literature review on viral load suppression

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Viral load monitoring for people living with HIV in the era of test and treat: progress made and challenges ahead – a systematic review

Minh d. pham.

1 Burnet Institute, Melbourne, Australia

2 Department of Epidemiology and Preventive Medicine, Faculty of Medicine Nursing and Health Science, Monash University, Melbourne, Australia

Huy V. Nguyen

3 Health Innovation and Transformation Centre, Federation University, Victoria, Australia

4 School of Medicine and Dentistry, Griffith University, Brisbane, Australia

David Anderson

5 Department of Microbiology, Faculty of Medicine Nursing and Health Science, Monash University, Melbourne, Australia

Suzanne Crowe

6 Central Clinical School, Faculty of Medicine Nursing and Health Science, Monash University, Melbourne, Australia

Stanley Luchters

7 Centre for Sexual Health and HIV & AIDS Research, Harare, Zimbabwe

8 Department of Public health and Primary care, Ghent University, Ghent, Belgium

Associated Data

All data generated or analysed during this study are included in the manuscript.

In 2016, we conducted a systematic review to assess the feasibility of treatment monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in low and middle-income countries (LMICs), in line with the 90-90-90 treatment target. By 2020, global estimates suggest the 90-90-90 target, particularly the last 90, remains unattainable in many LMICs. This study aims to review the progress and identify needs for public health interventions to improve viral load monitoring and viral suppression for PLHIV in LMICs.

A literature search was conducted using an update of the initial search strategy developed for the 2016 review. Electronic databases (Medline and PubMed) were searched to identify relevant literature published in English between Dec 2015 and August 2021. The primary outcome was initial viral load (VL) monitoring (the proportion of PLHIV on ART and eligible for VL monitoring who received a VL test). Secondary outcomes included follow-up VL monitoring (the proportion of PLHIV who received a follow-up VL after an initial elevated VL test), confirmation of treatment failure (the proportion of PLHIV who had two consecutive elevated VL results) and switching treatment regimen rates (the proportion of PLHIV who switched treatment regimen after confirmation of treatment failure).

The search strategy identified 1984 non-duplicate records, of which 34 studies were included in the review. Marked variations in initial VL monitoring coverage were reported across study settings/countries (range: 12–93% median: 74% IQR: 46–82%) and study populations (adults (range: 25–96%, median: 67% IQR: 50–84%), children, adolescents/young people (range: 2–94%, median: 72% IQR: 47–85%), and pregnant women (range: 32–82%, median: 57% IQR: 43–71%)). Community-based models reported higher VL monitoring (median: 85%, IQR: 82-88%) compared to decentralised care at primary health facility (median: 64%, IRQ: 48-82%). Suboptimal uptake of follow-up VL monitoring and low regimen switching rates were observed.

Conclusions

Substantial gaps in VL coverage across study settings and study populations were evident, with limited data availability outside of sub-Saharan Africa. Further research is needed to fill the data gaps. Development and implementation of innovative, community-based interventions are required to improve VL monitoring and address the “failure cascade” in PLHIV on ART who fail to achieve viral suppression.

In 2014, UNAIDS launched the 90-90-90 treatment target: by 2020, 90% of all people living with HIV (PLHIV) know their status, 90% of all people diagnosed with HIV infections receive antiretroviral therapy (ART) and 90% of all people on ART have suppressed viral load [ 1 ]. Evidence from a large body of research demonstrates that ART can improve the health of PLHIV and stop onward transmission [ 2 – 4 ]. Modelling data suggests achieving the 90-90-90 target, which means having 73% of all PLHIV virally suppressed, coupled with scaling up other prevention measures, could reduce new HIV infection and HIV-related death worldwide by 90% between 2010 and 2030 [ 5 ]. On the basis of this evidence, universal HIV testing and treatment in a broader health system approach has been identified as a key strategy for ending the epidemic by 2030, even in the absence of an effective vaccine [ 6 ].

In low and middle-income countries (LMICs), there has been an intense focus on scale-up of ART programs to increase treatment coverage in PLHIV through decentralisation of HIV services [ 7 – 9 ]. Global estimates indicate a significant increase in the number of PLHIV with access to ART over the past decade: from 6.4 (95% uncertainty intervals (UIs) 5.9–6.4) million in 2009 to 25.4 (95% UIs 24.5–25.6) million by the end of 2019, with 95% of people taking ART residing in LMICs [ 10 , 11 ]. Decentralised HIV care, with services delivered at primary care level, is feasible and can improve patient access and adherence to HIV treatment whilst maintaining high quality of care in various settings [ 12 – 14 ]. However, there is legitimate concern about the sustainability of ART programs in LMICs without substantial financial and technical support from international donors and implementing partners [ 15 , 16 ]. An increase in ART coverage means a greater need for treatment monitoring to ensure program effectiveness and efficiency. Treatment monitoring, however, requires substantial infrastructure, supply chain management system, financial and human resources, which are already scarce in many decentralised settings [ 17 ].

In 2016, we conducted a systematic review to assess the feasibility of ART monitoring for PLHIV in the context of decentralised HIV treatment and care in LMICs [ 18 ]. The conclusions were as follows: (1) There were limited published data on the coverage of treatment monitoring, particularly viral load (VL) monitoring for PLHIV on ART in real-world settings; (2) There were potential gaps in the coverage and quality of treatment monitoring services across countries and regions; (3) There was an urgent need to strengthen treatment monitoring (particularly VL monitoring) to improve the HIV continuum of care in LMICs; and (4) Point-of-care (POC) diagnostics could play an important role in scaling up and improving the quality of treatment monitoring for PLHIV on ART in decentralised settings.

Despite continuous gains in access to testing and treatment since 2015, the ambitious 90-90-90 treatment target, particularly the last 90, remains unattainable in many LMICs [ 19 ]. Reaching the new 95-95-95 target in 2030 will be an uphill task for these countries. To make meaningful progress towards this treatment goal will require much greater use of VL monitoring – the gold standard approach for assessment of HIV treatment at individual, program and population levels. The objectives of this study were to: (1) outline the current state of research and progress on VL monitoring for PLHIV on ART in decentralised settings in LMICs, and (2) identify gaps in research and the needs for public health interventions to improve VL monitoring coverage and quality of HIV treatment programs for PLHIV in LMICs.

The study was designed and reported in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 20 ]. The initial search strategy developed for the 2016 review was used to search MEDLINE for articles published from 1 to 2015 (end date of prior search) to 31 May 2020. The search strategy is available online [ 18 ]. In addition, a PubMed search was conducted using following search terms: “HIV”, “routine viral load”, and “viral load monitoring” for the same period (1 December 2015–31 May 2020) with an updated search conducted in August 2021. Bibliographies of all articles included for full-text review were searched manually to identify relevant studies.

Prior to July 2021, WHO recommended that patients with elevated VL (≥ 1000 copies/ml) should be given enhanced adherence consultation (EAC) followed by a repeat VL test within 3–6 months of the initial VL. If the repeat VL remains greater than 1000 copies/ml, treatment failure is confirmed and patients should be switched to second-line ART [ 21 ]. For the purpose of this review, the following outcomes of interest were pre-defined:  Primary outcome : Initial VL monitoring (the proportion of PLHIV active on first-line ART (the main treatment option available at decentralised settings in LMICs) and eligible for VL monitoring who receive a VL test for treatment monitoring purposes). Secondary outcomes include: (i) Follow-up VL monitoring (the proportion of PLHIV on ART who received a follow-up VL test following an initial elevated VL as defined by included studies); (ii) Confirmation of treatment failure (the proportion of PLHIV on ART with two consecutive elevated VL results among those who received a follow-up VL test) and; (iii) Switching treatment regimen (the proportion of PLHIV on ART switching treatment regimen among those with confirmed treatment failure as defined in included studies).

To be included in this review, studies must meet the following inclusion criteria: (1) was conducted in LMICs; (2) involved PLHIV receiving first-line ART and eligible for VL monitoring; (3) involved decentralised HIV treatment and care, defined as having treatment and treatment follow-up provided in non-hospital settings – primary health care facilities or community-based health care services; and (4) reported the primary outcome of interest. Only studies published in English were included.

Data were extracted electronically using a pre-defined data extraction form. The following information was extracted: study details (first author and year of publication, study design and data source, study population, study sites/locations, study period and study objective); VL testing model; external funding and/or technical supports received and outcome of interests. Information on treatment regimen and VL threshold for definition of elevated VL and treatment failure were also extracted, if reported. Data on outcomes of interest are presented by time point or follow-up period as per the included studies. Outcomes by model of care (community-based vs. primary health care) and subgroups of study population (e.g., children, adolescent, pregnant women, etc.) are extracted (if reported) and presented to enable data comparison. Descriptive statistics were applied to describe the outcomes of interest across countries and study settings, study populations and models of care.

The search strategy yielded 1984 records after removal of duplicates. Screening titles and abstracts identified 66 studies for full-text examination, of which 32 studies met the inclusion criteria and were included. Bibliography review identified two additional studies, making a total of 34 studies included in the review (Fig.  1 ).

Study selection process

Twenty-nine of the 34 included studies were conducted in and/or had data collected from sub-Saharan Africa (SSA) countries, including South Africa [ 22 – 32 ], Zimbabwe [ 33 – 36 ], Rwanda [ 37 , 38 ], Lesotho [ 39 ], Swaziland [ 40 ], Senegal [ 41 ], Malawi [ 42 ], Democratic Republic of Congo [ 43 ], Kenya [ 44 ], Mozambique [ 45 ] and Uganda [ 46 – 48 ]. Twenty studies were designed to assess VL monitoring or VL cascade in PLHIV on ART with long-term follow-up of > = 12 months and large sample sizes (> 500). Most (28/34) studies used routinely collected program data in real-world settings, with seven studies focusing on children, adolescent and young people aged 0–24 years, four studies on pregnant women. One study reported data from 18 LMICs in Asia and Africa over 12 year-period (2006–2018) [ 49 ] and one study was conducted among HIV infected incarcerated people [ 50 ] at three correctional complexes in South Africa and Zambia (Table  1 ).

Characteristics of included studies

a Key populations include: people who inject drug, female sex worker, men who have sex with men and transgender women

Wide ranges of VL monitoring coverage in program settings were observed. Studies of adults/patients of all ages, children, adolescents (aged 0–19 years) and young people (aged < 25) years), and pregnant women reported VL coverage of 25–96% (median: 67% interquartile range IQR: 50-84%), 2–94% (median: 72%, IQR: 47-85%) and 32–82% (median: 57%, IQR: 43-71%), respectively. Studies include community-based care models reported higher initial VL monitoring coverage (median: 85%, IQR: 82-88%) compared to decentralised care at primary health facility (median: 64%, IRQ: 48-82%) (Fig.  2 ). Reported proportions of patients on first-line ART who received a first VL monitoring test within 6–12 months of ART initiation ranged from 12% [ 49 ] to 94% [ 31 ] (median: 74%, IQR: 46-82%). Similarly, reported annual uptake of VL monitoring varied across countries, from 25% in Zimbabwe [ 36 ] to 94% in Kenya [ 44 ] (median: 66%, IQR: 47-87%) (Table  2 ).

Proportion of patients with a viral load monitoring test within 6-12 months after ART initiation (median and 95% confidence interval)

Reported uptake of viral load monitoring, confirmation of treatment failure and switching treatment regimen rates from included studies

a Initial VL monitoring:

- Proportion of patients on ART who receive VL monitoring test

o Numerator: Number of patients active on 1st line ART who have a VL test for treatment monitoring

o Denominator: Total number of patients retained in care, active on 1st line ART and eligible for VL monitoring

b Follow-up VL monitoring:

- Proportion of patients on ART with an initial unsuppressed VL who receives a follow-up VL test

o Numerator: Number of patients active on 1st line ART who had a follow-up VL test after an initial unsuppressed VL

o Denominator: Total number of patients active on 1st line ART with a documented unsuppressed VL (defined as ≥ 1000 copies/ml unless otherwise noted) and eligible for follow-up VL monitoring test (e.g., have had EAC after initial unsuppressed VL)

c Confirmation of virological failure:

- Proportion of confirmed treatment failure among patients who were suspects of failing treatment

o Numerator: Number of patients on 1st line ART with two documented, consecutive unsuppressed VLs

o Denominator: Number of patients active on 1st line ART who had a follow-up VL test after an initial unsuppressed VL (defined as ≥ 1000 copies/ml unless otherwise noted)

d Switching treatment regimen:

- Proportion of patients switched to 2nd ART after confirmation of virological failure

o Numerator: Number of patients who switched to 2nd line ART after confirmation of virological failure

o Denominator: Total number of patients on 1st line ART with confirmation of virological failure (having two documented, consecutive VL results of ≥ 1000 copies/ml unless otherwise noted)

Of 11 studies from South Africa, four were conducted in Cape Town, reporting relatively high VL coverage of 72–89% [ 23 , 25 – 27 ]. Studies with interventions to improve quality of ART program had a VL coverage of > 90% whilst other studies reported a VL range of 25-81%. Of the 17 studies conducted in other SSA countries, 10 studies (59%) reported funding and/or technical support from international donors/implementing partners for implementation of ART and/or VL monitoring programs. Two of four studies from Zimbabwe with donors’ support reported VL coverage at 63% [ 35 ] and 91% [ 33 ], whilst the others (with no external funding/technical support) reported VL coverage of 32% [ 34 ] and 25% [ 36 ]. Two studies reported coverage by sites, enabling a comparison between VL monitoring in decentralised care versus centralized/hospital care. A study conducted in Malawi reported slightly higher VL coverage at decentralised clinics (with direct support from Médecins Sans Frontières – MSF) than district hospitals (86% vs. 82%) [ 42 ]. In contrast, a study at public health facilities in Zimbabwe reported a significantly lower uptake of VL testing at rural health clinics (26.5%) than hospital settings (44.6%) [ 34 ].

Of five studies in Asia, three were conducted in Myanmar using national HIV program data and reported a range of VL coverage from 34% [ 53 ] to 57% [ 52 , 55 ]. Two other studies were conducted in research contexts where VL testing was historically not available: one reported the outcomes of an intervention project to improve the cascade of care among key populations in Indonesia [ 54 ], and the other was a trial designed to assess the feasibility of dried blood spot (DBS) use for VL monitoring in remote regions in Vietnam [ 51 ]. Free VL testing was provided to study participants, and coverage was 71–73% at 6 months after ART initiation.

Thirteen studies provided data on the proportion of patients on ART receiving a follow-up VL test after an initial elevated VL (follow-up VL monitoring). Overall, the coverage for follow-up VL monitoring was lower than that of initial VL monitoring with nine out of 13 studies reporting gaps of 2–48% points (Table  2 ). The reported coverage also varies across study settings and countries, from 25 to 88% (median 65.5%, IQR: 38–77%). Eleven studies reported the outcomes of follow-up VL monitoring, and the proportions of patients with two consecutives elevated VL measurements (confirmation of treatment failure) varied from 26 to 83%, with a median of 62% (IQR: 49.5–74.5%). The reported proportion of patients switching to second-line ART after confirmation of treatment failure also varied, ranging from 18 to 85% (median 45%, IQR: 36–71%).

The findings of this review demonstrate an increasing interest in research on VL monitoring and VL cascades for PLHIV receiving treatment at decentralised settings in LMICs over the past six years. Nearly 60% (20/34) of the included studies were specifically designed to evaluate the implementation and/or reported the outcomes of VL monitoring program for PLHIV on ART. Most of these studies were published in 2019–2021. This represents a substantial increase in the number of studies focused on VL monitoring compared to our previous review [ 18 ], with only two of 21 included studies assessing the coverage of treatment/VL monitoring services for PLHIV on ART. Recent global estimates showed that whilst the number of PLHIV who know their HIV status and the number of PLHIV who are on treatment increased steadily between 2015 and 2018, the proportion of PLHIV with viral suppression has remained stable with substantial variations across regions and many LMICs lagging behind[ 19 ]. Insufficient access to VL testing, lack of appropriate action on VL results and lack of access to second and third ART regimens were key barriers in translating significant gains in knowledge of HIV status and treatment coverage to viral suppression among PLHIV in low-resource settings [ 56 ].

Consistent with findings from previous studies, the results of this review show that there are still significant gaps in VL monitoring across countries and regions. Studies that reported high VL monitoring coverage and use of VL results for patients’ management were conducted in settings with one or more of the following: (1) support from international donors and implementing partners; (2) innovative interventions and models of service delivery for decentralisation of HIV treatment and care, such as “hub and spoke”, “differentiated care” or “adherence club”; and (3) research clinics with free HIV services, including VL testing, for participants. From programmatic perspectives, whilst studies conducted in research or program contexts with external funding and technical supports may have limited generalizability, the finding that community-based models of care, implemented by local government or health authorities, can deliver high VL coverage is encouraging, and supports the continued scale-up of decentralisation of HIV treatment and care in LMICs.

LMICs face immense financial and implementation challenges in provision of HIV treatment and routine VL monitoring for PLHIV on ART. External financial and technical supports with a multi-sector approach are crucial for the set-up and delivery of such services, particularly in decentralised settings where VL monitoring was historically unavailable [ 57 ]. However, as HIV treatment (and VL monitoring) programs mature, such interventions and supports must be integrated within the local healthcare system to ensure sustainability and long-term gains. Evidence from this review shows that even within a program, clinical sites with more direct support outperformed others in term of service delivery (VL monitoring coverage) and patients’ outcomes (VL suppression) [ 42 ]. Therefore, it is critical to strengthen local health system capacity to ensure efficient use of available resources and maintain desirable outcomes when direct external support declines. Operational research is needed to identify cost-effective interventions and best practices to improve VL outcomes for PLHIV in LMICs.

There was also evidence of a narrow geographical focus for research on HIV treatment and VL monitoring programs with most of the data come from SSA countries. Even within SSA, almost all studies included in this review were conducted in Eastern and Southern Africa – the region with the second-highest point estimate of the proportion of people who are virally suppressed among all PLHIV (58%, 95%UIs: 50–66%), behind only high-income countries with well-developed health care systems in Western and Central Europe and North America (64%, 95%UIs: 54–74%) [ 19 ]. This raises a concern about the dearth of data from countries and regions with lower level of VL coverage and viral suppression rate. Our study findings call for a renewed focus of financial resources and international research efforts in settings with limited data available and likely lack of progress in improving VL monitoring and viral suppression among PLHIV on ART.

Our findings suggest that research and targeted interventions are needed to improve VL monitoring coverage in vulnerable populations, including children, adolescents and young people, pregnant women and key populations (KPs) living with HIV.

As HIV treatment programs expand in many LMICs, children and adolescents are a priority population for the scale-up of VL monitoring to improve quality of care and treatment outcomes [ 58 ]. The startling variation (2–94%) in VL testing coverage among children and adolescents identified herein suggests that in some low-resource settings in LMICs, the health care system is unprepared and unable to address the needs of this vulnerable population. This review found only four studies that report VL monitoring in pregnant women receiving care at decentralised care settings. The findings are in line with those of previous studies [ 59 , 60 ], suggesting suboptimal VL monitoring in pregnant women living with HIV on ART, with higher coverage in hospital settings [ 34 ] and/or programs funded by international donor/implementing partners [ 40 ]. Further research is needed to determine an optimal VL monitoring schedule in this population, develop and implement targeted interventions supporting those who receive PMTCT and HIV services at decentralised settings in LMICs. Ad hoc VL testing (e.g., using POC tests) should also be available for targeted VL monitoring as medically indicated or in case turnaround time for laboratory test is too long for meaningful clinical interventions.

Our review highlights the lack of data on VL monitoring for KPs in real-world settings. Only two studies [ 46 , 54 ] reported the proportion of PLHIV on ART receiving VL monitoring among members of KPs with high coverage. These data, however, have poor generalizability, because levels of dedicated staff and resources would not be sustainable outside the research context. Many LMICs have concentrated HIV epidemics among KPs. Monitoring VL and level of viral suppression in PLHIV who are members of KPs and engage in high-risk behaviours is crucial to determine the trajectory of the epidemic. If those who do not achieve VL suppression and engage in high-risk behaviours are the driving force of HIV transmission in the community [ 61 ], then the ultimate goal of reducing population-level HIV incidence and ending the HIV epidemic will not be achieved [ 62 ].

Routine VL monitoring for PLHIV on ART is only meaningful if accompanied by the use of VL results for appropriate and timely clinical action. The findings of this review indicate suboptimal uptake of follow-up VL among patients with initial elevated VL (median 66%, IQR: 38–77%); high proportion of confirmed treatment failure among those patients who had a follow-up VL (median 62%, IQR: 50–75%) and a low switching rate among those with confirmed treatment failure (median 45%, IQR: 36–71%). These findings are of particular concern, because they could indicate inadequate EAC and/or a high level of treatment failure due to drug resistance that requires switching the ART regimen. It is known that prolonged treatment regimen failure significantly increases the risk of multiple drug-resistant mutations and compromises the efficacy of second-line ART in HIV-infected children [ 63 ], adults [ 64 ], and pregnant women [ 65 ]. PLHIV on ART who fail to achieve viral suppression enter a “failure cascade” that can jeopardise individual health and the overall effectiveness of HIV programs [ 66 ]. Operations research and intervention strategies are needed to address treatment adherence and the failure cascade to preserve the efficacy of first/second-line ART, thereby avoiding exhausting treatment options in LMICs.

This review contributes to a growing body of literature highlighting the importance of VL monitoring and VL cascade analysis for planning, implementation and evaluation of HIV treatment programs in the era of “Test and Treat” [ 67 – 69 ]. In decentralised settings in LMICs, technological and health system challenges occur in each step of the cascade. VL measurement is mostly done with laboratory assays, and fresh plasma is the preferred sample type. However, the cold chain system for blood sample transportation and 24-hour time window requirements preclude the use of this sample type in rural and remote areas. Dried blood spot (DBS) is an alternative sampling method, but may reduce the accuracy of VL measurement due to the detection of proviral DNA and intracellular RNA in whole blood samples, leading to over-quantification of viral load result [ 70 ]. It is noted that in the newly updated WHO guideline [ 71 ], a VL cut-off of 50 copies/ml was added on the treatment monitoring algorithm to identify PLHIV with low-level viremia (50-1000 copies/ml). This addition is likely to make the use of DBS for routine VL monitoring even more challenging as the limit of detection of 50 copies/ml, using this sampling method, is unlikely to be achieved with current VL testing platforms [ 72 ].

New sampling technologies [ 73 , 74 ] have emerged, enabling accurate VL measurement by removing blood cells from the plasma component without the need for centrifugation. These are promising alternatives to the DBS as they could allow the detection of low-level viremia. However, further research is needed to determine the limit of detection, feasibility, and cost-effectiveness of these new devices/methods in real-world settings. New POC VL technologies have also become available and have the potential to decentralise VL testing. The use of these technologies, especially when VL results are more time-sensitive (such as VL results for breast feeding women and their children, people with an initial elevated VL) would be important to enable timely clinical decision and improve treatment outcomes. As HIV treatment programs mature, the number of PLHIV on ART will continue to increase, as well as the need for VL monitoring, second-line [ 75 ] and third-line ART [ 76 ], even in settings with lack of access to drug resistance testing. These challenges need to be addressed simultaneously and systematically to ensure the long-term effectiveness and efficacy of HIV treatment in LMICs.

This review had several limitations. Only peer-reviewed articles published in English were considered, meaning grey literature (unpublished and/or non-peer-reviewed and/or non-English national/program reports) with data on the outcomes of interest (e.g., annual PEPFAR monitoring and evaluation reports) was overlooked. The lack of data from geographic regions outside of SSA also raises a concern about bias and the generalizability of the findings. Another limitation is that some of the recently published studies report data collected 10–15 years ago which may not necessarily represent the recent uptake of VL monitoring. However, given the nature of the data reported from included studies (e.g., a wide range of VL coverage across study settings); these limitations are unlikely to affect the results and their interpretation substantially. Few studies reported a complete viral load cascade (number/proportion of patients with routine VL tests, unsuppressed VL, enhanced adherence counselling, follow-up VL and confirmed treatment failure). Researchers are encouraged to report on the viral load cascade of patients failing first-line ART and patients on second-line ART to enable understanding of the magnitude of the problem and identify intervention strategies and resources required to meet the needs of these vulnerable patients.

Since 2016, there has been marked growth in the peer-reviewed literature on VL monitoring and VL cascade in PLHIV in LMICs. Most studies were conducted in SSA with significant financial and technical support from international/bilateral donors and implementing partners. Available data suggest significant gaps in VL monitoring services across countries and geographic regions, highlighting the needs to strengthen health system capacity for effective and sustainable implementation of routine VL monitoring for PLHIV who receive ART at decentralised care settings in LMICs. Particular attention is needed to rectify the failure cascade to ensure that VL monitoring and follow-up clinical actions are taken for individuals on ART who fail to achieve viral suppression. To advance the global agenda towards ending the HIV epidemic by 2030, we must fill the data gaps outside SSA; support the development and implementation of targeted interventions to improve VL monitoring and the VL cascade among populations at high risk of unsuppressed VL but with poor access to HIV treatment and care.

Acknowledgements

The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute. We thank Campbell Aitken at the Burnet Institute for his valuable comments on the draft of the manuscript.

Abbreviations

Authors’ contributions.

MDP, SL, SC conceptualise the study. MDP, HVN performed literature search, data extraction and data analysis. MDP wrote the main manuscript. HVN and MDP prepared the figure and tables. DA, SC, SL reviewed and commented on the first and final drafts of the manuscript. All authors read and approved the final manuscript.

The authors receive no funding for this work.

Availability of data and materials

Declarations.

Not Applicable.

The author declares no competing interests.

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Contributor Information

Minh D. Pham, Email: [email protected] .

Huy V. Nguyen, Email: [email protected] .

David Anderson, Email: [email protected] .

Suzanne Crowe, Email: [email protected] .

Stanley Luchters, Email: [email protected] .

Prevalence and Correlates of Viral Load Suppression and Human Immunodeficiency Virus (HIV) Drug Resistance Among Children and Adolescents in South Rift Valley and Kisumu, Kenya

Affiliations.

• 1 US Army Medical Research Directorate-Africa, Nairobi, Kenya.
• 2 HJF Medical Research International, Kericho, Kenya.
• 3 US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
• 4 Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
• 5 HJF Medical Research International, Kisumu, Kenya.
• 6 Ministry of Health, Kisumu County, Kisumu, Kenya.
• 7 The Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
• PMID: 35092424
• PMCID: PMC9522406
• DOI: 10.1093/cid/ciac059

Background: Children and adolescents living with HIV (CALHIV) face unique challenges, including poorer treatment outcomes, risk for drug-resistance mutations (HIVDRMs), and limited drug formulations. We estimated viral suppression (VS) prevalence and evaluated predictors of VS and HIVDRMs in Kenya.

Methods: From 2018-2020, CALHIV 1-19 years on antiretroviral therapy (ART) >6 months were enrolled in this cross-sectional study. Participants underwent viral load (VL) testing; those with VL ≥1000 copies/mL had HIVDRM testing. Sociodemographic questionnaires and medical record abstraction were completed. VS prevalence (VL <1000 copies/mL) was estimated; robust Poisson regression models were used to estimate prevalence ratios (PRs) and 95% CIs for associations between potential predictors of VS.

Results: Nine hundred and sixty-nine participants were enrolled. VS prevalence was .80 (95% CI: .78-.83). Being on ART >24 months (adjusted PR [aPR]: 1.22; 95% CI: 1.06-1.41), an integrase strand transfer inhibitor-containing regimen (1.13; 1.02-1.26), and attending a level 3 health facility (1.23; 1.11-1.36) were associated with VS. Missing ≥3 doses of ART in the past month (aPR: .73; 95% CI: .58-.92), having a viremic mother with HIV (.72; .53-.98), and having 3-7 (.90; .83-.97), 8-13 (.89; .82-.97), or ≥14 (.84; .77-.92) compared with <2 adherence counseling referrals were inversely associated with VS. A high proportion (n = 119, 81.5%) of unsuppressed participants had evidence of any major HIVDRM.

Conclusions: HIV treatment programs should target interventions for pediatric patients at risk for treatment failure-namely, those with a caregiver with failed VS and those struggling with adherence.

Keywords: HIV; Kenya; drug resistance; viral load.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Publication types

• Research Support, U.S. Gov't, Non-P.H.S.
• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Anti-HIV Agents* / pharmacology
• Anti-HIV Agents* / therapeutic use
• Cross-Sectional Studies
• Drug Resistance
• HIV Infections* / drug therapy
• HIV Infections* / epidemiology
• Kenya / epidemiology
• Anti-HIV Agents

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• T32 AI114398/AI/NIAID NIH HHS/United States

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• Volume 11, Issue 9
• Interventions for improving treatment outcomes in adolescents on antiretroviral therapy with unsuppressed viral loads: a systematic review protocol
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• http://orcid.org/0000-0003-4410-7005 Farai Kevin Munyayi 1 , 2 ,
• Brian van Wyk 3
• 1 School of Public Health , University of the Western Cape , Bellville , South Africa
• 2 Clinical services , I-TECH Namibia , Windhoek , Namibia
• 3 School of Public health , University of the Western Cape Faculty of Community and Health Sciences , Cape Town , South Africa
• Correspondence to Farai Kevin Munyayi; fmfanchom{at}gmail.com

Introduction Adolescents represent one of the most underserved population groups among people living with HIV. With successes in the elimination of mother to child transmission initiatives and advances in paediatric HIV treatment programmes, a large population of HIV-infected children are surviving into adolescence. Adolescence presents unique challenges that increase the risk of non-suppressed viral loads in adolescents living with HIV (ALHIV). There is a need to develop, implement and test interventions to improve viral suppression among ALHIV. Systematic reviews of recent studies present scarce and inconclusive evidence of effectiveness of current interventions, especially for adolescents. This protocol provides a description of a planned review of interventions to improve treatment outcomes among unsuppressed ALHIV.

Methods and analysis A comprehensive search string will be used to search six bibliographic databases: PubMed/MEDLINE, Sabinet, EBSCOhost, CINAHL, Scopus and ScienceDirect, for relevant studies published between 2010 and 2020 globally, and grey literature. Identified articles will be exported into Mendeley Reference Management software and two independent reviewers will screen the titles, abstracts and full texts for eligibility. A third reviewer will resolve any discrepancies between the two initial reviewers. Studies reporting on interventions to improve viral suppression, retention and adherence for adolescents will be considered for inclusion. The systematic review will be performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Where feasible, a meta-analysis will be conducted using Stata Statistical Software: Release V.16. The quality of the studies and risk of bias will be assessed using the Critical Appraisal Skills Programme checklists and Risk of Bias in Non-randomised Studies of Interventions tool, respectively.

Ethics and dissemination The systematic review entails abstracting and reviewing already publicly available data rather than any involvement of participants, therefore, no ethical clearance will be required. Results will be shared with relevant policy-makers, programme managers and service providers, and published and share through conferences and webinars.

PROSPERO registration number CRD42021232440.

• epidemiology
• HIV & AIDS
• public health

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2021-049452

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Strengths and limitations of this study

This review contributes to the available knowledge on evaluated interventions targeting adolescents with unsuppressed viral loads that could inform adolescent-friendly HIV services guidelines in both health facilities and community settings.

This protocol uses the standardised Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols 2015 guidelines.

The search strategy uses six major electronic databases which will include peer-reviewed articles and grey literature.

A potential limitation of this study includes the limitation to studies published in English language only, which has the potential to miss other relevant studies published in other languages.

The study limitations may be associated with the timeline for the search strategy (2010–2020).

Introduction

Along with the successes in elimination of mother-to-child transmission initiatives worldwide and developments in paediatric HIV treatment, more children with HIV are surviving to reach adolescence. 1 Innovations for early infant diagnosis, such as point-of-care diagnostics and prompt initiation of life-saving HIV treatment, have meant a large population of perinatally HIV-infected children are growing into adolescence. 2 A mixed adolescent population exists consisting of perinatally infected and behaviourally infected adolescents living with HIV (ALHIV) who may respond to interventions differently. 3 Worldwide, 1.6 million adolescents aged 10–19 years were estimated to be living with HIV in 2018; with approximately 85% residing in sub-Saharan Africa. 4 5 WHO defines adolescents as individuals aged between 10 and 19 years. 6 The proposed systematic review seeks to look at literature on both perinatally and behaviourally infected adolescents, aged 10–19 years. Although data on HIV treatment among adolescents are scarce, access and uptake of comprehensive care and treatment packages among this vulnerable population group is reportedly lower than adults. 7 In 2019, only 53% (36%–64%) of children aged 0–14 years were accessing treatment as compared with 68% (54%–80%) coverage among 15 years and older individuals living with HIV. 8 In the majority of sub-Saharan Africa countries, public sector health settings are ill equipped to provide guidance and adequate support for ALHIV to stay engaged in HIV care and adhere to treatment regimens. 9

Good adherence to treatment regimens and consistent engagement in HIV care is essential for achieving sustained viral suppression, which is vital for ensuring the well-being of ALHIV and reducing chances of onward HIV transmission. 10 Poor adherence to antiretrovirals increases the risk of emergence of drug resistance mutations, reduces treatment efficacy, thereby advancing disease progression and reducing future treatment options and increasing the risk of further transmission driven by unsuppressed viral loads. 11 Despite reportedly high levels of adherence to antiretroviral therapy (ART) globally (>95%), diminishing adherence levels over time remains a concern, primarily the loss of patients during scaling up of HIV programmes. 12 Evidence-based strategies to mitigate adherence challenges for individuals on HIV treatment include facility and community-based interventions, which includes individual or group adherence counselling, pharmacist counselling and medication fast-tracking, mHealth, home-based/community-based strategies, financial incentives, nutritional support, motivational interviewing and awarding of disability grants. 13 Individual counselling, peer-led support groups and different models of group adherence counselling interventions, such as teen clubs, are the most common interventions for ALHIV.

Adolescents receiving HIV treatment have distinct and unique needs and are notably underserved worldwide in national HIV responses. Ultimately, this negatively affects access to ART for adolescents, and results in suboptimal ART adherence and poorer treatment outcomes including achieving sustained viral suppression. 14 WHO defines viral suppression as a maintained viral load count of less than 1000 RNA copies/mL of plasma. 15 However, recent debates have suggested reducing the suppression threshold to 200 copies/mL, informed by evidence from HPTN 052 findings, PARTNERS and Opposites Attract, who all reported that successful ART with viral suppression prevented transmission when viral load was undetectable below 200 copies/mL. 16 Variations in viral load assay limit of detection has also been tied to the debates around threshold setting for viral load suppression, and these need to be paid attention to in any evaluation.

A systematic review conducted in 2014 estimated global ART adherence levels ranging between 16% and 99% among adolescents and a meta-analysis of data representing adolescents and young adults between 12 and 24 years found a pooled adherence estimate of 84% in 53 Asian and African countries. Viral suppression (cut-off <400 copies/mL) rates were between 52% and 87% in Asia, 27% and 89% in Africa, and between 37.5% and 49% in Central and South America. 17 A 2018 systematic review of 11 studies on factors impacting ART adherence among HIV positive adolescents in sub-Saharan Africa reported a complex web of 29 facilitators and 44 barriers among adolescents. These factors include stigma, forgetfulness, ART side effects and lack of assistance as main barriers, while knowledge of status, caregiver support and peer support groups were the dominant facilitators. 18 Other barriers and facilitators of treatment adherence among adolescents in countries in the global south have been noted as family support, a heavy pill burden/treatment regimen, attitudes towards medication and various health delivery system factors. 19 Often these studies reported on adherence only using self-report or pill counts, with no viral load results reported. Self-reported adherence is mostly challenging, especially in adolescents, as clearly demonstrated in Pre-Exposure Prophylaxis (PrEP) studies where there was no correlation between therapeutic drug monitoring and self-report especially in younger populations. 20

Despite recent increased focus and several systematic reviews synthesising interventions to improve treatment outcomes among adolescents, we could not find reviews specifically focusing on studies targeting unsuppressed adolescents. Although our focus is predominantly on viral suppression, broader outcomes such as adherence and retention in care will be considered. Previous reviews have identified specific types of interventions that show promise for improved adherence to ART and retention in HIV care with very limited quantity of studies and low quality in several studies focusing on adolescents aged 10–19 years published up until 2015. 21 A review by MacPherson et al focused on studies published between 2001 and 2014 evaluating effectiveness of interventions on service delivery to improve linkage to treatment initiation, retention in HIV care and ART adherence among ALHIV aged 10–19 years. 14 Considering that only 11 studies were included in the study, with low-to-moderate methodological quality, from high-income countries and none from countries with a generalised HIV epidemic, the authors suggested further investigations on their findings which included promising results from individual and group education and counselling, increased accessibility to clinics, youth-friendly services and financial incentives. 14

Casale et al reviewed studies published between January 2016 and June 2018, and provided an update on evidence from empirical evaluations on interventions designed to enhance ART adherence and retention in care for adolescents aged 10–19 years and youth aged 15–24 years living with HIV. 21 The authors reported on 10 relevant studies, mostly from sub-Saharan Africa, using six clinic-level interventions, three community-level or household-level intervention, and one mHealth trial at individual level, and they concluded that there is a need for continued development and testing of multifaceted interventions over and above facility-based interventions, that address broader socioeconomic barriers, prioritising adolescents aged 10–19 years, if we are to address the treatment gap among this population group. 21 A more recent review of studies published from September 2015 to January 2019 by Lindsey et al reported that ART adherence interventions for adolescents and youth implemented in low- and middle-income countries showed mixed results from interventions at patient-level and health services level, with none of the interventions improving treatment adherence or virologic suppression. 22 The authors argued that intensive home-based case management approaches to care hold much promise in improving treatment outcomes in adolescents and youth and warrant further research. 22 Most recent published studies focusing on interventions such as Enhanced Adherence Counselling and Community Adolescent Treatment Supporters to improve treatment outcomes among ALHIV challenged with viral suppression and retention in care may provide new evidence for consideration. 23–25

Rationale for the review

Globally, it is apparent that there has been an increased focus in addressing the treatment gap among ALHIV, and in recent years, there have been a number of systematic reviews focusing on interventions to improve ART adherence and retention in HIV care among adolescents and young adults in general. While the gaps described above and the systematic reviews cited present opportunities and specific interventions that show promise, they also highlight the limited quantity and low-to-moderate quality of studies and evidence on interventions targeting ALHIV. These reviews commonly include interventions for all adolescents and youth, despite their viral load suppression levels, which include clinic-level interventions, individual-level and community-level or household-level interventions. Considering the urgent need to design, implement and test interventions to keep adolescents in care and achieve and maintain viral load suppression, we propose to review studies that specifically evaluated interventions targeting adolescents challenged with staying engaged in care and maintaining viral suppression. This review will focus on adolescents experiencing poor treatment outcomes to provide an updated data synthesis of all adherence and retention interventions to close the treatment gap. We aim to broaden the synthesised knowledge base to include new and innovative interventions for this particular population, at health facility, community and household levels, and potentially reinforce or modify already existing promising interventions for achievement of sustained viral suppression.

This systematic review will use the seven steps as set out by Eggar and Smith. 26 The seven steps are outlined as (1) formulate the review question; (2) define the inclusion and exclusion criteria; (3) develop a search strategy; (4) study selection; (5) assess the quality of studies; (6) extract data and (7) analyse or synthesise the data.

Review question

The following questions will guide the review of the literature published between 2010 and 2020:

What interventions are being implemented to improve treatment outcomes for adolescents on ART with challenges suppressing their viral load?

How effective have the interventions been in achieving better treatment outcomes among adolescents on ART with challenges suppressing their viral load?

Inclusion and exclusion criteria

The literature search will be guided by the following inclusion criteria:

Published studies in peer-reviewed journals and grey literature.

The study population includes ALHIV aged 10–19 years, both perinatally and behaviourally infected adolescents included.

Reported the association between the intervention, and viral suppression, retention and adherence.

Reported comparisons in quantitative measures of viral suppression, retention and adherence, including prearm/postarm or multiarm comparison groups.

Study outcomes include viral suppression, retention and ART adherence.

Studies published in English language.

Studies from all countries, high-income, middle-income and low-income settings, published between 2010 and 2020.

The Population/Patient/Problem, Intervention, Comparison, Outcome and Time (PICOT)-based inclusion criteria has been summarised in table 1 . Studies that are not available in English language will be excluded, as well as review papers, editorials and letters.

• View inline

PICOT-based inclusion criteria

The decision to only include studies reported in English language was necessitated by the limitations in capacity and resources among the review team, which restricts the review to English language only. Studies may include younger children below 10 years or young adults over 19 years, and justification for inclusion will be provided if these are included in the analysis. Additionally, other studies may focus on adherence interventions and viral load suppression for all people living with HIV, including adolescents in the study population or sample. Age disaggregation will be performed where there are age overlaps and the authors have provided age-disaggregated data.

Outcome measures

Viral load suppression: although WHO viral load suppression threshold in 1000 copies/mL, more recent studies may have used lower levels of viral load counts to define viral load suppression or disaggregate low level viraemia and suppression. All definitions of viral load suppression will be considered in this review. Where different cut-offs for viral load suppression are used, we will run sensitivity analyses.

ART adherence: adherence can be measured using pill counts, pharmacy refill data, self-reporting, as well as physician/nurse assessments and appointment keeping. Self-report is a common measure of adherence although there are concerns about its validity (limitation in correlation to viral loads), and socially desirable responses from especially younger individuals may overestimate adherence. 27 More robust measures such as Medical Events Monitoring System and other new technologies will all be considered in this review. Optimal adherence will be considered to be at ≥95% of prescribed medication doses taken per specified period.

Retention in HIV care: approaches to evaluating retention in HIV care may be determined from missed clinic appointments or based on kept clinic visits. Retention variables may also include interruption in treatment, lost to follow-up, transferred-out or died. A subanalysis of the different categories of adolescents who are not still engaged in care will be performed if possible (when different retention variables are reported).

Search strategy for identification of studies

The search strategy was developed with the assistance of the faculty librarian who will provide further guidance and advice in conducting the searches for the review. A comprehensive database search of literature reporting on treatment interventions and viral load suppression will be systematically conducted in six major databases: PubMed/MEDLINE, Sabinet, EBSCOhost, CINAHL, Scopus and ScienceDirect. Grey literature searches will be performed on OpenGrey, Grey Literature report, International AIDS Conference abstract archive, and HIV and Adolescence. We will search the identified databases for all articles published between 2010 and 2020 that meet the specified selection criteria. The search syntax will first be used to perform a database search on PubMed/MEDLINE to test and optimise the strategy, which will subsequently be replicated and adapted as needed for the other database searches. Full-text articles will be sourced using a list of key words and terms for the search strategy using the “AND” and “OR” Boolean operators as appropriate. The search terms will include “Adolescents”, “antiretroviral therapy”, “retention”, “adherence”, “viral load”, “suppression”, “unsuppressed”. The search strategies used for the selected databases are provided in online supplemental material , titled “ALL Database search Results”.

Supplemental material

Study selection.

Studies will be included in this systematic review according to the PICOT mnemonics. We will also consider studies done using quantitative or mixed methods, with a worldwide search without any particular geographical location limitations. Restricting reviews to a particular study design, such as randomised controlled trial (RCTs) only, may restrict findings to effectiveness only rather than seeking answers to more complex phenomena such as why an intervention may or may not be effective. 28

The selection, screening and reporting of this review will be done in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocol 2015 guidelines. 29 Selected studies will be collated and exported into Mendeley Reference Management Software, which will be used to manage the citations and recording the number of hits for each article from all databases, as well as removing duplicate records. 30 Two reviewers will independently review titles and abstracts of all articles retrieved to assess eligibility for inclusion. The two reviewers will further review full texts of the selected articles independently, to establish compliance with the eligibility criteria for inclusion in the final assessment. 26 Any disagreements on inclusion or exclusion of any article will be referred to a third reviewer authorised to resolve any disagreements for inclusion of articles. A PRISMA flow diagram will be presented to describe the study selection decisions made.

Data extraction and quality assessment

Conducting a quality assessment may determine the inclusion or exclusion of an initially selected study, and this should consider the robustness (validity and reliability) of findings of a particular study. 28 We will create a data extraction matrix in Microsoft Excel to capture study characteristics and outcomes data, such as author(s), study year and duration, publication year, geographical location, target population, sample, purpose, study design, intervention, data collection and analyses, outcomes, results, limitations and conclusions. Only the data reported in the articles will be extracted and used in the quality assessment although additional information may be sought from authors for clarification.

Data analysis/synthesis: assessment of evidence using the Grading of Recommendations Assessment, Development and Evaluation system

The two primary review authors will independently assess the selected articles using the Grading of Recommendations Assessment, Development and Evaluation considerations to downgrade or upgrade the certainty of evidence on the interventions and the specific outcomes reported by each study. Independent conclusions will be drawn on how the interventions compare to each other, on the specified treatment outcomes considering the estimates of effects, and the certainty of the evidence (risk of bias, confidence in evidence/consistency in effects, quality of evidence, imprecision, indirectness and publication bias). 31 32 The quality of evidence and risk of bias for non-RCTs will be assessed using the Critical Appraisal Skills Programme Checklist and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) Assessment Tool, respectively. 33 Studies which included clinical or medication issues such as drug resistance, and not necessarily adherence and retention challenges only, may be considered with appropriate justifications, especially reports on recent improved ART regimens.

We will conduct a meta-analysis only if the interventions, research questions or focus, and study participants allow for a meaningful meta-analysis. If possible, we will analyse results from the review by mode of infection among the adolescents included in meta-analysis. The meta-analysis will be conducted using Stata Statistical Software: Release V.16 (StataCorp). The χ 2 test and the Higgins I² statistic will be used to quantify statistical heterogeneity by estimating the variability between study estimates, with I² statistic values of 25%, 50% and 75% representing low, medium and high heterogeneity, respectively. 34 Forest plots will be used to visualise the extent of heterogeneity or homogeneity among the selected studies.

Publication bias described as the tendency by authors to report positive findings, will be presented and visualised on a funnel plot, as well as statistically assessed using the Harbord’s regression test to assess the asymmetry of the funnel plot. 35 36 The contour-enhanced funnel plot will be used to distinguish between asymmetry caused by publication bias versus other causes, which may not have been successfully accomplished by the standard method. 37 If it is not possible to do a meta-analysis, the findings extracted onto the Excel spreadsheet described above will be summarised and reported in a table form presenting key components of the studies. Subgroup analysis may include facility versus community-based interventions and younger versus older adolescents.

Patient and public involvement

No patients or public population is involved in the development and conducting of this study, as this is a protocol for a systematic review of already available literature.

Ethics and dissemination

The systematic review entails abstracting and reviewing already publicly available data rather than any involvement of participants, therefore, no ethical clearance or approval will be required.

We plan to share results of this review with relevant policy-makers and guidelines developers, programme managers and service providers, particularly providing evidence-based guidance for interventions targeting unsuppressed adolescents. We also plan to publish the results of the review, as well as sharing the findings with key stakeholders using platforms such as conferences, and presentations through webinars and the HIV Project Extension for Community Health Outcomes. 38

Ethics statements

Patient consent for publication.

Not required.

Acknowledgments

Ms Karen Cook, Senior Librarian: Community and Health Sciences Branch Library, at the University of the Western Cape, for assisting with developing the search strategy and the data base searches.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Contributors FKM conceived the idea, developed the research questions and study methods and contributed meaningfully to the drafting and editing, he also approved the final manuscript. BvW aided in developing the research questions and study methods contributed meaningfully to the drafting and editing and approved the final manuscript.

Funding Self-funded.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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