Sorting nexin 5 mediates virus-induced autophagy and immunity.

Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism-SNX5-dependent PI3KC3-C1 activation at endosomes-for initiation of autophagy during viral infection.

Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.

OBJECTIVE: Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. METHODS: We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. RESULTS: The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. INTERPRETATION: Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.

Etiological Mechanisms and Genetic/Biological Modulation Related to PTH1R in Primary Failure of Tooth Eruption.

Primary failure of eruption (PFE) is a rare disorder that is characterized by the inability of a molar tooth/teeth to erupt to the occlusal plane or to normally react to orthodontic force. This condition is related to hereditary factors and has been extensively researched over many years. However, the etiological mechanisms of pathogenesis are still not fully understood. Evidence from studies on PFE cases has shown that PFE patients may carry parathyroid hormone 1 receptor (PTH1R) gene mutations, and genetic detection can be used to diagnose PFE at an early stage. PTH1R variants can lead to altered protein structure, impaired protein function, and abnormal biological activities of the cells, which may ultimately impact the behavior of teeth, as observed in PFE. Dental follicle cells play a critical role in tooth eruption and root development and are regulated by parathyroid hormone-related peptide (PTHrP)-PTH1R signaling in their differentiation and other activities. PTHrP-PTH1R signaling also regulates the activity of osteoblasts, osteoclasts and odontoclasts during tooth development and eruption. When interference occurs in the PTHrP-PTH1R signaling pathway, the normal function of dental follicles and bone remodeling are impaired. This review provides an overview of PTH1R variants and their correlation with PFE, and highlights that a disruption of PTHrP-PTH1R signaling impairs the normal process of tooth development and eruption, thus providing insight into the underlying mechanisms related to PTH1R and its role in driving PFE.

Low-dose venetoclax combined with azacitidine for blastic plasmacytoid dendritic cell neoplasm: a case report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is highly aggressive with a poor prognosis. There is no standard treatment for BPDCN. Although conventional chemotherapies are usually sensitive in the initial therapy, relapse and drug resistance are inevitable within a short duration. Targeted therapies have enlightened new prospects for the treatment of BPDCN, especially for those in a frail state and intolerable to standard chemotherapies or hematopoietic stem cell transplantation. Here, we report an 82-year-old man diagnosed with cutaneous-limited BPDCN. Considering the old age and limited involvement of the tumor, we reduced the dosage of venetoclax. His skin lesions subsided significantly after 1 cycle of azacytidine (100 mg d1-7) combined with reduced doses of venetoclax (200 mg d1-14). The reduction in the dose of venetoclax avoided severe myelosuppression while achieving satisfactory outcomes. The patient received 2 cycles of therapy with no skin lesions re-occurred for 7 months before relapsing.

Missouri's overdose field report: descriptive analysis, survival trends, and naloxone dosing patterns from a community-based survey tool, 2018-2022.

Background: Missouri's Overdose Field Report (ODFR) is a community-based reporting system which intends to capture overdoses which may not be otherwise recorded.Objectives: Describe the factors related to non-fatal overdoses reported to Missouri's ODFR.Methods: This study used a descriptive epidemiological approach to examine the demographics and circumstances of overdoses reported to the ODFR. We used binary logistic regression to evaluate factors associated with survival and ordinal logistic regression to evaluate factors associated with number of doses used. Factors were chosen based on their relevance to overdose education and survival, and naloxone distribution.Results: Between 2018 and 2022, 12,225 overdoses (67% male; 78% White) were reported through the ODFR, with a 96% (n = 11,225) survival rate. Overdose survival (ps < .02) was associated with younger age (OR = .58), no opioid and stimulant co-involvement (OR = .61), and private location (OR = .48). Intramuscular naloxone in particular was associated with a significantly higher odds of survival compared to nasal naloxone (OR = 2.11). An average of 1.6 doses of naloxone per incident were administered. Additional doses were associated (ps < .02) with being older (OR = .45), female (OR = .90), nasal naloxone (versus intravenous) (OR = .65), and the belief fentanyl was present (OR = 1.49).Conclusion: Our reporting form provides a comprehensive picture of the events surrounding reported overdoses, including factors associated with survival, how much naloxone was used, and the effects of respondents believing fentanyl was involved. Missouri's report can provide support for current naloxone dosing, contextualize refusing post-overdose transport, and can be used to improve overdose response by community and first responders.

The association between naloxone claims and proportion of independent vs. chain pharmacies: A longitudinal analysis of naloxone claims in the US.

BACKGROUND: Expanding access to naloxone through pharmacies is an important policy goal. Our objective was to characterize national county-level naloxone dispensing of chain versus independent pharmacies. METHODS: The primary exposure in our longitudinal analysis was the proportion of chain pharmacies in a county, identified through the US Department of Homeland Security 2010 Infrastructure Foundation-Level Data. We defined counties as having "higher proportion" of chain pharmacies if at least 50% of pharmacies were large national chains. The primary outcome was quarter-year (2016Q1-2019Q2) rate of pharmacy naloxone claims per 100,000 persons from Symphony Health at the county-level. We compared the naloxone dispensing rate between county types using two-sample t-tests. We estimated the association between county-level chain pharmacy proportion and rate of naloxone claims using a linear model with year-quarter fixed effects. RESULTS: Nearly one third of counties (n=946) were higher proportion. Higher proportion counties had a significantly higher rate of naloxone claims across the study period, in 4 of 6 urban-rural classifications, and in counties with and without naloxone access laws. The linear model confirmed that higher proportion counties had a significantly higher rate of naloxone claims, adjusting for urban/rural designation, income, population characteristics, opioid mortality rate, co-prescribing laws and naloxone access laws. CONCLUSION: In this national study, we found an association between naloxone dispensing rates and the county-level proportion of chain (versus independent) pharmacies. Incentivizing naloxone dispensing through educational, regulatory, or legal efforts may improve naloxone availability and dispensing rates - particularly in counties with proportionately high numbers of independent pharmacies.

The Testing Imperative: Why the US Ending the Human Immunodeficiency Virus (HIV) Epidemic Program Needs to Renew Efforts to Expand HIV Testing in Clinical and Community-Based Settings.

Data from several modeling studies demonstrate that large-scale increases in human immunodeficiency virus (HIV) testing across settings with a high burden of HIV may produce the largest incidence reductions to support the US Ending the HIV Epidemic (EHE) initiative's goal of reducing new HIV infections 90% by 2030. Despite US Centers for Disease Control and Prevention's recommendations for routine HIV screening within clinical settings and at least yearly screening for individuals most at risk of acquiring HIV, fewer than half of US adults report ever receiving an HIV test. Furthermore, total domestic funding for HIV prevention has remained unchanged between 2013 and 2019. The authors describe the evidence supporting the value of expanded HIV testing, identify challenges in implementation, and present recommendations to address these barriers through approaches at local and federal levels to reach EHE targets.

Racial/ethnic differences in receipt of naloxone distributed by opioid overdose prevention programs in New York City.

INTRODUCTION: We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC). METHODS: We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White, and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group. RESULTS: Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents (22.0 per 100,000), non-Latino White (13.6 per 100,000) and non-Latino Other residents (13.3 per 100,000). In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate, and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents. CONCLUSIONS: This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations.

Translating and disseminating a localised economic model to support implementation of the 'Ending the HIV Epidemic' initiative to public health policymakers.

Background: Despite significant progress in HIV treatment and prevention, the US remains far from its goal of 'Ending the HIV Epidemic' by 2030. Economic models using local data can synthesise the evidence to help policymakers allocate HIV resources efficiently, but persistent research-to-practice gaps remain. Little is known about how to facilitate the use of economic modelling data among local public health policymakers in real-world settings. Aims and objectives: To explore the dissemination of results from a locally-calibrated economic model for HIV prevention and treatment and identify the factors influencing potential uptake of the model for public health decision making at the local level. Methods: Four virtual focus groups with 26 local health department policymakers in Baltimore, Miami, Seattle, and New York City were held between July 2020 and May 2021. Qualitative content analysis of transcripts identified key themes around using the localised economic model in policy decisions. Results: Participants were interested in using local data in their decisions to allocate resources for HIV prevention/treatment. Six themes emerged: 1) importance of understanding local policy context; 2) health equity considerations; 3) using evidence to support current priorities; 4) difficulty of changing strategies, even incrementally; 5) bang for the incremental buck (efficiency) vs. previous impact; and 6) community values. Conclusion and relevance: To optimise acceptance and use of results from economic models, researchers should engage with local community members and public health decision makers early to understand budgetary and community priorities. Participants prioritised evidence that supports their existing strategies, considers budgets and funding streams, and improves health equity; however, real-world budget constraints and conflicting interests serve as barriers to implementing model recommendations and reaching national goals.

The Potential Epidemiological Impact of Coronavirus Disease 2019 (COVID-19) on the Human Immunodeficiency Virus (HIV) Epidemic and the Cost-effectiveness of Linked, Opt-out HIV Testing: A Modeling Study in 6 US Cities.

BACKGROUND: Widespread viral and serological testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present a unique opportunity to also test for human immunodeficiency virus (HIV) infection. We estimated the potential impact of adding linked, opt-out HIV testing alongside SARS-CoV-2 testing on the HIV incidence and the cost-effectiveness of this strategy in 6 US cities. METHODS: Using a previously calibrated dynamic HIV transmission model, we constructed 3 sets of scenarios for each city: (1) sustained current levels of HIV-related treatment and prevention services (status quo); (2) temporary disruptions in health services and changes in sexual and injection risk behaviors at discrete levels between 0%-50%; and (3) linked HIV and SARS-CoV-2 testing offered to 10%-90% of the adult population in addition to Scenario 2. We estimated the cumulative number of HIV infections between 2020-2025 and the incremental cost-effectiveness ratios of linked HIV testing over 20 years. RESULTS: In the absence of linked, opt-out HIV testing, we estimated a total of a 16.5% decrease in HIV infections between 2020-2025 in the best-case scenario (50% reduction in risk behaviors and no service disruptions), and a 9.0% increase in the worst-case scenario (no behavioral change and 50% reduction in service access). We estimated that HIV testing (offered at 10%-90% levels) could avert a total of 576-7225 (1.6%-17.2%) new infections. The intervention would require an initial investment of $20.6M-$220.7M across cities; however, the intervention would ultimately result in savings in health-care costs in each city. CONCLUSIONS: A campaign in which HIV testing is linked with SARS-CoV-2 testing could substantially reduce the HIV incidence and reduce direct and indirect health care costs attributable to HIV.

A metal-organic framework with multienzyme activity as a biosensing platform for real-time electrochemical detection of nitric oxide and hydrogen peroxide.

A Metal-Organic Framework (MOFs) with large surface area, exposed active site, excellent catalytic performance and high chemical stability has been used as an artificial enzyme and designed for nonenzymatic electrochemical sensors. Here, a strategy of using an enhanced electrochemical sensing platform for the detection of nitic oxide (NO) and hydrogen peroxide (H2O2) was designed via a nano-metalloporphyrinic metal-organic framework (NporMOF(Fe)) as an electrode material. By taking advantage of the small size, high surface area and exposed Fe active site, the obtained NporMOF(Fe) displays excellent electrocatalytic activity toward NO and H2O2. The NporMOF(Fe) modified electrode shows high sensing ability toward the in situ generated NO in NO2- containing phosphate buffer (PB) solution with a wide linear detection range of 5 µM to 200 µM and a very low detection limit of 1.3 µM. Moreover, NporMOF(Fe) exhibits high electrocatalytic activity toward the reduction of H2O2 and the practical detection of H2O2 released from HeLa cells. Furthermore, the NporMOF(Fe) modified electrode shows excellent selectivity toward the detection of NO and H2O2 in the presence of other physiologically important analytes. This method shows excellent biosensing performance, implying the universal applicability of MOFs-based artificial nanozymes for biosensors and the potential application for third generation biosensors.

The effect of British Columbia's Pharmacare coverage expansion for opioid agonist treatment.

Opioid agonist treatment (OAT) is the evidence-based standard of care for people with opioid use disorder. In British Columbia, Canada, only social assistance registrants received full coverage for OAT prior to the introduction of the Pharmacare Plan G coverage expansion on February 1st, 2017. We aimed to determine the effect of the coverage expansion on OAT initiation, re-initiation, and retention. Using linked population-level data, we executed a difference-in-differences analysis to compare outcomes of individuals eligible for the additional coverage and social assistance registrants already receiving the most generous coverage for OAT prior to the policy change, adjusting for individual and prescriber characteristics. We found Plan G coverage expansion significantly increased OAT retention. Specifically, coverage expansion decreased the number of OAT episode discontinuations by 12.8% (95% CI: 8.4%, 17.2%).

Ending the HIV Epidemic Among Persons Who Inject Drugs: A Cost-Effectiveness Analysis in Six US Cities.

BACKGROUND: Persons who inject drugs (PWID) are at a disproportionately high risk of HIV infection. We aimed to determine the highest-valued combination implementation strategies to reduce the burden of HIV among PWID in 6 US cities. METHODS: Using a dynamic HIV transmission model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City, and Seattle, we assessed the value of implementing combinations of evidence-based interventions at optimistic (drawn from best available evidence) or ideal (90% coverage) scale-up. We estimated reduction in HIV incidence among PWID, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) for each city (10-year implementation; 20-year horizon; 2018 $ US). RESULTS: Combinations that maximized health benefits contained between 6 (Atlanta and Seattle) and 12 (Miami) interventions with ICER values ranging from $94 069/QALY in Los Angeles to $146 256/QALY in Miami. These strategies reduced HIV incidence by 8.1% (credible interval [CI], 2.8%-13.2%) in Seattle and 54.4% (CI, 37.6%-73.9%) in Miami. Incidence reduction reached 16.1%-75.5% at ideal scale. CONCLUSIONS: Evidence-based interventions targeted to PWID can deliver considerable value; however, ending the HIV epidemic among PWID will require innovative implementation strategies and supporting programs to reduce social and structural barriers to care.

"Ending the Epidemic" Will Not Happen Without Addressing Racial/Ethnic Disparities in the United States Human Immunodeficiency Virus Epidemic.

We estimated human immunodeficiency virus incidence and incidence rate ratios (IRRs) for black and Hispanic vs white populations in 6 cities in the United States (2020-2030). Large reductions in incidence are possible, but without elimination of disparities in healthcare access, we found that wide disparities persisted for black compared with white populations in particular (lowest IRR, 1.69 [95% credible interval, 1.19-2.30]).

Prioritizing Additional Data Collection to Reduce Decision Uncertainty in the HIV/AIDS Response in 6 US Cities: A Value of Information Analysis.

OBJECTIVES: The ambitious goals of the US Ending the HIV Epidemic initiative will require a targeted, context-specific public health response. Model-based economic evaluation provides useful guidance for decision making while characterizing decision uncertainty. We aim to quantify the value of eliminating uncertainty about different parameters in selecting combination implementation strategies to reduce the public health burden of HIV/AIDS in 6 US cities and identify future data collection priorities. METHODS: We used a dynamic compartmental HIV transmission model developed for 6 US cities to evaluate the cost-effectiveness of a range of combination implementation strategies. Using a metamodeling approach with nonparametric and deep learning methods, we calculated the expected value of perfect information, representing the maximum value of further research to eliminate decision uncertainty, and the expected value of partial perfect information for key groups of parameters that would be collected together in practice. RESULTS: The population expected value of perfect information ranged from $59 683 (Miami) to $54 108 679 (Los Angeles). The rank ordering of expected value of partial perfect information on key groups of parameters were largely consistent across cities and highest for parameters pertaining to HIV risk behaviors, probability of HIV transmission, health service engagement, HIV-related mortality, health utility weights, and healthcare costs. Los Angeles was an exception, where parameters on retention in pre-exposure prophylaxis ranked highest in contributing to decision uncertainty. CONCLUSIONS: Funding additional data collection on HIV/AIDS may be warranted in Baltimore, Los Angeles, and New York City. Value of information analysis should be embedded into decision-making processes on funding future research and public health intervention.

Self-management Among Elderly Patients With Hypertension and Its Association With Individual and Social Environmental Factors in China.

BACKGROUND: The hypertension control rate in China is much lower than that in developed countries. Self-management among elderly patients with hypertension can improve blood pressure control; thus, it is necessary to explore its association with individual and social environmental factors. OBJECTIVE: Our objective was to investigate self-management among elderly patients with hypertension in China and its association with individual and social environmental factors based on the social ecological model. METHODS: A total of 301 elderly patients with hypertension were recruited to do a questionnaire survey based on the social ecological model, which included the General Demographic Information Questionnaire, Hypertension Patients Self-Management Behavior Rating Scale, World Health Organization Well-Being Index, Family APGAR Index, and Social Support Rating Scale. RESULTS: The lowest level of self-management behaviors was in exercise management, and the highest was in medication management. The results of multiple linear regression analysis showed that well-being, family function, sex, education level, and age were pivotal individual and social environmental factors influencing self-management behaviors among elderly patients with hypertension. CONCLUSIONS: There is a need to develop and test interventions that improve self-management in elderly patients with hypertension. Specifically, individualized interventions to promote exercise among elderly persons with hypertension who are single and living alone are needed. Male patients with a lower education level, poor well-being, poor family function, and the lowest self-management levels are a key population to target.

Ending the Epidemic in America Will Not Happen if the Status Quo Continues: Modeled Projections for Human Immunodeficiency Virus Incidence in 6 US Cities.

We estimated 10-year (2020-2030) trajectories for human immunodeficiency virus incidence in 6 US cities. Estimated incidence will only decrease in 2 of 6 cities, with the overall population-weighted incidence decreasing 3.1% (95% credible interval [CrI], -1.0% to 8.5%) by 2025, and 4.3% (95% CrI, -2.6% to 12.7%) by 2030 across cities. Targeted, context-specific combination implementation strategies will be necessary to meet the newly established national targets.

Impact of public hospital pricing reform on medical expenditure structure in Jiangsu, China: a synthetic control analysis.

BACKGROUND: The synthetic control method (SCM) is a useful tool in providing unbiased analysis on the policy effect in real-world health policy evaluations. Through controlling for a few confounding factors, we aim to apply SCM in analyzing the impact of the pricing reform on medical expenditure structure in Jiangsu Province, China. METHODS: We constructed a synthetic control for Zhenjiang, a city where the reform was piloted in Jiangsu, by selecting weights on those potential control units to define a linear combination of the control outcomes to replicate the counterfactual as if the intervention is in absence. The policy effect was measured by the differences in the percentage of drug expenditure among average outpatient and inpatient care cost per visit in the post-policy period between Zhenjiang and its synthetic control. We also examined the significance of the estimated results by performing placebo tests, and cross-validated the results with a difference-in-differences analysis. RESULTS: The medical pricing reform was found to be effective in reducing the drug expenditure proportions in both outpatient and inpatient care by an estimated mean level of 7.7 and 3.2% (or 16.3 and 9.2% relative decrease to their 2012 levels) respectively. This reform effect was estimated to be significant in the placebo tests and was further confirmed by a cross-validation. CONCLUSION: We conclude that the pricing reform in public hospitals has significantly reduced drug expenditure incurred in both outpatient and inpatient care. This study also highlights the applicability of SCM method as an effective tool for health policy evaluation using publicly available data in the context of Chinese healthcare system.

The Cost-Effectiveness of Human Immunodeficiency Virus Testing and Treatment Engagement Initiatives in British Columbia, Canada: 2011-2013.

Background: Recognition of the secondary preventive benefits of antiretroviral therapy (ART) has mobilized global efforts to "seek, test, treat, and retain" people living with human immunodeficiency virus [HIV]/AIDS (PLHIV) in HIV care. We aimed to determine the cost-effectiveness of a set of HIV testing and treatment engagement interventions initiated in British Columbia, Canada, in 2011-2013. Methods: Using a previously validated dynamic HIV transmission model, linked individual-level health administrative data for PLHIV, and aggregate-level HIV testing data, we estimated the cost-effectiveness of primary care testing (hospital, emergency department [ED], outpatient), ART initiation, and ART retention initiatives vs a counterfactual scenario that approximated the status quo. HIV incidence, mortality, costs (in 2015$CDN), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios were estimated. Analyses were executed over 5- to 25-year time horizons from a government-payer perspective. Results: ED testing was the best value at $30216 per QALY gained and had the greatest impact on incidence and mortality among PLHIV, while ART initiation provided the greatest QALY gains. The ART retention initiative was not cost-effective. Delivered in combination at the observed scale and sustained throughout the study period, we estimated a 12.8% reduction in cumulative HIV incidence and a 4.7% reduction in deaths among PLHIV at $55258 per QALY gained. Results were most sensitive to uncertainty in the number of undiagnosed PLHIV. Conclusions: HIV testing and ART initiation interventions were cost-effective, while the ART retention intervention was not. Developing strategies to reengage PLHIV lost to care is a priority moving forward.