Exploring the mechanisms behind HIV drug resistance in sub-Saharan Africa: conceptual mapping of a complex adaptive system based on multi-disciplinary expert insights.

BACKGROUND: HIV drug resistance (HIVDR) continues to threaten the effectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR are driven by several interconnected factors. Though much has been done to uncover factors influencing HIVDR, overall interconnectedness between these factors remains unclear and African policy makers encounter difficulties setting priorities combating HIVDR. By viewing HIVDR as a complex adaptive system, through the eyes of multi-disciplinary HIVDR experts, we aimed to make a first attempt to linking different influencing factors and gaining a deeper understanding of the complexity of the system. METHODS: We designed a detailed systems map of factors influencing HIVDR based on semi-structured interviews with 15 international HIVDR experts from or with experience in sub-Saharan Africa, from different disciplinary backgrounds and affiliated with different types of institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence. RESULTS: Factors influencing HIVDR in sub-Saharan Africa and their interactions were sorted in five categories: biology, individual, social context, healthcare system and 'overarching'. We identified three causal loops cross-cutting these layers, which relate to three interconnected subsystems of mechanisms influencing HIVDR. The 'adherence motivation' subsystem concerns the interplay of factors influencing people living with HIV to alternate between adherence and non-adherence. The 'healthcare burden' subsystem is a reinforcing loop leading to an increase in HIVDR at local population level. The 'ART overreliance' subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at different levels. CONCLUSIONS: Interconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in sub-Saharan Africa in order to target interventions and to prevent unwanted effects on other parts of the system. The three theories that emerged while studying HIVDR as a complex adaptive system form a starting point for further qualitative and quantitative investigation.

Insights into vaccine hesitancy from systems thinking, Rwanda.

OBJECTIVE: To investigate vaccine hesitancy leading to underimmunization and a measles outbreak in Rwanda and to develop a conceptual, community-level model of behavioural factors. METHODS: Local immunization systems in two Rwandan communities (one recently experienced a measles outbreak) were explored using systems thinking, human-centred design and behavioural frameworks. Data were collected between 2018 and 2020 from: discussions with 11 vaccination service providers (i.e. hospital and health centre staff); interviews with 161 children's caregivers at health centres; and nine validation interviews with health centre staff. Factors influencing vaccine hesitancy were categorized using the 3Cs framework: confidence, complacency and convenience. A conceptual model of vaccine hesitancy mechanisms with feedback loops was developed. FINDINGS: A comparison of service providers' and caregivers' perspectives in both rural and peri-urban settings showed that similar factors strengthened vaccine uptake: (i) high trust in vaccines and service providers based on personal relationships with health centre staff; (ii) the connecting role of community health workers; and (iii) a strong sense of community. Factors identified as increasing vaccine hesitancy (e.g. service accessibility and inadequate follow-up) differed between service providers and caregivers and between settings. The conceptual model could be used to explain drivers of the recent measles outbreak and to guide interventions designed to increase vaccine uptake. CONCLUSION: The application of behavioural frameworks and systems thinking revealed vaccine hesitancy mechanisms in Rwandan communities that demonstrate the interrelationship between immunization services and caregivers' vaccination behaviour. Confidence-building social structures and context-dependent challenges that affect vaccine uptake were also identified.

Advancing sustainable development goals through immunization: a literature review.

BACKGROUND: Immunization directly impacts health (SDG3) and brings a contribution to 14 out of the 17 Sustainable Development Goals (SDGs), such as ending poverty, reducing hunger, and reducing inequalities. Therefore, immunization is recognized to play a central role in reaching the SDGs, especially in low- and middle-income countries (LMICs). Despite continuous interventions to strengthen immunization systems and to adequately respond to emergency immunization during epidemics, the immunization-related indicators for SDG3 lag behind in sub-Saharan Africa. Especially taking into account the current Covid19 pandemic, the current performance on the connected SDGs is both a cause and a result of this. METHODS: We conduct a literature review through a keyword search strategy complemented with handpicking and snowballing from earlier reviews. After title and abstract screening, we conducted a qualitative analysis of key insights and categorized them according to showing the impact of immunization on SDGs, sustainability challenges, and model-based solutions to these challenges. RESULTS: We reveal the leveraging mechanisms triggered by immunization and position them vis-à-vis the SDGs, within the framework of Public Health and Planetary Health. Several challenges for sustainable control of vaccine-preventable diseases are identified: access to immunization services, global vaccine availability to LMICs, context-dependent vaccine effectiveness, safe and affordable vaccines, local/regional vaccine production, public-private partnerships, and immunization capacity/capability building. Model-based approaches that support SDG-promoting interventions concerning immunization systems are analyzed in light of the strategic priorities of the Immunization Agenda 2030. CONCLUSIONS: In general terms, it can be concluded that relevant future research requires (i) design for system resilience, (ii) transdisciplinary modeling, (iii) connecting interventions in immunization with SDG outcomes, (iv) designing interventions and their implementation simultaneously, (v) offering tailored solutions, and (vi) model coordination and integration of services and partnerships. The research and health community is called upon to join forces to activate existing knowledge, generate new insights and develop decision-supporting tools for Low-and Middle-Income Countries' health authorities and communities to leverage immunization in its transformational role toward successfully meeting the SDGs in 2030.

A Systems-Based Framework for Immunisation System Design: Six Loops, Three Flows, Two Paradigms.

Despite massive progress in vaccine coverage globally, the region of sub-Saharan Africa is lagging behind for Sustainable Development Goal 3 by 2030. Sub-national under-immunisation is part of the problem. In order to reverse the current immunisation system's (IMS) underperformance, a conceptual model is proposed that captures the complexity of IMSs in low- and middle-income countries (LMICs) and offers directions for sustainable redesign. The IMS model was constructed based on literature and stakeholder interaction in Rwanda and Kenya. The model assembles the paradigms of planned and emergency immunisation in one system and emphasises the synchronised flows of vaccinee, vaccinator and vaccine. Six feedback loops capture the main mechanisms governing the system. Sustainability and resilience are assessed based on loop dominance and dependency on exogenous factors. The diagram invites stakeholders to share their mental models and. The framework provides a systems approach for problem structuring and policy design.

Modeling Supply and Demand Dynamics of Vaccines against Epidemic-Prone Pathogens: Case Study of Ebola Virus Disease.

Health emergencies caused by epidemic-prone pathogens (EPPs) have increased exponentially in recent decades. Although vaccines have proven beneficial, they are unavailable for many pathogens. Furthermore, achieving timely and equitable access to vaccines against EPPs is not trivial. It requires decision-makers to capture numerous interrelated factors across temporal and spatial scales, with significant uncertainties, variability, delays, and feedback loops that give rise to dynamic and unexpected behavior. Therefore, despite progress in filling R&D gaps, the path to licensure and the long-term viability of vaccines against EPPs continues to be unclear. This paper presents a quantitative system dynamics modeling framework to evaluate the long-term sustainability of vaccine supply under different vaccination strategies. Data from both literature and 50 expert interviews are used to model the supply and demand of a prototypical Ebolavirus Zaire (EBOV) vaccine. Specifically, the case study evaluates dynamics associated with proactive vaccination ahead of an outbreak of similar magnitude as the 2018-2020 epidemic in North Kivu, Democratic Republic of the Congo. The scenarios presented demonstrate how uncertainties (e.g., duration of vaccine-induced protection) and design criteria (e.g., priority geographies and groups, target coverage, frequency of boosters) lead to important tradeoffs across policy aims, public health outcomes, and feasibility (e.g., technical, operational, financial). With sufficient context and data, the framework provides a foundation to apply the model to a broad range of additional geographies and priority pathogens. Furthermore, the ability to identify leverage points for long-term preparedness offers directions for further research.

How Can Authorities Support Distributed Improvisation During Major Crises? A Study of Decision Bottlenecks Arising During Local COVID-19 Vaccine Roll-Out.

Despite the increased importance attributed to distributed improvisation in major crises, few studies investigate how central authorities can promote a harmonic, coordinated national response while allowing for distributed autonomy and improvisation. One idea implicit in the literature is that central authorities could help track and tackle common decision bottlenecks as they emerge across "improvising" local authorities as a result of shared, dynamic external constraints. To explore this idea we map central functions needed to roll-out vaccines to local populations and identify and classify bottlenecks to decision-making by local authorities managing COVID-19 vaccine roll-out in Norway. We found five bottlenecks which emerged as vaccine roll-out progressed, three of which could feasibly have been addressed by changing the local authorities' external constraints as the crisis developed. While the national crisis response strategy clearly allowed for distributed improvisation, our overall findings suggest that there is potential for central authorities to address external constraints in order to ease common bottlenecks as they emerge across local authorities responding to the crisis. More research is to explore alternative centralized response strategies and assess how well they effectively balance centralized and distributed control. The study contributes to the growing literature examining the interaction between local and centralized response in crisis management.

Strategic silences, eroded trust: The impact of divergent COVID-19 vaccine sentiments on healthcare workers' relations with peers and patients.

BACKGROUND: Polarized debates about Covid-19 vaccination and vaccine mandates for healthcare workers (HCWs) challenge Belgian HCWs ability to discuss Covid-19 vaccine sentiments with peers and patients.Although studies have identified drivers of HCWs vaccine hesitancy, they do not include effects of workplace interactions and have not addressed consequences beyond vaccine coverage. METHODS: Interviews and focus group discussions with 74 HCWs practicing in Belgium addressed Covid-19 vaccine sentiments and experiences of discussing vaccination with peers and patients. RESULTS: Most participating HCWs reported difficulties discussing Covid-19 vaccination with peers and patients. Unvaccinated HCWs often feared that expressing their vaccine sentiments might upset patients or peers and that they would be suspended. Consequently, they used social cues to evaluate others' openness to vaccine-skeptical discourses and avoided discussing vaccines. Surprisingly, some vaccine-confident HCWs hid their vaccine sentiments to avoid peer and patient conflicts. Both vaccinated and unvaccinated HCWs observed that unvaccinated patients occasionally received suboptimal care. Suboptimal care was central in unvaccinated HCW unwillingness to express their vaccine sentiments to peers. Both vaccinated and unvaccinated HCWs described loss of trust and ruptured social relations with peers and patients holding divergent vaccine sentiments. DISCUSSION: Belgian HCW perceived Covid-19 vaccines as a risky discussion topic and engaged in "strategic silences" around vaccination to maintain functional work relationships and employment in health institutions. Loss of trust between HCW and peers or patients, along with suboptimal patient care based on vaccination status, threaten to weaken Belgium's, and by implication, other health systems, and to catalyze preventable disease outbreaks.

Embracing context: Lessons from designing a dialogue-based intervention to address vaccine hesitancy.

Dialogue with people who are vaccine hesitant has been recommended as a method to increase vaccination uptake. The process of cultivating dialogue is shaped by the context in which it occurs, yet the development of interventions addressing vaccine hesitancy with dialogue often overlooks the role of context and favors relatively fixed solutions. This reflexive paper shares three key lessons related to context for dialogue-based interventions. These lessons emerged during a participatory research project to develop a pilot intervention to create open dialogue among healthcare workers in Belgium about COVID-19 vaccination concerns. Through a mixed methods study consisting of in-depth interviews, focus group discussions, and surveys, we engaged healthcare workers in the design, testing, and evaluation of a digital platform featuring text-based and video-based (face-to-face) interactions. The lessons are: (1) what dialogue means, entails, and requires can vary for a population and context, (2) inherent tension exists between helping participants voice (and overcome) their concerns and exposing them to others' ideas that may exacerbate those concerns, and (3) interactional exchanges (e.g., with peers or experts) that matter to participants may shape the dialogue in terms of its content and form. We suggest that having a discovery-orientation-meaning to work not only inductively and iteratively but also reflexively-is a necessary part of the development of dialogue-based interventions. Our case also sheds light on the influences between: dialogue topic/content, socio-political landscape, population, intervention aim, dialogue form, ethics, researcher position, and types of interactional exchanges.

High viral suppression and detection of dolutegravir-resistance associated mutations in treatment-experienced Tanzanian adults living with HIV-1 in Dar es Salaam.

To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ([Formula: see text] standard deviation) was 44.0 ([Formula: see text] 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9-10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34-96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Understanding the complexity of demand-side determinants on vaccine uptake in sub-Saharan Africa.

Routine vaccination annually prevents millions of deaths worldwide but is underutilized in sub-Saharan Africa (SSA). The complexity of socio-cultural factors impacting vaccine uptake is not well understood. Hence, this paper aims to review the socio-cultural determinants of vaccine uptake and visualize their interrelationships. We conducted a literature search using Pubmed and Embase databases, including articles published from 2000 to 2019 describing socio-cultural demand-side determinants for vaccine uptake. Using the Andersen and Newman Framework of Health Services Utilization, demand-side determinants were categorized as predisposing, enabling or need factors. A qualitative system dynamics approach was employed to visualize how these factors and their dynamic interrelationships influence vaccine uptake. This visualization, by means of a causal-loop diagram (CLD), was mostly based on a qualitative input, with the majority being statements of the authors. These statements were abstracted from the papers found in the review. Quantification was done by counting direct (statistical) associations between each determinant and 'timely and full routine immunization coverage'. A total of 90 articles, primarily from Nigeria (n = 23), Ethiopia (n = 17) and Kenya (n = 11), met the inclusion criteria. We find that maternal autonomy and the perceived benefits caregivers attach to vaccination and exert their influences on many other factors through several feedback loops, thereby influencing timely and full routine immunization coverage. Utilization of health services (supply-related) and access to information (demand-related) were considered as high-potential leverage points. Quantification has shown that maternal autonomy and perceived benefit have an unclear evidence base. Future research should focus on these key players as they play a central role in multiple complex pathways, through which they could influence the uptake of vaccines in SSA.

Factors Associated with HIV Drug Resistance in Dar es Salaam, Tanzania: Analysis of a Complex Adaptive System.

HIV drug resistance (HIVDR) is a complex problem with multiple interconnected and context dependent causes. Although the factors influencing HIVDR are known and well-studied, HIVDR remains a threat to the effectiveness of antiretroviral therapy. To understand the complexity of HIVDR, a comprehensive, systems approach is needed. Therefore, a local systems map was developed integrating all reported factors influencing HIVDR in the Dar es Salaam Urban Cohort Study area in Tanzania. The map was designed based on semi-structured interviews and workshops with people living with HIV and local actors who encounter people living with HIV during their daily activities. We visualized the feedback loops driving HIVDR, compared the local map with a systems map for Sub-Saharan Africa, previously constructed from interviews with international HIVDR experts, and suggest potential interventions to prevent HIVDR. We found several interconnected balancing and reinforcing feedback loops related to poverty, stigmatization, status disclosure, self-esteem, knowledge about HIVDR and healthcare system workload, among others, and identified three potential leverage points. Insights from this local systems map were complementary to the insights from the Sub-Saharan systems map showing that both viewpoints are needed to fully understand the system. This study provides a strong baseline for quantitative modelling, and for the identification of context-dependent, complexity-informed leverage points.

Insights into vaccine hesitancy from systems thinking, Rwanda

Objective To investigate vaccine hesitancy leading to underimmunization and a measles outbreak in Rwanda and to develop a conceptual, community-level model of behavioural factors. Methods Local immunization systems in two Rwandan communities (one recently experienced a measles outbreak) were explored using systems thinking, human-centred design and behavioural frameworks. Data were collected between 2018 and 2020 from: discussions with 11 vaccination service providers (i.e. hospital and health centre staff ); interviews with 161 children's caregivers at health centres; and nine validation interviews with health centre staff. Factors influencing vaccine hesitancy were categorized using the 3Cs framework: confidence, complacency and convenience. A conceptual model of vaccine hesitancy mechanisms with feedback loops was developed. Findings/ A comparison of service providers' and caregivers' perspectives in both rural and peri-urban settings showed that similar factors strengthened vaccine uptake: (i) high trust in vaccines and service providers based on personal relationships with health centre staff; (ii) the connecting role of community health workers; and (iii) a strong sense of community. Factors identified as increasing vaccine hesitancy (e.g. service accessibility and inadequate follow-up) differed between service providers and caregivers and between settings. The conceptual model could be used to explain drivers of the recent measles outbreak and to guide interventions designed to increase vaccine uptake. Conclusion The application of behavioural frameworks and systems thinking revealed vaccine hesitancy mechanisms in Rwandan communities that demonstrate the interrelationship between immunization services and caregivers' vaccination behaviour. Confidencebuilding social structures and context-dependent challenges that affect vaccine uptake were also identified.