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1.  HIV Cure Strategies: How Good Must They Be to Improve on Current Antiretroviral Therapy? 
PLoS ONE  2014;9(11):e113031.
Background
We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART).
Methods
We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY.
Results
For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving.
Conclusions
Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.
doi:10.1371/journal.pone.0113031
PMCID: PMC4232561  PMID: 25397616
2.  Conceptualizing a Model: A Report of the ISPOR-SMDM Modeling Good Research Practices Task Force-2 
The appropriate development of a model begins with understanding the problem that is being represented. The aim of this article was to provide a series of consensus-based best practices regarding the process of model conceptualization. For the purpose of this series of articles, we consider the development of models whose purpose is to inform medical decisions and health-related resource allocation questions. We specifically divide the conceptualization process into two distinct components: the conceptualization of the problem, which converts knowledge of the health care process or decision into a representation of the problem, followed by the conceptualization of the model itself, which matches the attributes and characteristics of a particular modeling type with the needs of the problem being represented. Recommendations are made regarding the structure of the modeling team, agreement on the statement of the problem, the structure, perspective, and target population of the model, and the interventions and outcomes represented. Best practices relating to the specific characteristics of model structure and which characteristics of the problem might be most easily represented in a specific modeling method are presented. Each section contains a number of recommendations that were iterated among the authors, as well as among the wider modeling taskforce, jointly set up by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making.
doi:10.1016/j.jval.2012.06.016
PMCID: PMC4207095  PMID: 22999129
conceptualization; best practices; methods; modeling
3.  The Clinical and Economic Impact of Point-of-Care CD4 Testing in Mozambique and Other Resource-Limited Settings: A Cost-Effectiveness Analysis 
PLoS Medicine  2014;11(9):e1001725.
Emily Hyle and colleagues conduct a cost-effectiveness analysis to estimate the clinical and economic impact of point-of-care CD4 testing compared to laboratory-based tests in Mozambique.
Please see later in the article for the Editors' Summary
Background
Point-of-care CD4 tests at HIV diagnosis could improve linkage to care in resource-limited settings. Our objective is to evaluate the clinical and economic impact of point-of-care CD4 tests compared to laboratory-based tests in Mozambique.
Methods and Findings
We use a validated model of HIV testing, linkage, and treatment (CEPAC-International) to examine two strategies of immunological staging in Mozambique: (1) laboratory-based CD4 testing (LAB-CD4) and (2) point-of-care CD4 testing (POC-CD4). Model outcomes include 5-y survival, life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Input parameters include linkage to care (LAB-CD4, 34%; POC-CD4, 61%), probability of correctly detecting antiretroviral therapy (ART) eligibility (sensitivity: LAB-CD4, 100%; POC-CD4, 90%) or ART ineligibility (specificity: LAB-CD4, 100%; POC-CD4, 85%), and test cost (LAB-CD4, US$10; POC-CD4, US$24). In sensitivity analyses, we vary POC-CD4-specific parameters, as well as cohort and setting parameters to reflect a range of scenarios in sub-Saharan Africa. We consider ICERs less than three times the per capita gross domestic product in Mozambique (US$570) to be cost-effective, and ICERs less than one times the per capita gross domestic product in Mozambique to be very cost-effective. Projected 5-y survival in HIV-infected persons with LAB-CD4 is 60.9% (95% CI, 60.9%–61.0%), increasing to 65.0% (95% CI, 64.9%–65.1%) with POC-CD4. Discounted life expectancy and per person lifetime costs with LAB-CD4 are 9.6 y (95% CI, 9.6–9.6 y) and US$2,440 (95% CI, US$2,440–US$2,450) and increase with POC-CD4 to 10.3 y (95% CI, 10.3–10.3 y) and US$2,800 (95% CI, US$2,790–US$2,800); the ICER of POC-CD4 compared to LAB-CD4 is US$500/year of life saved (YLS) (95% CI, US$480–US$520/YLS). POC-CD4 improves clinical outcomes and remains near the very cost-effective threshold in sensitivity analyses, even if point-of-care CD4 tests have lower sensitivity/specificity and higher cost than published values. In other resource-limited settings with fewer opportunities to access care, POC-CD4 has a greater impact on clinical outcomes and remains cost-effective compared to LAB-CD4. Limitations of the analysis include the uncertainty around input parameters, which is examined in sensitivity analyses. The potential added benefits due to decreased transmission are excluded; their inclusion would likely further increase the value of POC-CD4 compared to LAB-CD4.
Conclusions
POC-CD4 at the time of HIV diagnosis could improve survival and be cost-effective compared to LAB-CD4 in Mozambique, if it improves linkage to care. POC-CD4 could have the greatest impact on mortality in settings where resources for HIV testing and linkage are most limited.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has already killed about 36 million people, and a similar number of people (mostly living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, HIV-infected individuals usually died within ten years of infection. After effective antiretroviral therapy (ART) became available in 1996, HIV infection became a chronic condition for people living in high-income countries, but because ART was expensive, HIV/AIDS remained a fatal disease in low- and middle-income countries. In 2003, the international community began to work towards achieving universal ART coverage, and by the end of 2012, 61% of HIV-positive people (nearly 10 million individuals) living low- and middle-income countries who were eligible for treatment—because their CD4 cell count had fallen below 350 cells/mm3 of blood or they had developed an AIDS-defining condition—were receiving treatment.
Why Was This Study Done?
In sub-Saharan Africa nearly 50% of HIV-infected people eligible for treatment remain untreated, in part because of poor linkage between HIV diagnosis and clinical care. After patients receive a diagnosis of HIV infection, their eligibility for ART initiation is determined by sending a blood sample away to a laboratory for a CD4 cell count (the current threshold for treatment is a CD4 count below 500/mm3, although low- and middle-income countries have yet to update their national guidelines from the threshold CD4 count below 350/mm3). Patients have to return to the clinic to receive their test results and to initiate ART if they are eligible for treatment. Unfortunately, many patients are “lost” during this multistep process in resource-limited settings. Point-of-care CD4 tests at HIV diagnosis—tests that are done on the spot and provide results the same day—might help to improve linkage to care in such settings. Here, the researchers use a mathematical model to assess the clinical outcomes and cost-effectiveness of point-of-care CD4 testing at the time of HIV diagnosis compared to laboratory-based testing in Mozambique, where about 1.5 million HIV-positive individuals live.
What Did the Researchers Do and Find?
The researchers used a validated model of HIV testing, linkage, and treatment called the Cost-Effectiveness of Preventing AIDS Complications–International (CEPAC-I) model to compare the clinical impact, costs, and cost-effectiveness of point-of-care and laboratory CD4 testing in newly diagnosed HIV-infected patients in Mozambique. They used published data to estimate realistic values for various model input parameters, including the probability of linkage to care following the use of each test, the accuracy of the tests, and the cost of each test. At a CD4 threshold for treatment of 250/mm3, the model predicted that 60.9% of newly diagnosed HIV-infected people would survive five years if their immunological status was assessed using the laboratory-based CD4 test, whereas 65% would survive five years if the point-of-care test was used. Predicted life expectancies were 9.6 and 10.3 years with the laboratory-based and point-of-care tests, respectively, and the per person lifetime costs (which mainly reflect treatment costs) associated with the two tests were US$2,440 and $US2,800, respectively. Finally, the incremental cost-effectiveness ratio—calculated as the incremental costs of one therapeutic intervention compared to another divided by the incremental benefits—was US$500 per year of life saved, when comparing use of the point-of-care test with a laboratory-based test.
What Do These Findings Mean?
These findings suggest that, compared to laboratory-based CD4 testing, point-of-care testing at HIV diagnosis could improve survival for HIV-infected individuals in Mozambique. Because the per capita gross domestic product in Mozambique is US$570, these findings also indicate that point-of-care testing would be very cost-effective compared to laboratory-based testing (an incremental cost-effectiveness ratio less than one times the per capita gross domestic product is regarded as very cost-effective). As with all modeling studies, the accuracy of these findings depends on the assumptions built into the model and on the accuracy of the input parameters. However, the point-of-care strategy averted deaths and was estimated to be cost-effective compared to the laboratory-based test over a wide range of input parameter values reflecting Mozambique and several other resource-limited settings that the researchers modeled. Importantly, these “sensitivity analyses” suggest that point-of-care CD4 testing is likely to have the greatest impact on HIV-related deaths and be economically efficient in settings in sub-Saharan Africa with the most limited health care resources, provided point-of-care CD4 testing improves the linkage to care for HIV-infected people.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001725.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its “Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infections: Recommendations for a Public Health Approach”, which highlights the potential of point-of-care tests to improve the linkage of newly diagnosed HIV-infected patients to care, is available
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment; it has a fact sheet on CD4 testing
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on starting, monitoring, and switching treatment and on HIV and AIDS in sub-Saharan Africa (in English and Spanish)
The “UNAIDS Report on the Global AIDS Epidemic 2013” provides up-to-date information about the AIDS epidemic and efforts to halt it
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001725
PMCID: PMC4165752  PMID: 25225800
4.  Dengue dynamics and vaccine cost-effectiveness in Brazil 
Vaccine  2013;31(37):3957-3961.
Recent Phase 2b dengue vaccine trials have demonstrated the safety of the vaccine and estimated the vaccine efficacy with further trials underway. In anticipation of vaccine roll-out, cost-effectiveness analysis of potential vaccination policies that quantify the dynamics of disease transmission are fundamental to the optimal allocation of available doses.
We developed a dengue transmission and vaccination model and calculated, for a range of vaccination costs and willingness-to-pay thresholds, the level of vaccination coverage necessary to sustain herd-immunity, the price at which vaccination is cost-effective and is cost-saving, and the sensitivity of our results to parameter uncertainty. We compared two vaccine efficacy scenarios, one a more optimistic scenario and another based on the recent lower-than-expected efficacy from the latest clinical trials.
We found that herd-immunity may be achieved by vaccinating 82% (95% CI 58–100%) of the population at a vaccine efficacy of 70%. At this efficacy, vaccination may be cost-effective for vaccination costs up to US $534 (95% CI $369–1008) per vaccinated individual and cost-saving up to $204 (95% CI $39–678). At the latest clinical trial estimates of an average of 30% vaccine efficacy, vaccination may be cost-effective and cost-saving at costs of up to $237 (95% CI $159–512) and $93 (95% CI $15–368), respectively.
Our model provides an assessment of the cost-effectiveness of dengue vaccination in Brazil and incorporates the effect of herd immunity into dengue vaccination cost-effectiveness. Our results demonstrate that at the relatively low vaccine efficacy from the recent Phase 2b dengue vaccine trials, age-targeted vaccination may still be cost-effective provided the total vaccination cost is sufficiently low.
doi:10.1016/j.vaccine.2013.06.036
PMCID: PMC3755607  PMID: 23791696
Dengue; vaccine; modeling; cost-effectiveness
5.  Cost-effectiveness of canine vaccination to prevent human rabies in rural Tanzania 
Annals of internal medicine  2014;160(2):91-100.
Background
The annual mortality rate of human rabies in rural Africa is 3.6 deaths per 100,000 individuals. Rabies can be prevented by prompt post-exposure prophylaxis, but this is costly and often inaccessible in rural Africa. As 99% of human exposures occur through rabid dogs, canine vaccination also prevents transmission of rabies to humans.
Objective
Evaluate the cost-effectiveness of rabies control through annual canine vaccination campaigns in rural sub-Saharan Africa.
Design
We model transmission dynamics in dogs and wildlife and assess empirical uncertainty in the biological parameters to make probability-based evaluations of cost-effectiveness.
Data Sources
Epidemiological parameters from contact tracing study and literature; cost data from ongoing vaccination campaigns
Target Population
Two districts of rural Tanzania, Ngorongoro and Serengeti
Time Horizon
Ten years
Perspective
Health policymaker
Interventions
Vaccination coverage ranging from 0 to 95% in increments of 5%
Outcome Measures
Life-years for health outcomes and 2010 USD for economic outcomes
Results of Base-Case Analysis
Annual canine vaccination campaigns are very cost-effective in both districts compared with no canine vaccination. In Serengeti, annual campaigns up to 70% coverage are cost-saving.
Results of Sensitivity Analysis
Across a wide range of parameter assumptions and levels of societal willingness-to-pay for life-years, the optimal vaccination coverage for Serengeti is 70%. In Ngorongoro, though optimal coverage depends on willingness-to-pay, vaccination campaigns are always cost-effective and life-saving, and therefore preferred.
Limitations
Canine vaccination is very cost-effective in both districts, but there is greater uncertainty regarding the optimal coverage in Ngorongoro.
Conclusions
Annual canine rabies vaccination campaigns confer extraordinary value and dramatically reduce the health burden of rabies.
Primary Funding Source
US National Institutes of Health (U01 GM087719)
PMCID: PMC4084874  PMID: 24592494
6.  Disease-modifying drugs for knee osteoarthritis: can they be cost-effective? 
Objective
Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment.
Design
We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20–100%), pain relief (10–100%), major toxicity (0.1–2%), and cost ($1,000–$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization.
Results
Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%.
Conclusions
Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.
doi:10.1016/j.joca.2013.01.016
PMCID: PMC3670115  PMID: 23380251
7.  Cost-Effectiveness of HIV Treatment as Prevention in Serodiscordant Couples 
The New England journal of medicine  2013;369(18):1715-1725.
BACKGROUND
The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons.
METHODS
For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART.
RESULTS
In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries.
CONCLUSIONS
In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.)
doi:10.1056/NEJMsa1214720
PMCID: PMC3913536  PMID: 24171517
8.  The Cost-effectiveness of Rapid HIV Testing in Substance Abuse Treatment: Results of a Randomized Trial* 
Drug and alcohol dependence  2012;128(1-2):90-97.
BACKGROUND
The President’s National HIV/AIDS Strategy calls for coupling HIV screening and prevention services with substance abuse treatment programs. Fewer than half of US community-based substance abuse treatment programs make HIV testing available on-site or through referral.
METHODS
We measured the cost-effectiveness of three HIV testing strategies evaluated in a randomized trial conducted in 12 community-based substance abuse treatment programs in 2009: off-site testing referral, on-site rapid testing with information only, on-site rapid testing with risk reduction counseling. Data from the trial included patient demographics, prior testing history, test acceptance and receipt of results, undiagnosed HIV prevalence (0.4%) and program costs. The Cost Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model was used to project life expectancy, lifetime costs, and quality-adjusted life years (QALYs) for HIV-infected individuals. Incremental cost-effectiveness ratios (2009 US $/QALY) were calculated after adding costs of testing HIV-uninfected individuals; costs and QALYs were discounted at 3% annually.
RESULTS
Referral for off-site testing is less efficient (dominated) compared to offering on-site testing with information only. The cost-effectiveness ratio for on-site testing with information is $60,300/QALY in the base case, or $76,300/QALY with 0.1% undiagnosed HIV prevalence. HIV risk-reduction counseling costs $36 per person more without additional benefit.
CONCLUSIONS
A strategy of on-site rapid HIV testing offer with information only in substance abuse treatment programs increases life expectancy at a cost-effectiveness ratio <$100,000/QALY. Policymakers and substance abuse treatment leaders should seek funding to implement on-site rapid HIV testing in substance abuse treatment programs for those not recently tested.
doi:10.1016/j.drugalcdep.2012.08.009
PMCID: PMC3546145  PMID: 22971593
Rapid HIV testing; substance use; cost-effectiveness
9.  Mobile HIV Screening in Cape Town, South Africa: Clinical Impact, Cost and Cost-Effectiveness 
PLoS ONE  2014;9(1):e85197.
Background
Mobile HIV screening may facilitate early HIV diagnosis. Our objective was to examine the cost-effectiveness of adding a mobile screening unit to current medical facility-based HIV testing in Cape Town, South Africa.
Methods and Findings
We used the Cost Effectiveness of Preventing AIDS Complications International (CEPAC-I) computer simulation model to evaluate two HIV screening strategies in Cape Town: 1) medical facility-based testing (the current standard of care) and 2) addition of a mobile HIV-testing unit intervention in the same community. Baseline input parameters were derived from a Cape Town-based mobile unit that tested 18,870 individuals over 2 years: prevalence of previously undiagnosed HIV (6.6%), mean CD4 count at diagnosis (males 423/µL, females 516/µL), CD4 count-dependent linkage to care rates (males 31%–58%, females 49%–58%), mobile unit intervention cost (includes acquisition, operation and HIV test costs, $29.30 per negative result and $31.30 per positive result). We conducted extensive sensitivity analyses to evaluate input uncertainty. Model outcomes included site of HIV diagnosis, life expectancy, medical costs, and the incremental cost-effectiveness ratio (ICER) of the intervention compared to medical facility-based testing. We considered the intervention to be “very cost-effective” when the ICER was less than South Africa's annual per capita Gross Domestic Product (GDP) ($8,200 in 2012). We projected that, with medical facility-based testing, the discounted (undiscounted) HIV-infected population life expectancy was 132.2 (197.7) months; this increased to 140.7 (211.7) months with the addition of the mobile unit. The ICER for the mobile unit was $2,400/year of life saved (YLS). Results were most sensitive to the previously undiagnosed HIV prevalence, linkage to care rates, and frequency of HIV testing at medical facilities.
Conclusion
The addition of mobile HIV screening to current testing programs can improve survival and be very cost-effective in South Africa and other resource-limited settings, and should be a priority.
doi:10.1371/journal.pone.0085197
PMCID: PMC3898963  PMID: 24465503
10.  Routine HIV Screening in Portugal: Clinical Impact and Cost-Effectiveness 
PLoS ONE  2013;8(12):e84173.
Objective
To compare the clinical outcomes and cost-effectiveness of routine HIV screening in Portugal to the current practice of targeted and on-demand screening.
Design
We used Portuguese national clinical and economic data to conduct a model-based assessment.
Methods
We compared current HIV detection practices to strategies of increasingly frequent routine HIV screening in Portuguese adults aged 18-69. We considered several subpopulations and geographic regions with varying levels of undetected HIV prevalence and incidence. Baseline inputs for the national case included undiagnosed HIV prevalence 0.16%, annual incidence 0.03%, mean population age 43 years, mean CD4 count at care initiation 292 cells/μL, 63% HIV test acceptance, 78% linkage to care, and HIV rapid test cost €6 under the proposed routine screening program. Outcomes included quality-adjusted survival, secondary HIV transmission, cost, and incremental cost-effectiveness.
Results
One-time national HIV screening increased HIV-infected survival from 164.09 quality-adjusted life months (QALMs) to 166.83 QALMs compared to current practice and had an incremental cost-effectiveness ratio (ICER) of €28,000 per quality-adjusted life year (QALY). Screening more frequently in higher-risk groups was cost-effective: for example screening annually in men who have sex with men or screening every three years in regions with higher incidence and prevalence produced ICERs of €21,000/QALY and €34,000/QALY, respectively.
Conclusions
One-time HIV screening in the Portuguese national population will increase survival and is cost-effective by international standards. More frequent screening in higher-risk regions and subpopulations is also justified. Given Portugal’s challenging economic priorities, we recommend prioritizing screening in higher-risk populations and geographic settings.
doi:10.1371/journal.pone.0084173
PMCID: PMC3867470  PMID: 24367639
11.  The Survival Benefits of Antiretroviral Therapy in South Africa 
The Journal of Infectious Diseases  2013;209(4):491-499.
Background. We sought to quantify the survival benefits attributable to antiretroviral therapy (ART) in South Africa since 2004.
Methods. We used the Cost-Effectiveness of Preventing AIDS Complications–International model (CEPAC) to simulate 8 cohorts of human immunodeficiency virus (HIV)–infected patients initiating ART each year during 2004–2011. Model inputs included cohort-specific mean CD4+ T-cell count at ART initiation (112–178 cells/µL), 24-week ART suppressive efficacy (78%), second-line ART availability (2.4% of ART recipients), and cohort-specific 36-month retention rate (55%–71%). CEPAC simulated survival twice for each cohort, once with and once without ART. The sum of the products of per capita survival differences and the total numbers of persons initiating ART for each cohort yielded the total survival benefits.
Results. Lifetime per capita survival benefits ranged from 9.3 to 10.2 life-years across the 8 cohorts. Total estimated population lifetime survival benefit for all persons starting ART during 2004–2011 was 21.7 million life-years, of which 2.8 million life-years (12.7%) had been realized by December 2012. By 2030, benefits reached 17.9 million life-years under current policies, 21.7 million life-years with universal second-line ART, 23.3 million life-years with increased linkage to care of eligible untreated patients, and 28.0 million life-years with both linkage to care and universal second-line ART.
Conclusions. We found dramatic past and potential future survival benefits attributable to ART, justifying international support of ART rollout in South Africa.
doi:10.1093/infdis/jit584
PMCID: PMC3903379  PMID: 24307741
HIV; South Africa; highly active antiretroviral therapy
12.  Home HIV Testing: Good News but Not a Game Changer 
Annals of internal medicine  2012;157(10):744-746.
doi:10.7326/0003-4819-157-10-201211200-00545
PMCID: PMC3661188  PMID: 23044643
13.  Economic savings versus health losses: The cost-effectiveness of generic antiretroviral therapy in the United States 
Annals of internal medicine  2013;158(2):84-92.
Background
US HIV treatment guidelines recommend branded once-daily, one-pill efavirenz/emtricitabine/tenofovir as preferred first-line antiretroviral treatment (ART). With the anticipated approval of generic efavirenz in 2012 in the US, the cost of a once-daily, three-pill alternative (generic efavirenz, generic lamivudine, tenofovir) will decrease, but adherence and virologic suppression may be reduced.
Objectives
To assess the clinical impact, costs, and cost-effectiveness of the generic-based three-pill regimen compared to the branded, co-formulated regimen. To project the potential national savings in the first year of a switch to generic-based ART.
Design
Mathematical simulation of HIV disease.
Data Sources
Published data from US clinical trials and observational cohorts.
Target Population
HIV-infected patients eligible to start on or switch to an efavirenz-based generic ART regimen.
Time Horizon
Lifetime, One-year
Perspective
US health system
Interventions
No ART (for comparison), Three-pill Generic ART, and Branded ART
Outcome Measures
Quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratios (ICER, $/quality-adjusted life expectancy [QALY]).
Results of Base-Case Analysis
Compared to No ART, Generic ART has an ICER of $21,100/QALY. Compared to Generic ART, Branded ART increases lifetime costs by $42,500, and per-person survival gains by 0.37 QALYs, for an ICER of $114,800/QALY. Estimated first-year savings, if all eligible US patients start on or switch to Generic ART, are $920 million.
Results of Sensitivity Analysis
Most plausible assumptions about Generic ART efficacy and costs lead to Branded ART ICERs >$100,000/QALY.
Limitations
The efficacy and price reduction associated with generics are unknown; estimates are intended to be conservative.
Conclusions
Compared to a slightly less effective generic-based regimen, the cost-effectiveness of first-line Branded ART exceeds $100,000/QALY. Generic-based ART in the US could yield substantial budgetary savings to HIV programs.
doi:10.7326/0003-4819-158-2-201301150-00002
PMCID: PMC3664029  PMID: 23318310
14.  The Cost-effectiveness of Pre-Exposure Prophylaxis for HIV Infection in South African Women 
As a long-term strategy to decrease HIV acquisition in South African women, pre-exposure prophylaxis is both effective, reducing lifetime risk of infection to 27%, and cost-effective, with an incremental cost-effectiveness ratio of $2700 per years of life saved.
Background. Recent trials report the short-term efficacy of tenofovir-based pre-exposure prophylaxis (PrEP) for prevention of human immunodeficiency virus (HIV) infection. PrEP’s long-term impact on patient outcomes, population-level transmission, and cost-effectiveness remains unknown.
Methods. We linked data from recent trials to a computer model of HIV acquisition, screening, and care to project lifetime HIV risk, life expectancy (LE), costs, and cost-effectiveness, using 2 PrEP-related strategies among heterosexual South African women: (1) women receiving no PrEP and (2) women not receiving PrEP (a tenofovir-based vaginal microbicide). We used a South African clinical cohort and published data to estimate population demographic characteristics, age-adjusted incidence of HIV infection, and HIV natural history and treatment parameters. Baseline PrEP efficacy (percentage reduction in HIV transmission) was 39% at a monthly cost of $5 per woman. Alternative parameter values were examined in sensitivity analyses.
Results. Among South African women, PrEP reduced mean lifetime HIV risk from 40% to 27% and increased population discounted (undiscounted) LE from 22.51 (41.66) to 23.48 (44.48) years. Lifetime costs of care increased from $7280 to $9890 per woman, resulting in an incremental cost-effectiveness ratio of $2700/year of life saved, and may, under optimistic assumptions, achieve cost savings. Under baseline HIV infection incidence assumptions, PrEP was not cost saving, even assuming an efficacy >60% and a cost <$1. At an HIV infection incidence of 9.1%/year, PrEP achieved cost savings at efficacies ≥50%.
Conclusions. PrEP in South African women is very cost-effective by South African standards, conferring excellent value under virtually all plausible data scenarios. Although optimistic assumptions would be required to achieve cost savings, these represent important benchmarks for future PrEP study design.
doi:10.1093/cid/cis225
PMCID: PMC3334365  PMID: 22474224
15.  Placing a Price on Medical Device Innovation: The Example of Total Knee Arthroplasty 
PLoS ONE  2013;8(5):e62709.
Background
Total knee arthroplasty (TKA) is common, effective, and cost-effective. Innovative implants promising reduced long-term failure at increased cost are under continual development. We sought to define the implant cost and performance thresholds under which innovative TKA implants are cost-effective.
Methods
We performed a cost-effectiveness analysis using a validated, published computer simulation model of knee osteoarthritis. Model inputs were derived using published literature, Medicare claims, and National Health and Nutrition Examination Survey data. We compared projected TKA implant survival, quality-adjusted life expectancy (QALE), lifetime costs, and cost-effectiveness (incremental cost-effectiveness ratios or ICERs) of standard versus innovative TKA implants. We assumed innovative implants offered 5–70% decreased long-term TKA failure rates at costs 20–400% increased above standard implants. We examined the impact of patient age, comorbidity, and potential increases in short-term failure on innovative implant cost-effectiveness.
Results
Implants offering ≥50% decrease in long-term TKA failure at ≤50% increased cost offered ICERs <$100,000 regardless of age or baseline comorbidity. An implant offering a 20% decrease in long-term failure at 50% increased cost provided ICERs <$150,000 per QALY gained only among healthy 50–59-year-olds. Increasing short-term failure, consistent with recent device failures, reduced cost-effectiveness across all groups. Increasing the baseline likelihood of long-term TKA failure among younger, healthier and more active individuals further enhanced innovative implant cost-effectiveness among younger patients.
Conclusions
Innovative implants must decrease actual TKA failure, not just radiographic wear, by 50–55% or more over standard implants to be broadly cost-effective. Comorbidity and remaining life span significantly affect innovative implant cost-effectiveness and should be considered in the development, approval and implementation of novel technologies, particularly in orthopedics. Model-based evaluations such as this offer valuable, unique insights for evaluating technological innovation in medical devices.
doi:10.1371/journal.pone.0062709
PMCID: PMC3646021  PMID: 23671626
16.  Impact of Program Scale and Indirect Effects on the Cost-Effectiveness of Vaccination Programs 
doi:10.1177/0272989X12441397
PMCID: PMC3570235  PMID: 22472916
scale dependency; herd protection; epidemiological model; resource allocation
18.  Predicting the Impact of a Partially Effective HIV Vaccine and Subsequent Risk Behavior Change on the Heterosexual HIV Epidemic in Low- and Middle-Income Countries A South African Example 
Summary
We developed a mathematical model to simulate the impact of various partially effective preventive HIV vaccination scenarios in a population at high risk for heterosexually transmitted HIV. We considered an adult population defined by gender (male/female), disease stage (HIV-negative, HIV-positive, AIDS, and death), and vaccination status (unvaccinated/vaccinated) in Soweto, South Africa. Input data included initial HIV prevalence of 20% (women) and 12% (men), vaccination coverage of 75%, and exclusive male negotiation of condom use. We explored how changes in vaccine efficacy and post-vaccination condom use would affect HIV prevalence and total HIV infections prevented over a 10-year period. In the base-case scenario, a 40% effective HIV vaccine would avert 61,000 infections and reduce future HIV prevalence from 20% to 13%. A 25% increase (or decrease) in condom use among vaccinated individuals would instead avert 75,000 (or only 46,000) infections and reduce the HIV prevalence to 12% (or only 15%). Furthermore, certain combinations of increased risk behavior and vaccines with <43% efficacy could worsen the epidemic. Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, programs to reduce risk behavior may be important components of successful vaccination campaigns.
doi:10.1097/QAI.0b013e31812506fd
PMCID: PMC3570247  PMID: 17589368
AIDS vaccines; mathematical models; sexual behavior; heterosexual transmission; Africa; condoms; models/projections
19.  SOCIAL COSTS OF ROBBERY AND THE COST-EFFECTIVENESS OF SUBSTANCE ABUSE TREATMENT 
Health economics  2008;17(8):927-946.
SUMMARY
Reduced crime provides a key benefit associated with substance abuse treatment (SAT). Armed robbery is an especially costly and frequent crime committed by some drug-involved offenders. Many studies employ valuation methods that understate the true costs of robbery, and thus the true social benefits of SAT-related robbery reduction. At the same time, regression to the mean and self-report bias may lead pre–post comparisons to overstate crime reductions associated with SAT.
Using 1992–1997 data from the National Treatment Improvement Evaluation Study (NTIES), we examined pre–post differences in self-reported robbery among clients in five residential and outpatient SAT modalities. Fixed-effect negative binomial regression was used to examine incidence rate reductions (IRR) in armed robbery. Published data on willingness to pay to avoid robbery were used to determine the social valuation of these effects. Differences in IRR across SAT modalities were explored to bound potential biases.
All SAT modalities were associated with large and statistically significant reductions in robbery. The average number of self-reported robberies declined from 0.83/client/year pre-entry to 0.12/client/year following SAT (p < 0.001). Under worst-case assumptions, monetized valuations of reductions in armed robbery associated with outpatient methadone and residential SAT exceeded economic costs of these interventions. Conventional wisdom posits the economic benefits of SAT. We find that SAT is even more beneficial than is commonly assumed.
doi:10.1002/hec.1305
PMCID: PMC3512566  PMID: 17992708
drug treatment; robbery; contingent valuation; cost-benefit; substance abuse
20.  Modeling the Potential Impact of a Prescription Drug Copayment Increase on the Adult Asthmatic Medicaid Population 
Objectives
The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries.
Method
We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model.
Results
In a target population of 17,500 adult asthmatics, increased copayments from 50¢ to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million.
Conclusion
Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders.
doi:10.1111/j.1524-4733.2007.00219.x
PMCID: PMC3476042  PMID: 18237365
asthma; copayment; medicaid; prescription drug
21.  Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model 
Background
Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.
Objective
We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.
Methods
We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).
Results
For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.
Conclusion
Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.
Clinical implications
Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.
doi:10.1016/j.jaci.2007.07.055
PMCID: PMC3476046  PMID: 17904628
Omalizumab; cost-effectiveness; asthma; anti-IgE
22.  The potential impact of an HIV vaccine with rapidly waning protection on the epidemic in Southern Africa: Examining the RV144 trial results 
Vaccine  2011;29(36):6107-6112.
Background
The prime-boost HIV vaccine regimen used in the recent RV144 trial resulted in modest efficacy of 31% over 3.5 years, but was substantially higher in the first year post-vaccination. We sought to explore the potential impact of a vaccine with rapidly waning efficacy in a South African population.
Methods
We explored two strategies using a dynamic compartmental epidemic model for heterosexual transmission of HIV: (1) vaccination of a single cohort (30%, 60% or 90% of the initial population), with potential booster vaccinations at 5-year or 2-year intervals over time, and (2) vaccination of the overall population at coverage levels (30%, 60% or 90%) that are constant over time, such that individuals are vaccinated or revaccinated to maintain effective coverage levels, given the rapidly waning protection of the vaccine. We also examined potential changes in post-vaccination condom use.
Results
The single cohort vaccination strategies did not have a substantial impact on HIV prevalence, although without boosters they still prevented 2–6% of the expected infections at 20 years, depending on the population coverage. The 5-year and 2-year booster strategies prevented 8–24% and 17–45% of the expected infections, respectively. The continuous vaccination strategies resulted in more substantial reductions in population HIV prevalence and greater numbers of infections prevented: HIV prevalence at 20 years was reduced from 23% to 8–14% and the number of expected infections was decreased by 34–59%, depending on the population coverage level. Moderate changes in post-vaccination condom use did not substantially affect these outcomes.
Conclusions
An HIV vaccine with partial efficacy and declining protection similar to the RV144 vaccine could prevent a substantial proportion of HIV infections if booster vaccinations were effective and available. Our estimates of the population impact of vaccination would be improved by further understanding of the duration of protection, the effectiveness of booster vaccination, and whether the vaccine efficacy varies between subpopulations at higher and lower risk of exposure.
doi:10.1016/j.vaccine.2011.06.076
PMCID: PMC3164284  PMID: 21736912
HIV vaccine; mathematical model; HIV prevention; South Africa; combination prevention
23.  Dengue vector control strategies in an urban setting: an economic modelling assessment 
Lancet  2011;377(9778):1673-1680.
Summary
Background
An estimated 2·5 billion people are at risk of dengue. Incidence of dengue is especially high in resource-constrained countries, where control relies mainly on insecticides targeted at larval or adult mosquitoes. We did epidemiological and economic assessments of different vector control strategies.
Methods
We developed a dynamic model of dengue transmission that assesses the evolution of insecticide resistance and immunity in the human population, thus allowing for long-term evolutionary and immunological effects of decreased dengue transmission. We measured the dengue health burden in terms of disability-adjusted life-years (DALYs) lost. We did a cost-effectiveness analysis of 43 insecticide-based vector control strategies, including strategies targeted at adult and larval stages, at varying efficacies (high-efficacy [90% mortality], medium-efficacy [60% mortality], and low-efficacy [30% mortality]) and yearly application frequencies (one to six applications). To assess the effect of parameter uncertainty on the results, we did a probabilistic sensitivity analysis and a threshold analysis.
Findings
All interventions caused the emergence of insecticide resistance, which, with the loss of herd immunity, will increase the magnitude of future dengue epidemics. In our model, one or more applications of high-efficacy larval control reduced dengue burden for up to 2 years, whereas three or more applications of adult vector control reduced dengue burden for up to 4 years. The incremental cost-effectiveness ratios of the strategies for two high-efficacy adult vector control applications per year was US$615 per DALY saved and for six high-efficacy adult vector control applications per year was $1267 per DALY saved. Sensitivity analysis showed that if the cost of adult control was more than 8·2 times the cost of larval control then all strategies based on adult control became dominated.
Interpretation
Six high-efficacy adult vector control applications per year has a cost-effectiveness ratio that will probably meet WHO's standard for a cost-effective or very cost-effective intervention. Year-round larval control can be counterproductive, exacerbating epidemics in later years because of evolution of insecticide resistance and loss of herd immunity. We suggest the reassessment of vector control policies that are based on larval control only.
Funding
The Fulbright Programme, CAPES (Brazilian federal agency for post-graduate education), the Miriam Burnett trust, and the Notsew Orm Sands Foundation.
doi:10.1016/S0140-6736(11)60246-8
PMCID: PMC3409589  PMID: 21546076
24.  Scaling Up Circumcision Programs in Southern Africa: The Potential Impact of Gender Disparities and Changes in Condom Use Behaviors on Heterosexual HIV Transmission 
AIDS and behavior  2011;15(5):938-948.
Circumcision significantly reduces female-to-male transmission of HIV infection, but changes in behavior may influence the overall impact on transmission. We sought to explore these effects, particularly for societies where women have less power to negotiate safe sex. We developed a compartmental epidemic model to simulate the population-level impact of various circumcision programs on heterosexual HIV transmission in Soweto. We incorporated gender-specific negotiation of condom use in sexual partnerships and explored post-circumcision changes in condom use. A 5-year prevention program in which only an additional 10% of uncircumcised males undergo circumcision each year, for example, would prevent 13% of the expected new HIV infections over 20 years. Outcomes were sensitive to potential changes in behavior and differed by gender. For Southern Africa, even modest programs offering circumcision would result in significant benefits. Because decreases in male condom use could diminish these benefits, particularly for women, circumcision programs should emphasize risk-reduction counseling.
doi:10.1007/s10461-010-9784-y
PMCID: PMC3112296  PMID: 20924783
Male circumcision; Mathematical models; HIV prevention; Africa; Sexual behavior
25.  Simulating school closure policies for cost effective pandemic decision making 
BMC Public Health  2012;12:449.
Background
Around the globe, school closures were used sporadically to mitigate the 2009 H1N1 influenza pandemic. However, such closures can detrimentally impact economic and social life.
Methods
Here, we couple a decision analytic approach with a mathematical model of influenza transmission to estimate the impact of school closures in terms of epidemiological and cost effectiveness. Our method assumes that the transmissibility and the severity of the disease are uncertain, and evaluates several closure and reopening strategies that cover a range of thresholds in school-aged prevalence (SAP) and closure durations.
Results
Assuming a willingness to pay per quality adjusted life-year (QALY) threshold equal to the US per capita GDP ($46,000), we found that the cost effectiveness of these strategies is highly dependent on the severity and on a willingness to pay per QALY. For severe pandemics, the preferred strategy couples the earliest closure trigger (0.5% SAP) with the longest duration closure (24 weeks) considered. For milder pandemics, the preferred strategies also involve the earliest closure trigger, but are shorter duration (12 weeks for low transmission rates and variable length for high transmission rates).
Conclusions
These findings highlight the importance of obtaining early estimates of pandemic severity and provide guidance to public health decision-makers for effectively tailoring school closures strategies in response to a newly emergent influenza pandemic.
doi:10.1186/1471-2458-12-449
PMCID: PMC3495022  PMID: 22713694

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