Introduction
Despite the availability of tolerable and effective antiretroviral therapy (ART), estimated virologic suppression among US youth with HIV (YWH), including those undiagnosed and not in care, remains low, with estimates ranging from 12 to 27% [
1,
2]. With over 50,000 YWH in the US [
3], poor HIV control among YWH is an important clinical and public health issue. Compared to adults with HIV, YWH are less likely to know their HIV serostatus, to initiate HIV care and ART, and to remain in care [
4]. YWH who face challenges with adhering to medications are at risk of developing viral resistance [
5]. YWH without sustained viremia are at increased risk of disease progression, opportunistic infections, and may transmit HIV to others [
6].
Adolescents with chronic illness, who transition from childhood to adulthood within a fractured health care system, fare more poorly than their adult counterparts [
7]. For YWH, the challenges of experiencing adolescence with a chronic illness are further compounded by HIV-related stigma and negotiating new relationships, including intimate relationships while living with a sexually transmissible infection [
4]. Youth-tailored interventions to improve HIV medication adherence, such as 2-way text messaging systems [
8] and daily cell phone calls [
9] have been effective at improving virologic suppression (with observed increases in virologic suppression of 9–36 percentage points at 6–12 months).
The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) is currently evaluating several interventions to improve ART adherence among YWH [
10]. For proven and emerging strategies to be implemented at scale, program planners and policy makers will also need to understand the likely clinical outcomes and costs of any intervention [
11]. Our objective was to model the short- and long-term clinical and economic impact of a hypothetical adherence intervention for YWH, in order to identify the efficacy, duration, and cost at which such interventions would provide good value.
Discussion
The Adolescent Medicine Trials Network for HIV/AIDS Interventions is evaluating several technology-based interventions to improve ART adherence among youth with HIV. Using an adolescent-focused microsimulation model, our objective was to model the impact of hypothetical adherence interventions, based on the example of an interactive smartphone-based reminder system, to identify combinations of intervention characteristics that would render the intervention cost-effective for YWH across a lifetime.
We demonstrated that adherence interventions targeted to YWH to improve virologic suppression, if effective, could have a substantial impact on HIV transmissions, life expectancy, deaths, and costs. An adherence intervention that led to a 10 percentage point cohort-level increase in virologic suppression compared to the standard-of-care [
8,
9] would decrease primary transmissions by 15% and deaths by 12% over the 12-month horizon of the intervention. The AI would increase projected overall life expectancy by 12 months, due to improvements in virologic suppression, and would lead to lasting clinical benefits (
i.e., fewer opportunistic infections and reduced mortality). These results build on findings from model-based studies of adherence interventions in adults, which have also reported increased adherence corresponding to virologic suppression [
48], reduced transmissions [
49,
50] and deaths [
51], and increased life expectancy (range: 1.7–6.4 discounted quality-adjusted life-months) [
16,
50,
52]. Our results suggest that investments in adherence interventions that improve virologic suppression, when implemented during adolescence and young adulthood, could have substantial impacts on long-term clinical outcomes.
While the AI would lead to a projected increase in cost of $5,300/person over a lifetime, only a small proportion of this increase was due to the cost of the intervention itself. The intervention-specific costs amounted to < 1% of a patient’s overall HIV-related lifetime costs. The greatest contributor to a patient’s lifetime cost was the cost of ART. Given the current high cost of ART in the US ($36,080-$48,000 annually in 2018) [
53], any decrease in the cost of ART would improve the value of adherence interventions, since these interventions result in more people incurring the cost of ART who otherwise would not. When the cost of ART was reduced by half, the additional lifetime cost of the AI strategy decreased by 89% compared to SOC; these results suggest that efforts to reduce drug costs, such as improved access to generic ART, could further improve the value of adherence interventions.
We found that adherence interventions among youth could be cost-effective at a wide range of intervention effects on virologic suppression, particularly when the monthly per-person intervention cost was less than $500. Among other published cost-effectiveness analyses of adherence interventions for people with HIV (not necessarily specific to YWH), many report cost-effectiveness [
16,
47,
48,
50,
52,
54,
55] or the potential for cost-effectiveness [
51,
56,
57]. However, the existing body of literature on adherence interventions specifically for YWH remains limited [
58‐
60]. Evaluations of adherence interventions in YWH, including cell phone calls or text messaging systems [
8,
9,
39,
61‐
63], directly observed therapy [
64] and social support systems [
65], all report some level of feasibility and/or acceptability. Of these interventions, however, many remain untested in the setting of randomized, controlled clinical trials or implementation trials [
39,
61‐
64]. Protocols currently underway in the ATN and elsewhere hold promise to provide valuable contributions to our current understanding of adherence interventions in YWH [
10]. If these interventions are shown to be even modestly effective, our results suggest that they have the potential to improve individual- and population-level outcomes and could provide excellent value for money.
This analysis had several limitations. We made selected assumptions that may have led us to either over- or underestimate the clinical and economic value of the example adherence intervention. First, input values for adherence by age were derived separately from youth-specific and adult-specific literature. Although the trajectories of individuals’ adherence from childhood through adulthood are unknown, we assumed adherence improved in all people with HIV after age 25 on the basis of this literature [
23,
24]. Second, we also assumed that the intervention had no lasting impact on adherence after the intervention ended. Removing either of these assumptions in sensitivity analyses did not change our conclusions. Third, detailed data are limited regarding the impact of adherence to virologic suppression for YWH with and without resistance. Data are also limited regarding the impact of adherence interventions among the poorest adherers (
e.g. those who are ≤ 30% adherent at baseline) [
29]. However, when we varied assumptions about the likelihood of YWH to virologically suppress, to derive any benefit from ART, and/or to become lost to follow-up, our conclusions remained unchanged. Finally, model parameters were derived from studies comprised of youth who acquired HIV both perinatally and non-perinatally; however, these groups have different clinical characteristics and associated resource utilization [
17,
66]. While youth with perinatally-acquired HIV who age through adolescence into early adulthood face higher risks of viremia, advanced immunosuppression, HIV-associated illnesses, and mortality increases as they age [
33,
67,
68], less is known regarding the long-term outcomes of youth with non-perinatally acquired HIV. Whenever feasible, data for youth with perinatally and non-perinatally acquired HIV should be reported separately, which would enable different projections for these distinct groups.
Acknowledgements
The authors gratefully acknowledge Dr. Sonia Lee for her review of design, results and final manuscript, as well as the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) research team in the Medical Practice Evaluation Center at Massachusetts General Hospital for providing feedback on study design and interpretation. The authors also thank Ms. Giulia Park and Mr. Chris Alba with assistance in preparing the manuscript for submission. The findings in this manuscript were presented at the 2020 Conference on Retroviruses and Opportunistic Infections in Boston, MA. This research received funding from the Adolescent Medicine Trials Network for HIV/AIDS Interventions (U24HD089880 to AMN, ALC, and ALA), the Eunice Kennedy Shriver National Institute for Child Health and Human Development (K08 HD 094638 to AMN, R01 HD079214 to ALC), the Eleanor and Miles Shore Scholars in Medicine Fellowship (to AMN), the National Institute of Allergy and Infectious Diseases (R01 AI042006 to RPW, KAF, EPH, and MCW), the National Heart, Lung, and Blood Institute (K01 HL123349 to EPH), and the Massachusetts General Hospital Executive Committee on Research (Steve and Deborah Gorlin Research Scholars Award to RPW and Weissman Family Research Scholars Award to IVB). The content is solely the responsibility of the authors, and the study’s findings and conclusions do not necessarily represent the official views of the National Institutes of Health or other funders.
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