Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries.

Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average

En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de

Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de

Cost-effectiveness of facility-based, stand-alone and mobile-based voluntary counseling and testing for HIV in Addis Ababa, Ethiopia.

BACKGROUND: Globally, there is a consensus to end the HIV/AIDS epidemic by 2030, and one of the strategies to achieve this target is that 90% of people living with HIV should know their HIV status. Even if there is strong evidence of clients' preference for testing in the community, HIV voluntary counseling and testing (VCT) continue to be undertaken predominantly in health facilities. Hence, empirical cost-effectiveness evidence about different HIV counseling and testing models is essential to inform whether such community-based testing are justifiable compared with additional resources required. Therefore, the purpose of this study was to compare the cost-effectiveness of facility-based, stand-alone and mobile-based HIV voluntary counseling and testing methods in Addis Ababa, Ethiopia. METHODS: Annual economic costs of counseling and testing methods were collected from the providers' perspective from July 2016 to June 2017. Ingredients based bottom-up costing approach was applied. The effectiveness of the interventions was measured in terms of the number of HIV seropositive clients identified. Decision tree modeling was built using TreeAge Pro 2018 software, and one-way and probabilistic sensitivity analyses were conducted by varying HIV positivity rate, costs, and probabilities. RESULTS: The cost of test per client for facility-based, stand-alone and mobile-based VCT was $5.06, $6.55 and $3.35, respectively. The unit costs of test per HIV seropositive client for the corresponding models were $158.82, $150.97 and $135.82, respectively. Of the three models, stand-alone-based VCT was extendedly dominated. Mobile-based VCT costs, an additional cost of USD 239 for every HIV positive client identified when compared to facility-based VCT. CONCLUSION: Using a mobile-based VCT approach costs less than both the facility-based and stand-alone approaches, in terms of both unit cost per tested individual and unit cost per HIV seropositive cases identified. The stand-alone VCT approach was not cost-effective compared to facility-based and mobile-based VCT. The incremental cost-effectiveness ratio for mobile-based VCT compared with facility-based VCT was USD 239 per HIV positive case.

Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response.

Palbociclib is a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor approved for breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative. We profiled palbociclib in cells either sensitive or resistant to the drug using an ATP/ADP probe-based chemoproteomics platform. Palbociclib only engaged CDK4 or CDK6 in sensitive cells. In resistant cells, no inhibition of CDK4 or CDK6 was observed, although the off-target profiles were similar in both cell types. Prolonged incubation of sensitive cells with the compound (24 h) resulted in the downregulation of additional kinases, including kinases critical for cell cycle progression. This downregulation is consistent with cell cycle arrest caused by palbociclib treatment. Both the direct and indirect targets were also observed in a human tumor xenograft study using the COLO-205 cell line in which phosphorylation of the retinoblastoma protein was tracked as the pharmacodyanamic marker. Together, these results suggest that this probe-based approach could be an important strategy toward predicting patient responsiveness to palbociclib.

Monitoring native p38α:MK2/3 complexes via trans delivery of an ATP acyl phosphate probe.

Here we describe a chemical proteomics strategy using ATP acyl phosphates to measure the formation of a protein:protein complex between p38α and mapkap kinases 2 and/or 3. Formation of the protein:protein complex results in a new probe labeling site on p38α that can be used to quantify the extent of interaction in cell lysates and the equilibrium binding constant for the interaction in vitro. We demonstrate through RNA interference that the labeling site is dependent on formation of the protein:protein complex in cells. Further, we identify that active-site-directed, small-molecule inhibitors of MK2/3 selectively inhibit the heterodimer-dependent probe labeling, whereas p38α inhibitors do not. These findings afford a new method to evaluate p38α and MK2/3 inhibitors within native biological systems and a new tool for improved understanding of p38α signaling pathways.

Economic evaluation of Health Extension Program packages in Ethiopia.

BACKGROUND: Ethiopia launched the Health Extension Program (HEP) in 2004, aimed at ensuring equitable community-level healthcare services through Health Extension Workers. Despite the program's being a flagship initiative, there is limited evidence on whether investment in the program represents good value for money. This study assessed the cost and cost-effectiveness of HEP interventions to inform policy decisions for resource allocation and priority setting in Ethiopia. METHODS: Twenty-one health care interventions were selected under the hygiene and sanitation, family health services, and disease prevention and control sub-domains. The ingredient bottom-up and top-down costing method was employed. Cost and cost-effectiveness were assessed from the provider perspective. Health outcomes were measured using life years gained (LYG). Incremental cost per LYG in relation to the gross domestic product (GDP) per capita of Ethiopia (US$852.80) was used to ascertain the cost-effectiveness. All costs were collected in Ethiopian birr and converted to United States dollars (US$) using the average exchange rate for 2018 (US$1 = 27.67 birr). Both costs and health outcomes were discounted by 3%. RESULT: The average unit cost of providing selected hygiene and sanitation, family health, and disease prevention and control services with the HEP was US$0.70, US$4.90, and US$7.40, respectively. The major cost driver was drugs and supplies, accounting for 53% and 68%, respectively, of the total cost. The average annual cost of delivering all the selected interventions was US$9,897. All interventions fall within 1 times GDP per capita per LYG, indicating that they are very cost-effective (ranges: US$22-$295 per LYG). Overall, the HEP is cost-effective by investing US$77.40 for every LYG. CONCLUSION: The unit cost estimates of HEP interventions are crucial for priority-setting, resource mobilization, and program planning. This study found that the program is very cost-effective in delivering community health services.

Cost-effectiveness of treating multidrug-resistant tuberculosis in treatment initiative centers and treatment follow-up centers in Ethiopia.

BACKGROUND: In Ethiopia, MDR-TB has become a significant public health threat; therefore, the Ministry of Health introduced two treatment approaches for MDR-TB cases: treatment initiative center (TIC) and treatment follow-up center (TFC). TIC is where patients usually are diagnosed and start the treatment. At TFC, we follow MDR-TB patients until they completed the treatment. However, there is no evidence about the cost-effectiveness of the approaches. Therefore, this study aimed to analyze the cost-effectiveness of MDR-TB treatment in TIC and TFC. METHODS: In this study, we employed a full economic evaluation from a providers' perspective. We followed a hypothetical cohort of individuals from the age of 15 for a lifetime using a Markov model with five mutually exclusive health states. We used both primary and secondary data sources for the study. Ingredient-based costing approach was used. The costs include healthcare provider costs (recurrent and capital cost) and patient-side costs (direct and indirect). We use a human capital approach to estimate the indirect cost. The cost estimates were reported in the 2017 United States Dollar (US$), and effectiveness was measured using disability-adjusted life-years (DALYs) averted. Both costs and health benefits were discounted using a 3% discount rate. Both average and incremental cost-effectiveness ratios (ICER) were reported calculated. One-way and probabilistic sensitivity analyses were reported to determine the robustness of the estimates. RESULTS: The cost per HIV negative patient successfully treated for MDR-TB was $8,416 at TIC and $6,657 at TFC. The average cost-effectiveness ratio per DALY averted at TFC was $671 and $1,417 per DALY averted at TIC. The incremental cost-effectiveness ratio (ICER) of MDR-TB treatment at TIC was $1,641 per DALYs averted. CONCLUSION: This study indicates that the treatment of MDR-TB at both TIC and TFC are cost-effective interventions compared with the willingness to pay threshold of three-times the GDP per capita in Ethiopia.

Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs.

The interaction of a drug with its target is critical to achieve drug efficacy. In cases where cellular environment influences target engagement, differences between individuals and cell types present a challenge for a priori prediction of drug efficacy. As such, characterization of environments conducive to achieving the desired pharmacologic outcome is warranted. We recently reported that the clinical CDK4/6 inhibitor palbociclib displays cell type-specific target engagement: Palbociclib engaged CDK4 in cells biologically sensitive to the drug, but not in biologically insensitive cells. Here, we report a molecular explanation for this phenomenon. Palbociclib target engagement is determined by the interaction of CDK4 with CDKN2A, a physiologically relevant protein inhibitor of CDK4. Because both the drug and CDKN2A prevent CDK4 kinase activity, discrimination between these modes of inhibition is not possible by traditional kinase assays. Here, we describe a chemo-proteomics approach that demonstrates high CDK4 target engagement by palbociclib in cells without functional CDKN2A and attenuated target engagement when CDKN2A (or related CDKN2/INK4 family proteins) is abundant. Analysis of biological sensitivity in engineered isogenic cells with low or absent CDKN2A and of a panel of previously characterized cell lines indicates that high levels of CDKN2A predict insensitivity to palbociclib, whereas low levels do not correlate with sensitivity. Therefore, high CDKN2A may provide a useful biomarker to exclude patients from CDK4/6 inhibitor therapy. This work exemplifies modulation of kinase target engagement by endogenous proteinaceous regulators and highlights the importance of cellular context in predicting inhibitor efficacy.

Correction: Identification of a Tumor Specific, Active-Site Mutation in Casein Kinase 1α by Chemical Proteomics.

[This corrects the article DOI: 10.1371/journal.pone.0152934.].

Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries / Argumentos de la economía de la salud para ampliar las medidas de control de la hipertensión de la iniciativa HEARTS de la OMS en los países de ingresos medianos y bajos / Ampliação do pacote de controle da hipertensão OMS-HEARTS em países de baixa e média renda: argumentos a partir da perspectiva da economia em saúde

ABSTRACT Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average <US$ 5 per patient per year in the public sector. This health economic evidence will make a compelling case for government ownership and financial support for national scale hypertension control programs.

RESUMEN En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de <US$ 5 por paciente al año en el sector público. Estos datos del ámbito de la economía de la salud serán argumentos convincentes para que los gobiernos se involucren en los programas de control de la hipertensión a escala nacional y les brinden apoyo financiero.

RESUMO Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de <US$ 18 por paciente por ano no setor público. Estas evidências do campo da economia em saúde serão um argumento convincente para que os governos se responsabilizem por programas de controle de hipertensão em escala nacional e os dotem de recursos financeiros.

Identification of a Tumor Specific, Active-Site Mutation in Casein Kinase 1α by Chemical Proteomics.

We describe the identification of a novel, tumor-specific missense mutation in the active site of casein kinase 1α (CSNK1A1) using activity-based proteomics. Matched normal and tumor colon samples were analyzed using an ATP acyl phosphate probe in a kinase-targeted LC-MS2 platform. An anomaly in the active-site peptide from CSNK1A1 was observed in a tumor sample that was consistent with an altered catalytic aspartic acid. Expression and analysis of the suspected mutant verified the presence of asparagine in the probe-labeled, active-site peptide for CSNK1A1. Genomic sequencing of the colon tumor samples confirmed the presence of a missense mutation in the catalytic aspartic acid of CSNK1A1 (GAC→AAC). To our knowledge, the D163N mutation in CSNK1A1 is a newly defined mutation to the conserved, catalytic aspartic acid of a protein kinase and the first missense mutation identified using activity-based proteomics. The tumorigenic potential of this mutation remains to be determined.

Profiling native kinases by immuno-assisted activity-based profiling.

The protocols in this unit describe efficient and cost-effective approaches to determine the interaction of small-molecule inhibitors with native kinases, and also analyze the interactions between kinases and their binding partners in a cellular setting. The combined attributes of activity-based probes and western blotting procedures provide for quantitative measurement of inhibitor efficacy, isoform selectivity, and post-translational modifications. We further demonstrate the ability to identify protein-protein interactions between a probe-labeled protein and its noncovalent binding partners.