Analysis of Mammography Screening Schedules under Varying Resource Constraints for Planning Breast Cancer Control Programs in Low- and Middle-Income Countries: A Mathematical Study.

Background. Low-and-middle-income countries (LMICs) have higher mortality-to-incidence ratio for breast cancer compared to high-income countries (HICs) because of late-stage diagnosis. Mammography screening is recommended for early diagnosis, however, the infrastructure capacity in LMICs are far below that needed for adopting current screening guidelines. Current guidelines are extrapolations from HICs, as limited data had restricted model development specific to LMICs, and thus, economic analysis of screening schedules specific to infrastructure capacities are unavailable. Methods. We applied a new Markov process method for developing cancer progression models and a Markov decision process model to identify optimal screening schedules under a varying number of lifetime screenings per person, a proxy for infrastructure capacity. We modeled Peru, a middle-income country, as a case study and the United States, an HIC, for validation. Results. Implementing 2, 5, 10, and 15 lifetime screens would require about 55, 135, 280, and 405 mammography machines, respectively, and would save 31, 62, 95, and 112 life-years per 1000 women, respectively. Current guidelines recommend 15 lifetime screens, but Peru has only 55 mammography machines nationally. With this capacity, the best strategy is 2 lifetime screenings at age 50 and 56 years. As infrastructure is scaled up to accommodate 5 and 10 lifetime screens, screening between the ages of 44-61 and 41-64 years, respectively, would have the best impact. Our results for the United States are consistent with other models and current guidelines. Limitations. The scope of our model is limited to analysis of national-level guidelines. We did not model heterogeneity across the country. Conclusions. Country-specific optimal screening schedules under varying infrastructure capacities can systematically guide development of cancer control programs and planning of health investments.

Cost-effective interventions for breast cancer, cervical cancer, and colorectal cancer: new results from WHO-CHOICE.

BACKGROUND: Following the adoption of the Global Action Plan for the Prevention and Control of NCDs 2013-2020, an update to the Appendix 3 of the action plan was requested by Member States in 2016, endorsed by the Seventieth World Health Assembly in May 2017 and provides a list of recommended NCD interventions. The main contribution of this paper is to present results of analyses identifying how decision makers can achieve maximum health gain using the cancer interventions listed in the Appendix 3. We also present methods used to calculate new WHO-CHOICE cost-effectiveness results for breast cancer, cervical cancer, and colorectal cancer in Southeast Asia and eastern sub-Saharan Africa. METHODS: We used "Generalized Cost-Effectiveness Analysis" for our analysis which uses a hypothetical null reference case, where the impacts of all current interventions are removed, in order to identify the optimal package of interventions. All health system costs, regardless of payer, were included. Health outcomes are reported as the gain in healthy life years due to a specific intervention scenario and were estimated using a deterministic state-transition cohort simulation (Markov model). RESULTS: Vaccination against human papillomavirus (two doses) for 9-13-year-old girls (in eastern sub-Saharan Africa) and HPV vaccination combined with prevention of cervical cancer by screening of women aged 30-49 years through visual inspection with acetic acid linked with timely treatment of pre-cancerous lesions (in Southeast Asia) were found to be the most cost effective interventions. For breast cancer, in both regions the treatment of breast cancer, stages I and II, with surgery ± systemic therapy, at 95% coverage, was found to be the most cost-effective intervention. For colorectal cancer, treatment of colorectal cancer, stages I and II, with surgery ± chemotherapy and radiotherapy, at 95% coverage, was found to be the most cost-effective intervention. CONCLUSION: The results demonstrate that cancer prevention and control interventions are cost-effective and can be implemented through a step-wise approach to achieve maximum health benefits. As the global community moves toward universal health coverage, this analysis can support decision makers in identifying a core package of cancer services, ensuring treatment and palliative care for all.

A Two-Step Markov Processes Approach for Parameterization of Cancer State-Transition Models for Low- and Middle-Income Countries.

Implementation of organized cancer screening and prevention programs in high-income countries (HICs) has considerably decreased cancer-related incidence and mortality. In low- and middle-income countries (LMICs), screening and early diagnosis programs are generally unavailable, and most cancers are diagnosed in late stages when survival is very low. Analyzing the cost-effectiveness of alternative cancer control programs and estimating resource needs will help prioritize interventions in LMICs. However, mathematical models of natural cancer onset and progression needed to conduct the economic analyses are predominantly based on populations in HICs because the longitudinal data on screening and diagnoses required for parameterization are unavailable in LMICs. Models currently used for LMICs mostly concentrate on directly calculating the shift in distribution of cancer diagnosis as an evaluative measure of screening. We present a mathematical methodology for the parameterization of natural cancer onset and progression, specifically for LMICs that do not have longitudinal data. This full onset and progression model can help conduct comprehensive analyses of cancer control programs, including cancer screening, by considering both the positive impact of screening as well as any adverse consequences, such as over-diagnosis and false-positive results. The methodology has been applied to breast, cervical, and colorectal cancers for 2 regions, under the World Health Organization categorization: Eastern Sub-Saharan Africa (AFRE) and Southeast Asia (SEARB). The cancer models have been incorporated into the Spectrum software and interfaced with country-specific demographic data through the demographic projections (DemProj) module and costing data through the OneHealth tool. These software are open-access and can be used by stakeholders to analyze screening strategies specific to their country of interest.

Combinations of interventions to achieve a national HIV incidence reduction goal: insights from an agent-based model.

OBJECTIVE: Analyzing HIV care service targets for achieving a national goal of a 25% reduction in annual HIV incidence and evaluating the use of annual HIV diagnoses to measure progress in incidence reduction. DESIGN: Because there are considerable interactions among HIV care services, we model the dynamics of 'combinations' of increases in HIV care continuum targets to identify those that would achieve 25% reductions in annual incidence and diagnoses. METHODS: We used Progression and Transmission of HIV/AIDS 2.0, an agent-based dynamic stochastic simulation of HIV in the United States. RESULTS: A 25% reduction in annual incidence could be achieved by multiple alternative combinations of percentages of persons with diagnosed infection and persons with viral suppression including 85 and 68%, respectively, and 90 and 59%, respectively. The first combination corresponded to an 18% reduction in annual diagnoses, and infections being diagnosed at a median CD4 cell count of 372 cells/µl or approximately 3.8 years from time of infection. The corresponding values on the second combination are 4%, 462 cells/µl, and 2.0 years, respectively. CONCLUSION: Our analysis provides policy makers with specific targets and alternative choices to achieve the goal of a 25% reduction in HIV incidence. Reducing annual diagnoses does not equate to reducing annual incidence. Instead, progress toward reducing incidence can be measured by monitoring HIV surveillance data trends in CD4 cell count at diagnosis along with the proportion who have achieved viral suppression to determine where to focus local programmatic efforts.

Assessment of epidemic projections using recent HIV survey data in South Africa: a validation analysis of ten mathematical models of HIV epidemiology in the antiretroviral therapy era.

BACKGROUND: Mathematical models are widely used to simulate the effects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012. METHODS: We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15-49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey. FINDINGS: All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models' central projections being below the survey 95% CI (17·5-20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (difference 1·9, 95% CI -0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI -0·3 to 3·5) in young adults aged 15-24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54-2·12 million. However, the differential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73-2·71). INTERPRETATION: Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections. FUNDING: Bill & Melinda Gates Foundation.

Updates to the spectrum model to estimate key HIV indicators for adults and children.

BACKGROUND: The Spectrum program is used to estimate key HIV indicators for national programmes. The purpose of the study is to describe the key updates made to Spectrum in the last 2 years to produce the version used in the 2013 global estimates of HIV/AIDS. METHODS: The United Nations Programme on HIV/AIDS (UNAIDS) Reference Group on Estimates, Models and Projections regularly reviews new data and information needs and recommends updates to the methodology and assumptions used in Spectrum. The latest data from surveys, census and special studies are used to estimate key parameter values for countries and regions. RESULTS: Country-specific life tables prepared by the United National Population Division (UNPD) have been incorporated into Spectrum's demographic projections replacing the model life tables used previously. This update includes revised estimates of non-AIDS life expectancy. Incidence among all adults 15-49 years generated from curve fitting to surveillance and survey data is now split by age using incidence rate ratios derived from Analysing Longitudinal Population-based HIV/AIDS data on Africa Network data for generalized epidemics. Methods for estimating the number of AIDS orphans have been updated to include the changing effects of PMTCT and antiretroviral therapy programmes. Procedures for estimating the number of adults eligible for treatment have been updated to reflect the 2013 WHO guidelines. Program data on AIDS mortality has been used to estimate prevalence trends in Argentina, Brazil and Mexico for the 2013 estimates. CONCLUSION: Spectrum was updated for the 2013 round of HIV estimates in order to support national programmes with improved methods and data to estimating national indicators.

How can we get close to zero? The potential contribution of biomedical prevention and the investment framework towards an effective response to HIV.

BACKGROUND: In 2011 an Investment Framework was proposed that described how the scale-up of key HIV interventions could dramatically reduce new HIV infections and deaths in low and middle income countries by 2015. This framework included ambitious coverage goals for prevention and treatment services resulting in a reduction of new HIV infections by more than half. However, it also estimated a leveling in the number of new infections at about 1 million annually after 2015. METHODS: We modeled how the response to AIDS can be further expanded by scaling up antiretroviral treatment (ART) within the framework provided by the 2013 WHO treatment guidelines. We further explored the potential contributions of new prevention technologies: 'Test and Treat', pre-exposure prophylaxis and an HIV vaccine. FINDINGS: Immediate aggressive scale up of existing approaches including the 2013 WHO guidelines could reduce new infections by 80%. A 'Test and Treat' approach could further reduce new infections. This could be further enhanced by a future highly effective pre-exposure prophylaxis and an HIV vaccine, so that a combination of all four approaches could reduce new infections to as low as 80,000 per year by 2050 and annual AIDS deaths to 260,000. INTERPRETATION: In a set of ambitious scenarios, we find that immediate implementation of the 2013 WHO antiretroviral therapy guidelines could reduce new HIV infections by 80%. Further reductions may be achieved by moving to a 'Test and Treat' approach, and eventually by adding a highly effective pre-exposure prophylaxis and an HIV vaccine, if they become available.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per µL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per µL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per µL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per µL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per µL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per µL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. INTERPRETATION: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. FUNDING: Bill & Melinda Gates Foundation, WHO.

The impact and cost of the 2013 WHO recommendations on eligibility for antiretroviral therapy.

OBJECTIVES: The present study presents estimates of the number of people who would become newly eligible for antiretroviral therapy if all countries adopted the 2013 WHO treatment guidelines. It also shows the cost and impact that would result if coverage expanded to 80% of those eligible. METHODS: The AIDS Impact Model (AIM) and the Goals model within the Spectrum modelling system were used for these estimates. Projections of costs and AIDS deaths are based on estimates for 116 low-income and middle-income countries. Projections of impact on HIV incidence are based on simulation modelling for 24 high burden countries, with the results scaled up to represent all low-income and middle-income countries. RESULTS: If the 2013 guidelines were adopted universally, the number eligible for treatment would rise to 28.6 million in 2013. Achieving 80% coverage would mean 28 million on antiretroviral therapy by 2025, and would avert 2.9 million deaths and 3.9 million new infections from 2013 to 2025 compared with the 2010 guidelines. CONCLUSION: The 2013 guidelines significantly expand the number eligible for treatment. Reaching those newly eligible will require additional resources, but is likely to produce significant benefits.

The costs and benefits of Option B+ for the prevention of mother-to-child transmission of HIV.

OBJECTIVE: Most countries follow WHO 2010 guidelines for the prevention of mother-to-child transmission (PMTCT) of HIV using either Option A or B for women not yet eligible for antiretroviral therapy (ART). Both of these approaches involve the use of antiretrovirals during pregnancy and breastfeeding. Some countries have adopted a new strategy, Option B+, in which HIV-positive pregnant women are started immediately on ART and continued for life. Option B+ is more costly than Options A or B, but provides additional health benefits. In this article, we estimate the additional costs and effectiveness of Option B+. METHODS: We developed a deterministic model to simulate births, breastfeeding, and HIV infection in women in four countries, Kenya, Zambia, South Africa, and Vietnam that differ in fertility rate, birth interval, age at first birth, and breastfeeding patterns, but have similar age at HIV infection. We estimated the total PMTCT costs and new child infections under Options A, B, and B+, and measured cost-effectiveness as the incremental PMTCT-related costs per child infection averted. We included adult sexual transmissions averted from ART, the corresponding costs saved, and estimated the total incremental cost per transmission (child and adult) averted. RESULTS: When considering PMTCT-related costs and child infections, Option B+ was the most cost-effective strategy costing between $6000 and $23 000 per infection averted compared with Option A. Option B+ averted more child infections compared with Option B in all four countries and cost less than Option B in Kenya and Zambia. When including adult sexual transmissions averted, Option B+ cost less and averted more infections than Options A and B.

Cost-effectiveness of screening men in Maricopa County jails for chlamydia and gonorrhea to avert infections in women.

BACKGROUND: Chlamydia and gonorrhea infections can lead to serious and costly sequelae in women, but sequelae in men are rare. In accordance with the Centers for Disease Control and Prevention guidelines, female jail inmates in Maricopa County (Phoenix area), Arizona, are screened for these infections. Owing to lack of evidence of screening benefits in men, male inmates are tested and treated based on symptoms only. METHODS: We developed a probabilistic simulation model to simulate chlamydia and gonorrhea infections in Maricopa County jail male inmates and transmissions to female partners per year. We estimated the cost-effectiveness of screening as the cost per infection averted. Costs were estimated from the perspective of the Maricopa County Department of Public Health and the Correctional Health Services. RESULTS: Compared with symptom-based testing and treating strategy, screening male arrestees of all ages and only those 35 years or younger yielded the following results: averted approximately 556 and 491 cases of infection in women at a cost of approximately US $1240 and $860 per case averted, respectively, if screened during physical examination (between days 8 and 14 from entry to jail), and averted approximately 1100 and 995 cases of infections averted at a cost of US $1030 and $710 per infection averted, respectively, if screened early, within 2 to 3 days from entry to jail. CONCLUSIONS: Screening of male inmates incurs a modest cost per infection averted in women compared with symptom-based testing. Screening in correctional settings can be used by public health programs to reduce disease burden, sequelae, and associated costs.

Updates of lifetime costs of care and quality-of-life estimates for HIV-infected persons in the United States: late versus early diagnosis and entry into care.

BACKGROUND: Lifetime costs of care and quality-of-life estimates for HIV-infected persons depend on the disease stage at which these persons are diagnosed, enter care, and start antiretroviral therapy. Updated estimates were used to analyze the effects of late versus early diagnosis/entry on US lifetime care costs, quality-of-life estimates, and HIV transmissions. METHODS: The Progression and Transmission of HIV/AIDS model was used to estimate discounted (3%) lifetime treatment costs ($US 2011) and quality-of-life variables from time of infection for cohorts of 10,000 HIV-infected index patients in 4 categories of CD4 count at diagnosis: (I) ≤200 cells/µL, (II) 201-350 cells/µL, (III) 351-500 cells/µL, and (IV) 501-900 cells/µL. It is assumed that index patient diagnoses were uniformly distributed across the CD4 count range in each category and that patients entered care at the time of diagnosis, remained in care, and were eligible to initiate antiretroviral therapy at a CD4 count of 500 cells/µL. Lifetime transmissions of the index patients were also estimated. RESULTS: Discounted average lifetime costs varied from $253,000 for category I index patients to $402,000 for category IV patients. Discounted quality-adjusted life years lost decreased from 7.95 to 4.45 across these categories, additional years of life expectancy increased from 30.8 to 38.1, and lifetime transmissions decreased from 1.40 to 0.72. CONCLUSIONS: Early diagnosis and treatment of HIV infection increases lifetime costs but improves length and quality of life and reduces the number of new infections transmitted by nearly 50%.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly. METHODS: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the $/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and 'cost-effective' if $/DALY was less than three times per capita GDP. FINDINGS: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective. INTERPRETATION: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets. FUNDING: The Bill and Melinda Gates Foundation and World Health Organization.

Cost effectiveness of the National HIV/AIDS Strategy goal of increasing linkage to care for HIV-infected persons.

BACKGROUND: One of the goals of the National HIV/AIDS Strategy (NHAS) is to increase the proportion of HIV-infected individuals linked to care within 3 months of diagnosis (early linkage) from 65% to 85%. Earlier access to care, and eventually, to treatment, increases life expectancy and quality of life for HIV-infected persons. However, longer treatment is also associated with higher costs, especially for antiretroviral drugs. We evaluated the cost effectiveness of achieving the NHAS goal and estimated the maximum cost that HIV programs could spend on linkage to care and remain cost effective. METHODS: We used the Progression and Transmission of HIV/AIDS model to estimate the effects on life measures and costs associated with increasing early linkage to care from 65% to 85%. We estimated an incremental cost-effectiveness ratio as the additional cost required to reach the target divided by the quality-adjusted life years (QALYs) gained and assumed that programs costing $100,000 or less per QALY gained are cost effective. RESULTS: Achieving the NHAS linkage-to-care goal increased life expectancy by 0.4 years and delayed the onset of AIDS by 1.2 years on average for every HIV-diagnosed person. Increasing early linkage to care cost an extra $62,200 per QALY gained, considering only benefits to index persons. The maximum that could be cost effectively spent on early linkage-to-care interventions was approximately $5100 per HIV-diagnosed person. CONCLUSIONS: Considerable investment can be cost effectively made to achieve the NHAS goal on early linkage to care.