Top

Published in:

Open Access 01-12-2022 | HIV Drug | Research article

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

Authors: Anneleen Kiekens, Bernadette Dierckx de Casterlé, Giampietro Pellizzer, Idda H. Mosha, Fausta Mosha, Tobias F. Rinke de Wit, Raphael Z. Sangeda, Alessio Surian, Nico Vandaele, Liesbet Vranken, Japhet Killewo, Michael Jordan, Anne-Mieke Vandamme

Published in: BMC Public Health | Issue 1/2022

Abstract

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.

Available only for authorised users

UN Joint Programme on HIV/AIDS (UNAIDS). 90–90–90 An ambitious treatment target to help end the AIDS epidemic. In: United Nations [Internet]. 2014 [cited 19 Sep 2019]. Available: https://www.unaids.org/en/resources/documents/2017/90-90-90.

World Health Organization (WHO). HIV Drug Resistance Report 2019. Geneva, Switserland; 2019.

Phillips AN, Stover J, Cambiano V, Nakagawa F, Jordan MR, Pillay D, et al. Impact of HIV drug resistance on HIV/AIDS-associated mortality, new infections, and antiretroviral therapy program costs in Sub-Saharan Africa. J Infect Dis. 2017;215:1362–5. https://doi.org/10.1093/infdis/jix089.CrossRefPubMedPubMedCentral

Hamers RL, Inzaule SC. Pan-resistant HIV-1: what’s next? Lancet Microbe. 2020;5247:11–2. https://doi.org/10.1016/S2666-5247(20)30058-6.CrossRef

Puertas MC, Ploumidis G, Ploumidis M, Fumero E, Clotet B, Walworth CM, et al. Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report. Lancet Microbe. 2020;5247:1–6. https://doi.org/10.1016/S2666-5247(20)30006-9.CrossRef

Rusconi S. The impact of adherence to HIV/AIDS antiretroviral therapy on the development of drug resistance. Future Virol. 2017;12:239–41. https://doi.org/10.2217/fvl-2017-0019.CrossRef

Shubber Z, Mills EJ, Nachega JB, Vreeman R, Freitas M, Bock P, et al. Patient-Reported Barriers to Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis. PLoS Med. 2016;13:1–14. https://doi.org/10.1371/journal.pmed.1002183.CrossRef

Minior T, Douglas M, Edgil D, Srivastava M, Crowley J, Firth J, et al. The Critical Role of Supply Chains in Preventing Human Immunodeficiency Virus Drug Resistance in Low-And Middle-Income Settings. J Infect Dis. 2017;216:S812–5. https://doi.org/10.1093/infdis/jix403.CrossRefPubMedPubMedCentral

Rough K, Dietrich J, Essien T, Gray G, Katz IT. Whoonga and the Abuse and Diversion of Antiretrovirals in Soweto. South Africa AIDS Behav. 2014;18:1378–80. https://doi.org/10.1007/s10461-013-0683-x.CrossRefPubMed

10.

Grelotti D, Closson EF, Matthew M. Pretreatment antiretroviral exposure from recreational use. Lancet. 2013;13:10–2. https://doi.org/10.1016/S1473-3099(12)70294-3.CrossRef

11.

Kuo C, Giovenco D, Deatley T, Hoare J, Underhill K, Atujuna M, et al. Recreational use of HIV antiretroviral medication and implications for HIV pre-exposure prophylaxis and treatment. AIDS Behav. 2021;24:2650–5. https://doi.org/10.1007/s10461-020-02821-5.CrossRef

12.

Gupta RK, Gregson J, Parkin N, Haile-selassie H, Tanuri A, Forero LA, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries : a systematic review and meta-regression analysis. Lancet Infect Dis. 2020;18:346–55. https://doi.org/10.1016/S1473-3099(17)30702-8.

13.

Plsek PE, Greenhalgh T. Complexity science: The challenge of complexity in health care. [Article 1 in series of 4]. BMJ. 2001;323:625–8. https://doi.org/10.1136/bmj.323.7313.625.CrossRefPubMedPubMedCentral

14.

Rutter H, Savona N, Glonti K, Bibby J, Cummins S, Finegood DT, et al. The need for a complex systems model of evidence for public health. Lancet. 2017;390:2602–4. https://doi.org/10.1016/S0140-6736(17)31267-9.CrossRefPubMed

15.

DeFries R, Nagendra H. Ecosystem management as a wicked problem. Science. 2017;356:265–70.CrossRef

16.

Wang Y, Xue H, Esposito L, Joyner M, Bar-yam Y. Applications of Complex Systems Science in Obesity and Noncommunicable Chronic Disease Research. Am Soc Nutr. 2018;5:574–7. https://doi.org/10.3945/an.114.006650.CrossRef

17.

Plsek PE, Wilson T. Complexity science: Complexity, leadership, and management in healthcare organisations. Br Med J. 2001;323:746–9. https://doi.org/10.1136/bmj.323.7315.746.CrossRef

18.

Rusoja E, Haynie D, Sievers J, Mustafee N, Nelson F, Reynolds M, et al. Thinking about complexity in health: A systematic review of the key systems thinking and complexity ideas in health. J Eval Clin Pract. 2018;24:600–6. https://doi.org/10.1111/jep.12856.CrossRefPubMed

19.

Decouttere C, Vandaele N, De Boeck K, Banzimana S. A Systems-Based Framework for Immunisation System Design: Six Loops, Three Flows, Two Paradigms. Fac Econ Business, KU Leuven. 2020. doi:https://doi.org/10.1101/2021.07.19.21260775.

20.

Yaya F, Bocoum S, Kouanda, Kouyaté B, Hounton S, Adam T. Exploring the effects of task shifting for HIV through a systems thinking lens: The case of Burkina Faso. BMC Public Health. 2013;13(1):1–10. https://doi.org/10.1186/1471-2458-13-997.CrossRef

21.

Meadows D. Places to Intervene in a System. Whole Earth. 1997;91(1):78–84.

22.

Nguyen NC, Bosch OJH. A Systems Thinking Approach to identify Leverage Points for Sustainability: A Case Study in the Cat Ba Biosphere Reserve. Vietnam Nam Syst Res Behav Sci. 2013;30:104–15. https://doi.org/10.1002/sres.2145.CrossRef

23.

Mcglashan J, Johnstone M, Creighton D, De HK, Allender S. Quantifying a Systems Map : Network Analysis of a Childhood Obesity Causal Loop Diagram. PLoS ONE. 2016;11:1–14. https://doi.org/10.1371/journal.pone.0165459.

24.

Braithwaite J, Churruca K, Long JC, Ellis LA, Herkes J. When complexity science meets implementation science : a theoretical and empirical analysis of systems change. BMC Med. 2018;16:1–14. https://doi.org/10.1186/s12916-018-1057-z.

25.

Dierckx de Casterlé B, Gastmans C, Bryon E, Denier Y. QUAGOL: A guide for qualitative data analysis. Int J Nurs Stud. 2012;49(3):360–71. https://doi.org/10.1016/j.ijnurstu.2011.09.012.CrossRefPubMed

26.

Mohr J, Mohr R. KUMU Inc. 2011. Available: https://kumu.io

27.

Kiekens A, Dierckx de Casterlé B, Pellizzer G, Mosha I, Mosha F, Rinke de Wit TF, et al. Interactive systems maps of factors influencing HIVDR in sub-Saharan Africa. Available: https://annemie.kumu.io/identifying-mechanisms-behind-hiv-drug-resistance-in-sub-saharan-africa-a-systems-approach?token=meUKVHYzmT1jrNse.

28.

Eshun-Wilson I, Rohwer A, Hendricks L, Oliver S, Garner P. Being HIV positive and staying on antiretroviral therapy in Africa: A qualitative systematic review and theoretical model. PLoS ONE. 2019;14:1–30. https://doi.org/10.1371/journal.pone.0210408.CrossRef

29.

World Health Organization. Density of physicians. In: Geneva, Switserland [Internet]. 2019 [cited 2 Apr 2020]. Available: https://www.who.int/gho/health_workforce/physicians_density/en/.

30.

Fokam J, Billong SC, Bissek ACZK, Kembou E, Milenge P, Abessouguie I, et al. Declining trends in early warning indicators for HIV drug resistance in Cameroon from 2008 – 2010 : lessons and challenges for low-resource settings. BMC Public Health. 2013;13(1):1–10. https://doi.org/10.1186/1471-2458-13-308.CrossRef

31.

Kuriakose S, George J, Dee N, Stoll P, Agan BK, Dewar RL, et al. High Level Resistance to Dolutegravir (DTG) after Emergence of T97A Mutation. CROI. 2018. Available: http://www.natap.org/2018/CROI/croi_140.htm.

32.

Lübke N, Jensen B, Hüttig F, Feldt T, Walker A, Kaiser R, et al. Failure of Dolutegravir First-Line ART with Selection of Virus Carrying R263K and G118R. N Engl J Med. 2019;381:885–7. https://doi.org/10.1056/nejmc1908155.CrossRef

33.

Ndashimye E, Avino M, Olabode AS, Poon AFY, Gibson RM, Li Y, et al. Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda. J Antimicrob Chemother. 2020;75:3525–33. https://doi.org/10.1093/jac/dkaa355.CrossRefPubMedPubMedCentral

34.

Siedner MJ, Moorhouse MA, Hill A, Oliveira T De, Lessells R, Simmons B, et al. Pre-Treatment HIV Drug Resistance and Virologic Outcomes in the ADVANCE Trial. CROI. 2020. Available: https://www.croiconference.org/abstract/pretreatment-hiv-drug-resistance-and-48-week-virologic-outcomes-in-the-advance-trial/.

35.

Hamers RL, Rinke de Wit TF, Holmes CB. HIV drug resistance in low-income and middle-income countries. Lancet HIV. 2018;5:e588–96. https://doi.org/10.1016/S2352-3018(18)30173-5.CrossRefPubMed

36.

Inzaule SC, Hamers RL, Doherty M, Shafer RW, Bertagnolio S, Rinke de Wit TF. Curbing the rise of HIV drug resistance in low-income and middle-income countries: the role of dolutegravir-containing regimens. Lancet Infect Dis. 2019;19:e246–52. https://doi.org/10.1016/S1473-3099(18)30710-2.CrossRefPubMedPubMedCentral

37.

Roux AVD. Complex Systems Thinking and Current Impasses in Health Disparities Research. Am J Public Health. 2011;101:1627–35. https://doi.org/10.2105/AJPH.2011.300149.CrossRef

38.

Kiekens A, Mosha IH, Zlatić L, Bwire GM, Mangara A, de Casterlé BD, et al. Factors Associated with HIV Drug Resistance in Dar es Salaam, Tanzania: Analysis of a Complex Adaptive System. Pathogens. 2021;10:1535. https://doi.org/10.3390/pathogens10121535.CrossRefPubMedPubMedCentral

39.

Chapman K. Complexity and creative capacity. 1st ed. New Ýork: Routledge; 2016.

40.

Belgian Law regarding research on human subjects of 7/5/2004. [cited 8 Feb 2021]. Available: http://www.ejustice.just.fgov.be/cgi_loi/change_lg.pl?language=nl&la=N&table_name=wet&cn=2004050732.

Title: Exploring the mechanisms behind HIV drug resistance in sub-Saharan Africa: conceptual mapping of a complex adaptive system based on multi-disciplinary expert insights
Authors: Anneleen Kiekens
Bernadette Dierckx de Casterlé
Giampietro Pellizzer
Idda H. Mosha
Fausta Mosha
Tobias F. Rinke de Wit
Raphael Z. Sangeda
Alessio Surian
Nico Vandaele
Liesbet Vranken
Japhet Killewo
Michael Jordan
Anne-Mieke Vandamme
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: HIV Drug
Human Immunodeficiency Virus
Published in: BMC Public Health / Issue 1/2022
Electronic ISSN: 1471-2458
DOI: https://doi.org/10.1186/s12889-022-12738-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Clinical and economic burden of physician-diagnosed influenza in adults during the 2017/2018 epidemic season in Spain

Age-specific prevalence, subtypes and risk factors of metabolic diseases in Chinese adults and the different patterns from other racial/ethnic populations

Urban-rural differences in China’s crude death rate changes

Dynamics of Hepatitis B infection prevention practices among pregnant women attending antenatal care at Lubaga Hospital Kampala, Uganda using the constructs of information-motivation-behavioural skills model

Diverging levels of COVID-19 governmental response satisfaction across middle eastern Arab countries: a multinational study

Real-world study of the effectiveness of BBIBP-CorV (Sinopharm) COVID-19 vaccine in the Kingdom of Morocco