Highlighting the need for investment and innovation in ART retention interventions

In The Lancet Global Health, Anna Bershteyn and colleagues1Bershteyn A Jamieson L Kim H-Y et al.Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models.Lancet Glob Health. 2022; 10: 1298-1306Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar highlight an issue of growing prominence in the global HIV/AIDS response. In their combined analysis, the authors used data from three HIV models set in South Africa, Malawi, and sub-Saharan Africa to estimate how improvement in retention on antiretroviral therapy (ART) could affect transmission, health, and upper-bound costs of interventions. Individuals disengaged from ART contribute to an increasing proportion of HIV-associated deaths and transmissions. This is most evident in settings with the most advanced epidemic responses—eg, we found that transmission attributable to individuals who discontinued ART across the USA was greatest in New York (NY, USA),2Zang X Mah C Quan AML et al.Human immunodeficiency virus transmission by HIV risk group and along the HIV care continuum: a contrast of 6 US cities.J Acquir Immune Defic Syndr. 2022; 89: 143-150Crossref PubMed Scopus (2) Google Scholar despite the city being a leader in HIV control in urban settings. Continued improvements in access to treatment and prevention interventions will only amplify the need to improve strategies in sustaining ART retention in the years to come. Challenges in ART persistence are unfortunately pervasive, even in settings with low financial barriers,3Nosyk B Lourenço L Min JE Shopin D Lima VD Montaner JS Characterizing retention in HAART as a recurrent event process: insights into ‘cascade churn’.AIDS. 2015; 29: 1681-1689Crossref PubMed Scopus (30) Google Scholar and poor persistence is typically tied to social and structural conditions that drive incidence in populations at greatest risk.4Wang L Krebs E Min JE et al.Combined estimation of disease progression and retention on antiretroviral therapy among treated individuals with HIV in the USA: a modelling study.Lancet HIV. 2019; 6: e531-e539Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar These factors further exacerbate inequities and might stifle the population-level benefits of ART.5Baral S Rao A Sullivan P et al.The disconnect between individual-level and population-level HIV prevention benefits of antiretroviral treatment.Lancet HIV. 2019; 6: e632-e638Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar Unfortunately, interventions to address these challenges have had only moderate effectiveness,3Nosyk B Lourenço L Min JE Shopin D Lima VD Montaner JS Characterizing retention in HAART as a recurrent event process: insights into ‘cascade churn’.AIDS. 2015; 29: 1681-1689Crossref PubMed Scopus (30) Google Scholar relatively high cost, and, subsequently, reduced marginal value. Bershteyn and colleagues provide a useful complement to this emerging research in identifying maximum cost thresholds for ART retention interventions.1Bershteyn A Jamieson L Kim H-Y et al.Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models.Lancet Glob Health. 2022; 10: 1298-1306Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar In their analyses, they found that interventions producing meaningful improvements in ART retention can still hold considerable value, particularly in individuals at greatest risk of interrupting ART. We applaud the authors’ methodological contribution to the field; that their results were in many respects consistent across three independently-developed simulation models made for an exceptionally strong argument. Addressing the inherent structural uncertainty in simulation modelling through collaborations and ensemble applications represents best methodological practice and should be pursued widely, especially in populations and interventions in which the best course of action is most uncertain. These findings, based on assumptions of 25–100% intervention improvements, now require reconciliation with the existing evidence base to determine what is possible, and economically feasible. The emerging research to this end, cited by Bershteyn and colleagues,1Bershteyn A Jamieson L Kim H-Y et al.Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models.Lancet Glob Health. 2022; 10: 1298-1306Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar holds promise. Of the studies cited in their introduction (more listed in the Article's appendix), increased duration of prescriptions, simplified diagnostic monitoring, differentiated ART delivery, contingency management, mHealth, and some forms of treatment support (by peers, family members, or health-care workers) have all been found to either improve effectiveness in promoting ART persistence or non-inferiority with cost savings in at least some applications. However, individually, most of these interventions did not reach even the lowest of the retention improvement thresholds assumed in this modelling exercise. Most notably, robust evidence from a cluster-randomised trial in Malawi and Zambia showed a 5% improvement in retention with 3-month prescription duration and a 9·1% improvement with 6-month prescription durations, compared with 1–3-month ART dispensations among individuals established in treatment.6Hoffman RM Moyo C Balakasi KT et al.Multimonth dispensing of up to 6 months of antiretroviral therapy in Malawi and Zambia (INTERVAL): a cluster-randomised, non-blinded, non-inferiority trial.Lancet Glob Health. 2021; 9: e628-e638Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar Although this cost-neutral change has been recommended by WHO since 2016, data compiled by the HIV Policy Lab indicates 77 (48%) of 160 countries with available data (out of 195) in their cross-national research platform7Kavanagh MM Graeden E Pillinger M et al.Understanding and comparing HIV-related law and policy environments: cross-national data and accountability for the global AIDS response.BMJ Glob Health. 2020; 5e003695Crossref Google Scholar currently allow for at least a 3-month supply of antiretrovirals, but only 38 (24%) allow for at least a 6-month supply of antiretrovirals. Iterations of differentiated care, entailing shifts in care provision and location, as well as multimonth prescribing, have shown mostly non-inferior outcomes, but offer cost savings that could potentially be reinvested elsewhere.8Roberts DA Tan N Limaye N Irungu E Barnabas RV Cost of differentiated HIV antiretroviral therapy delivery strategies in sub-Saharan Africa: a systematic review.J Acquir Immune Defic Syndr. 2019; 82: S339-S347Crossref PubMed Scopus (12) Google Scholar These strategies might all be implemented jointly and are readily scalable to the population level. These structural changes could be complemented by additional individual-level support for those at greatest risk of discontinuation. Results of a study assessing conditional economic incentives in Uganda were most promising, with a 23·7% increase in the proportion of patients with 90% medication adherence.9Linnemayr S Stecher C Mukasa B Behavioral economic incentives to improve adherence to antiretroviral medication.AIDS. 2017; 31: 719-726Crossref PubMed Scopus (28) Google Scholar The evidence on mHealth interventions has been mixed to date, although 12% of the studies assessed in a 2017 systematic review showed improved retention with such interventions.10Demena BA Artavia-Mora L Ouedraogo D Thiombiano BA Wagner N A systematic review of mobile phone interventions (SMS/IVR/calls) to improve adherence and retention to antiretroviral treatment in low- and middle-income countries.AIDS Patient Care STDS. 2020; 34: 59-71Crossref PubMed Scopus (32) Google Scholar Otherwise, treatment supporter interventions have shown effectiveness in improving ART adherence and viral suppression.11Nyoni T Sallah YH Okumu M Byansi W Lipsey K Small E The effectiveness of treatment supporter interventions in antiretroviral treatment adherence in sub-Saharan Africa: a systematic review and meta-analysis.AIDS Care. 2020; 32: 214-227Crossref PubMed Scopus (11) Google Scholar To date, these interventions have largely been delivered and assessed independently; however, there is no practical constraint from offering iterations of these interventions in combination. Evidence from one such study found a relative risk of 1·52 (95% CI 1·19–1·96) in obtaining retention at 12 months, compared with standard of care.12McNairy ML Lamb MR Gachuhi AB et al.Effectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: the Link4Health cluster randomized trial.PLoS Med. 2017; 14e1002420Crossref Scopus (46) Google Scholar Successful implementation, adapted to context and responsive to the stated needs of individuals and communities, could further increase this effect. Thus, Bershteyn and colleagues’ findings provide both guidance and a strong rationale for further inquiry and innovation in improving ART retention. Increased efforts to this end will be required to continue momentum towards global HIV control and elimination targets. BN and LH report grants from US National Institute of Health (award number R01-DA041747). Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical modelsUpper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART. Full-Text PDF Open Access

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