load 10 580 copies/ml and 48 of 54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51 of 60 [85%, 95% confidence interval (CI) 73-93%] were virologically suppressed, six had viral load 50-100 copies/ml, one had viral load 100-1000 copies/ml, one no viral load in window, and one switched because of tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29 of 35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11 of 13 (85%, 95% CI 55-98%) with resistance to XTC, and six of six (100%, 95% CI 54-100%) with resistance to neither. CONCLUSION: A high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/ml). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.

AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial.

Background: Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load <50 copies/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability. Discussion: Impaired viral fitness due to NRTI resistance mutations and dolutegravir's high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy's early virologic efficacy with and without a supplementary dolutegravir dosing. Registration: ClinicalTrials.gov NCT03991013 (19/06/2019).

Twenty-four-month outcomes from a cluster-randomized controlled trial of extending antiretroviral therapy refills in ART adherence clubs.

INTRODUCTION: The antiretroviral therapy (ART) adherence club (AC) model has supported clinically stable HIV patients' retention with group ART refills and psychosocial support. Reducing visit frequency by increasing ART refills to six months could further benefit patients and unburden health systems. We conducted a pragmatic non-inferiority cluster randomized trial comparing standard of care (SoC) ACs and six-month refill intervention ACs in a primary care facility in Khayelitsha, South Africa. METHODS: Existing community-based and facility-based ACs were randomized to either SoC or intervention ACs. SoC ACs met five times annually, receiving two-month refills with a four-month refill over year-end. Blood was drawn at one AC visit with a clinical assessment at the next. Intervention ACs met twice annually receiving six-month refills, with an individual blood collection visit before the annual clinical assessment AC visit. The first study visits were in October and November 2017 and participants followed for 27 months. We report retention in care, viral load completion and viral suppression (<400 copies/mL) 24 months after enrolment and calculated intention-to-treat risk differences for the primary outcomes using generalized estimating equations specifying for clustering by AC. RESULTS: Of 2150 participants included in the trial, 977 were assigned to the intervention arm (40 ACs) and 1173 to the SoC (48 ACs). Patient characteristics at enrolment were similar across groups. Retention in care at 24 months was similarly high in both arms: 93.6% (1098/1173) in SoC and 92.6% (905/977) in the intervention arm, with a risk difference of -1.0% (95% CI: -3.2 to 1.3). The intervention arm had higher viral load completion (90.8% (999/1173) versus 85.1% (887/977)) and suppression (87.3% (969 /1173) versus 82.6% (853/977)) at 24 months, with a risk difference for completion of 5.5% (95% CI: 1.5 to 9.5) and suppression of 4.6% (95% CI: 0.2 to 9.0). CONCLUSIONS: Intervention AC patients receiving six-month ART refills showed non-inferior retention in care, viral load completion and viral load suppression to those in SoC ACs, adding to a growing literature showing good outcomes with extended ART dispensing intervals.

'Only twice a year': a qualitative exploration of 6-month antiretroviral treatment refills in adherence clubs for people living with HIV in Khayelitsha, South Africa.

OBJECTIVE: Longer intervals between routine clinic visits and medication refills are part of patient-centred, differentiated service delivery (DSD). They have been shown to improve patient outcomes as well as optimise health services-vital as 'universal test-and-treat' targets increase numbers of HIV patients on antiretroviral treatment (ART). This qualitative study explored patient, healthcare worker and key informant experiences and perceptions of extending ART refills to 6 months in adherence clubs in Khayelitsha, South Africa. DESIGN AND SETTING: In-depth interviews were conducted in isiXhosa with purposively selected patients and in English with healthcare workers and key informants. All transcripts were audio-recorded, transcribed and translated to English, manually coded and thematically analysed. The participants had been involved in a randomised controlled trial evaluating multi-month ART dispensing in adherence clubs, comparing 6-month and 2-month refills. PARTICIPANTS: Twenty-three patients, seven healthcare workers and six key informants. RESULTS: Patients found that 6-month refills increased convenience and reduced unintended disclosure. Contrary to key informant concerns about patients' responsibility to manage larger quantities of ART, patients receiving 6-month refills were highly motivated and did not face challenges transporting, storing or adhering to treatment. All participant groups suggested that strict eligibility criteria were necessary for patients to realise the benefits of extended dispensing intervals. Six-month refills were felt to increase health system efficiency, but there were concerns about whether the existing drug supply system could adapt to 6-month refills on a larger scale. CONCLUSIONS: Patients, healthcare workers and key informants found 6-month refills within adherence clubs acceptable and beneficial, but concerns were raised about the reliability of the supply chain to manage extended multi-month dispensing. Stepwise, slow expansion could avoid overstressing supply and allow time for the health system to adapt, permitting 6-month ART refills to enhance current DSD options to be more efficient and patient-centred within current health system constraints.

Qualitative interview study exploring frontline managers' contributions to hand hygiene standards and audit: Local knowledge can inform practice.

BACKGROUND: Frontline managers promote hand hygiene standards and adherence to hand hygiene protocols. Little is known about this aspect of their role. METHODS: Qualitative interview study with frontline managers on 2 acute admission wards in a large National Health Service Trust in the United Kingdom. RESULTS: Managers reported that hand hygiene standards and audit were modeled on World Health Organization guidelines. Hand hygiene outside the immediate patient zone was not documented but managers could identify when additional indications for hand hygiene presented. They considered that audit was worthwhile to remind staff that hand hygiene is important but did not regard audit findings as a valid indicator of practice. Managers identified differences in the working patterns of nurses and doctors that affect the number and types of hand hygiene opportunities and barriers to hand hygiene. Ward managers were accepted as the custodians of hand-hygiene standards. CONCLUSIONS: Frontline managers identified many of the issues currently emerging as important in contemporary infection prevention practice and research and could apply them locally. Their views should be represented when hand hygiene guidelines are reviewed and updated.

A cluster randomized controlled trial of extending ART refill intervals to six-monthly for anti-retroviral adherence clubs.

BACKGROUND: The antiretroviral therapy (ART) adherence club (AC) differentiated service delivery model, where clinically stable ART patients receive their ART refills and psychosocial support in groups has supported clinically stable patients' retention and viral suppression. Patients and health systems could benefit further by reducing visit frequency and increasing ART refills. We designed a cluster-randomized control trial comparing standard of care (SoC) ACs and six-month ART refill (Intervention) ACs in a large primary care facility in Khayelitsha, South Africa. METHODS: Existing ACs were randomized to either the control (SOC ACs) or intervention (Intervention ACs) arm. SoC ACs meet five times annually, receiving two-month ART refills with a four-month ART refill over year-end. Blood is drawn at the AC visit ahead of the clinical assessment visit. Intervention ACs meet twice annually receiving six-month ART refills, with a third individual visit for routine blood collection anytime two-four weeks before the annual clinical assessment AC visit. Primary outcomes will be retention in care, annual viral load assessment completion and viral load suppression. (<400copies/mL) after 2 years. Ethics approval has been granted by the University of Cape Town (HREC 652/2016) and the Medecins Sans Frontieres (MSF) Ethics Review Board (#1639). Results will be published in peer-reviewed journals and made widely available through presentations and briefing documents. DISCUSSION: Evaluation of an extended ART refill interval in adherence clubs will provide evidence towards novel model adaptions that can be made to further improve convenience for patients and leverage health system efficiencies. TRIAL REGISTRATION: Registered with the Pan African Clinical Trial Registry: PACTR201810631281009. Registered 11 September 2018.

Developing recommendations for neonatal inpatient care service categories: reflections from the research, policy and practice interface in Kenya.

Neonatal deaths contribute a growing proportion to childhood mortality, and increasing access to inpatient newborn care has been identified as a potential driver of improvements in child health. However, previous work by this research team identified substantial gaps in the coverage and standardisation of inpatient newborn care in Nairobi City County, Kenya. To address the issue in this particular setting, we sought to draft recommendations on the categorisation of neonatal inpatient services through a process of policy review, evidence collation and examination of guidance in other countries. This work supported discussions by a panel of local experts representing a diverse set of stakeholders, who focused on formulating pragmatic, context-relevant guidance. Experts in the discussions rapidly agreed on overarching priorities guiding their decision-making, and that three categories of inpatient neonatal care (standard, intermediate and intensive care) were appropriate. Through a modified nominal group technique, they achieved consensus on allocating 36 of the 38 proposed services to these categories and made linked recommendations on minimum healthcare worker requirements (skill mix and staff numbers). This process was embedded in the local context where the need had been identified, and required only modest resources to produce recommendations on the categorisation of newborn inpatient care that the experts agreed could be relevant in other Kenyan settings. Recommendations prioritised the strengthening of existing facilities linked to a need to develop effective referral systems. In particular, expansion of access to the standard category of inpatient neonatal care was recommended. The process and the agreed categorisations could inform discussion in other low-resource settings seeking to address unmet needs for inpatient neonatal care.