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.

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.

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.

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.

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.

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.

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.

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.

Background

Although the Centers for Disease Control and Prevention recommends HIV testing in all settings unless patients refuse (opt-out consent), many state laws require written opt-in consent.

Objective

To quantify potential survival gains from passing state laws streamlining HIV testing consent.

Design

We retrieved surveillance data to estimate the current annual HIV diagnosis rate in states with laws requiring written opt-in consent (19.3%). Published data informed the effect of removing that requirement on diagnosis rate (48.5% increase). These parameters then served as input for a model-driven projection of survival based on consent method. Other inputs included undiagnosed HIV prevalence (0.101%); and annual HIV incidence (0.023%).

Patients

Hypothetical cohort of adults (>13 years) living in written opt-in states.

Measurements

Life years gained (LYG).

Results

In the base-case, of the 53,036,383 adult persons living in written opt-in states, 0.66% (350,040) will be infected with HIV. Due to earlier diagnosis, revised consent laws yield 1.5 LYG per HIV-infected person, corresponding to 537,399 LYG among this population. Sensitivity analyses demonstrate that diagnosis rate increases of 24.8-72.3% result in 304,765–724,195 LYG. Net survival gains vanish if the proportion of HIV-infected persons refusing all testing in response to revised laws exceeds 18.2%.

Conclusions

The potential survival gains of increased testing are substantial, suggesting that state laws requiring opt-in HIV testing should be revised.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-011-1637-5) contains supplementary material, which is available to authorized users.

Background

Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years.

Objective

To estimate quality-adjusted life-years lost due to obesity and knee osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago.

Design

The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group.

Setting

United States.

Participants

U.S. population aged 50 to 84 years.

Measurements

Quality-adjusted life-years lost owing to knee osteoarthritis and obesity.

Results

Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178 071 cases of coronary heart disease, 889 872 cases of diabetes, and 111 206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6 318 030 years and improve life expectancy by 7 812 120 quality-adjusted years in U.S. adults aged 50 to 84 years.

Limitations

Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources.

Conclusion

The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits.

Primary Funding Source

The National Institutes of Health and the Arthritis Foundation.

Background

Although 900,000 HIV-infected South Africans receive antiretroviral therapy (ART), the majority of South Africans with HIV remain undiagnosed.

Methods

We use a published simulation model of HIV case detection and treatment to examine three HIV screening scenarios, in addition to current practice: 1) one-time; 2) every five years; and 3) annually. South African model input data include: 16.9% HIV prevalence, 1.3% annual incidence, 49% test acceptance rate, HIV testing costs of $6.49/patient, and a 47% linkage-to-care rate (including two sequential ART regimens) for identified cases. Outcomes include life expectancy, direct medical costs, and incremental cost-effectiveness.

Results

HIV screening one-time, every five years, and annually increase HIV-infected quality-adjusted life expectancy (mean age 33 years) from 180.6 months (current practice) to 184.9, 187.6 and 197.2 months. The incremental cost-effectiveness of one-time screening is dominated by screening every five years. Screening every five years and annually each have incremental cost-effectiveness ratios of $1,570/quality-adjusted life year (QALY) and $1,720/QALY. Screening annually is very cost-effective even in settings with the lowest incidence/prevalence, with test acceptance and linkage rates both as low as 20%, or when accounting for a stigma impact at least four-fold that of the base case.

Conclusions

In South Africa, annual voluntary HIV screening offers substantial clinical benefit and is very cost-effective, even with highly constrained access to care and treatment.

Objective

The US Centers for Disease Control and Prevention (CDC) recently revised their HIV screening guidelines to promote testing and earlier entry to care. Prior analyses have examined the policy’s cost-effectiveness but have not evaluated its impact on government budgets.

Methods

We used a simulation model of HIV screening, disease, and treatment to determine the budget impact of expanded HIV screening to US government discretionary, entitlement, and testing programs. We estimated total and incremental testing and treatment costs over a five-year time horizon under current and expanded screening scenarios. We used CDC estimates of HIV prevalence and annual incidence, and considered variations in screening frequency, test return rates, linkage to care, test characteristics, and eligibility for government screening and treatment programs.

Results

Under current practice, 177,000 new HIV cases will be identified over five years. Expanded screening will identify an additional 46,000 cases at an incremental five-year cost of $2.7 billion. The financial burden of expanded HIV screening will fall disproportionately on discretionary programs that fund care for newly identified patients and will not be offset by entitlement program savings. Testing will represent a small proportion (18%) of the total budget increase. Costs are sensitive to the frequency of screening and the proportion linked to care.

Conclusions

The expanded HIV screening program will have a large downstream impact on government programs that fund HIV care. Expanded HIV screening will not meet early treatment goals unless government programs have sufficient budgets to expand testing and provide care for newly-identified cases.

Background

Revised World Health Organization recommendations seek to increase HIV testing. We assessed the need for expanded testing in South Africa by examining current testing and treatment trends among a high-prevalence population.

Methods

We determined the numbers of adults receiving HIV testing and antiretroviral treatment (ART) during 2001–2006 using testing registers linked to patient records from two healthcare facilities believed responsible for virtually all HIV services available to the population. We evaluated annual population testing rates using census population counts; proportions of clients testing seropositive (yield); CD4 counts and WHO stage at diagnosis; and ART initiation rates.

Results

HIV testing rates rose from 4% in 2001 to 20% in 2006 (p<0.001) and were highest among pregnant females receiving provider-initiated testing. Yield for first-time testers decreased from 47% in 2001 to 28% in 2006. Median CD4 counts and WHO stage distributions for newly-diagnosed clients remained stable. HIV-infected clients receiving ART within six months of eligibility increased from 0% in 2001 to 68% in 2006 (p<0.001).

Conclusions

Population testing and ART initiation rates rose dramatically during 2001–2006. Yet, yield remained high and HIV-infected persons continued to receive late diagnoses. These findings highlight the continuing need for expanded testing and linkage to care.

Background

Routine HIV screening in emergency department (ED) settings may require dedicated personnel. We evaluated the outcomes, costs and cost-effectiveness of HIV screening when offered by either a member of the ED staff or by an HIV counselor.

Methods

We employed a mathematical model to extend data obtained from a randomized clinical trial of provider- vs. counselor-based HIV screening in the ED. We compared the downstream survival, costs, and cost-effectiveness of three HIV screening modalities: 1) no screening program; 2) an ED provider-based program; and 3) an HIV counselor-based program. Trial arm-specific data were used for test offer and acceptance rates (provider offer 36%, acceptance 75%; counselor offer 80%, acceptance 71%). Undiagnosed HIV prevalence (0.4%) and linkage to care rates (80%) were assumed to be equal between the screening modalities. Personnel costs were derived from trial-based resource utilization data. We examined the generalizability of results by conducting sensitivity analyses on offer and acceptance rates, undetected HIV prevalence, and costs.

Results

Estimated HIV screening costs in the provider and counselor arms averaged $8.10 and $31.00 per result received. The Provider strategy (compared to no screening) had an incremental cost-effectiveness ratio of $58,700/quality-adjusted life year (QALY) and the Counselor strategy (compared to the Provider strategy) had an incremental cost-effectiveness ratio of $64,500/QALY. Results were sensitive to the relative offer and acceptance rates by strategy and the capacity of providers to target-screen, but were robust to changes in undiagnosed HIV prevalence and programmatic costs.

Conclusions

The cost-effectiveness of provider-based HIV screening in an emergency department setting compares favorably to other US screening programs. Despite its additional cost, counselor-based screening delivers just as much return on investment as provider based-screening. Investment in dedicated HIV screening personnel is justified in situations where ED staff resources may be insufficient to provide comprehensive, sustainable screening services.

Background

US and international agencies have signaled their commitment to containing the HIV epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately upon diagnosis. We forecast outcomes of this approach if implemented in Washington DC.

Methods

Using a mathematical model of HIV case detection and treatment, we evaluate combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at ≤350/μl, and test and treat as annual screening and ART upon diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA. Data, largely from DC, include undiagnosed HIV prevalence 0.6%, annual incidence 0.13%, 31% test offer, 60% acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses.

Results

Projected life expectancies, from an initial mean age 41 years, for current practice, test and treat, and test and treat with optimized ART are 23.9, 25.0, and 25.6 years. Compared to current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA in the next 5 years; test and treat with optimized ART results in a 27.2% reduction.

Conclusions

An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next five years and is unlikely to halt the HIV epidemic.

Summary

The CEPAC model shows a test and treat strategy in Washington DC would result in a substantial clinical impact to HIV-infected individuals. Results suggest a need to temper expectations regarding the extent to which test and treat will control the epidemic.

Background

Results of international clinical trials assessing when to initiate antiretroviral therapy (ART) will not be available for several years.

Objective

To inform HIV treatment decisions over the short- and long-term regarding the optimal CD4 threshold at which to initiate ART in South Africa, while awaiting “when to start” trial results.

Design

Cost-effectiveness analysis using a computer simulation model of HIV disease.

Data Sources

Published data from randomized trials and observational cohorts in South Africa.

Target Population

HIV-infected patients in South Africa.

Time Horizon

Five-year and lifetime.

Perspective

Modified societal.

Interventions

No treatment, initiate ART at CD4<250/μl, and initiate ART at CD4<350/μl.

Outcome Measures

Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness.

Results of Base-Case Analysis

If 10-100% of HIV-infected patients are diagnosed and linked to care, initiating ART at CD4<350/μl would reduce severe opportunistic diseases by 22,000-221,000 and deaths by 25,000-253,000 during the next 5 years, compared to initiating ART at CD4<250/μl; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART strategy increased long-term survival by at least 7.9 years, with a mean per person life expectancy of 3.8 years for no ART and 12.5 years for ART at <350/μl. Compared to initiating ART at <250/μl, initiating ART at <350/μl had an incremental cost-effectiveness ratio of $1,200/year of life saved.

Results of Sensitivity Analysis

Initiating ART at CD4<350/μl remained cost-effective over the next 5 years even if the probability that the trial would demonstrate superiority to earlier therapy is as low as 17%.

Limitations

This model does not consider the possible benefits of ART initiation at CD4>350/μl nor reduced HIV transmission.

Conclusions

Earlier ART initiation in South Africa will likely reduce morbidity and mortality, improve long-term survival, and be very cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow for earlier ART initiation (CD4<350/μl) than is currently recommended.

The Food and Drug Administration (FDA) is considering approval of an over-the-counter, rapid HIV test for home use. To support its decision, the FDA seeks evidence of the test’s performance. It has asked the manufacturer to conduct field studies of the test’s sensitivity and specificity when employed by untrained users. In this paper, we argue that additional information should be sought to evaluate the prevalence of undetected HIV in the end-user population. Our analytic framework produces the elementary but counterintuitive finding that the performance of the home HIV test – measured in terms of its ability to correctly detect the presence and absence of HIV infection among the people who purchase it – depends critically on the manufacturer’s retail price. This finding has profound implications for the FDA’s approval process.

Rochelle Walensky and colleagues use a model-based analysis to examine which of the 2010 WHO antiretroviral therapy guidelines should be implemented first in resource-limited settings by ranking them according to survival, cost-effectiveness, and equity.

Background

The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4<350 cells/µl instead of CD4<200 cells/µl), multiple sequential ART regimens, and replacement of first-line stavudine with tenofovir. This paper considers what to do first in resource-limited settings where immediate implementation of all of the WHO recommendations is not feasible.

Methods and Findings

We use a mathematical model and local input data to project clinical and economic outcomes in a South African HIV-infected cohort (mean age = 32.8 y, mean CD4 = 375/µl). For the reference strategy, we assume that all patients initiate stavudine-based ART with WHO stage III/IV disease and receive one line of ART (stavudine/WHO/one-line). We rank—in survival, cost-effectiveness, and equity terms—all 12 possible combinations of the following: (1) stavudine replacement with tenofovir, (2) ART initiation (by WHO stage, CD4<200 cells/µl, or CD4<350 cells/µl), and (3) one or two regimens, or lines, of available ART. Projected life expectancy for the reference strategy is 99.0 mo. Considering each of the guideline components separately, 5-y survival is maximized with ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, 87% survival) compared with stavudine/WHO/two-lines (66%) and tenofovir/WHO/one-line (66%). The greatest life expectancies are achieved via the following stepwise programmatic additions: stavudine/<350/µl/one-line (124.3 mo), stavudine/<350/µl/two-lines (177.6 mo), and tenofovir/<350/µl/two-lines (193.6 mo). Three program combinations are economically efficient: stavudine/<350/µl/one-line (cost-effectiveness ratio, US$610/years of life saved [YLS]), tenofovir/<350/µl/one-line (US$1,140/YLS), and tenofovir/<350/µl/two-lines (US$2,370/YLS).

Conclusions

In settings where immediate implementation of all of the new WHO treatment guidelines is not feasible, ART initiation at CD4<350 cells/µl provides the greatest short- and long-term survival advantage and is highly cost-effective.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Since 1981, acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people, and about 33 million people (30 million of them in low- and middle-income countries) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections (so-called opportunistic infections). Early in the AIDS epidemic, most people with HIV died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—a combination of several powerful antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians care for people with HIV by prescribing ART regimens tailored to each individual's needs. They also regularly measure the amount of virus in their patients' blood, test for antiretroviral-resistant viruses, and monitor the health of their patients' immune systems through regular CD4 cell counts. As a result, the life expectancy of patients with HIV in developed countries has dramatically improved.

Why Was This Study Done?

Initially, resource-limited countries could not afford to provide ART for their populations, and the life expectancy of HIV-positive people remained low. Now, through the concerted efforts of governments, the World Health Organization (WHO), and other international agencies, more than a third of the people in low- and middle-income countries who need ART are receiving it. However, many without access are still in need of ART, and ART programs in developing countries follow a public-health approach rather than an individualized approach. That is, drug regimens, clinical decision-making, and disease monitoring are all standardized and follow recommendations in the 2006 WHO ART guidelines. This year (2010), these guidelines were revised. The guidelines now recommend the following: earlier ART initiation—when the CD4 count falls below 350/µl of blood, instead of below 200/µl as in the 2006 guidelines; the provision of sequential ART regimens instead of a single regimen; and the replacement of the antiretroviral drug stavudine with tenofovir, a less toxic but more expensive drug, in first-line ART regimens. However, many resource-limited countries are still struggling to implement the 2006 guidelines, so which of these new recommendations should be prioritized? Here, the researchers use a mathematical model to address this question.

What Did the Researchers Do and Find?

The Cost Effectiveness of AIDS Complications (CEPAC)–International model simulates the natural history and treatment of HIV disease. The researchers entered South African clinical and cost data for HIV treatment into this model and then used it to project survival and costs in a hypothetical group of South African HIV-positive patients under alternative guideline prioritization scenarios. The reference strategy for the simulations (denoted as “stavudine/WHO/one-line”) assumed that patients (with a mean CD4 count of 375/µl) began a single stavudine-based ART regimen when they developed WHO stage III/IV HIV disease (i.e., when patients develop multiple opportunistic infections such as tuberculosis and pneumonia). When the new guideline recommendations were considered separately, ART initiation at CD4<350/µl (stavudine/<350/µl/one-line) maximized five-year survival. Stepwise adjustment from the reference strategy (which had a life expectancy 99.0 months) through strategies of stavudine/<350/µl/one-line (a projected life expectancy of 124.3 months), stavudine/<350/µl/two-lines (177.6 months), and tenofovir/<350/µl/two-lines (193.6 months) produced the greatest improvements in life expectancy. Finally, strategies of stavudine/<350/µl/one-line, tenofovir/<350/µl/one-line, and tenofovir/<350µl/two-lines produced incremental cost-effectiveness ratios of US$610, US$1,140, and US$2,370 per year of life saved, respectively.

What Do These Findings Mean?

As with all mathematical models, the accuracy of these findings are dependent on the assumptions included in the model and on the data populating it. Nevertheless, these findings suggest that, where resources are limited and immediate implementation of all the new WHO recommendations is impossible, ART initiation at a CD4 count of less than 350/µl would provide the greatest survival advantage and would be very cost-effective. In countries that are already initiating ART at this threshold and that have access to CD4 monitoring, a switch from stavudine to tenofovir would further increase survival and would also be cost-effective. Finally, although access to second-line ART regimen would provide more clinical benefits than access to tenofovir, the cost of this change in strategy would be substantially greater. Importantly, these findings should help to avoid the complete dismissal of the revised WHO guidelines on the basis of cost and should help policy makers adjust their ART program strategies to maximize their clinical benefits and cost effectiveness.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000382.

Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS

HIV InSite has comprehensive information on all aspects of HIV/AIDS

Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV/AIDS in South Africa and on HIV/AIDS treatment and care (in English and Spanish)

WHO provides information about universal access to AIDS treatment (in English, French, and Spanish); its 2010 ART guidelines can be downloaded

More information on the CEPAC model is available

Background

Most HIV-infected persons in the US present to care with advanced disease and many discontinue therapy prematurely. We sought to evaluate gender and racial/ethnic disparities in life-years lost due to risk behavior, late presentation and early discontinuation of HIV care, and to compare these survival losses in HIV-infected persons with losses from high-risk behavior and HIV disease itself.

Methods

Using a state-transition model of HIV disease, we simulated cohorts of HIV-infected persons and compared them to non-infected individuals with similar demographic characteristics. We estimated non-HIV-related mortality using risk-adjusted standardized mortality ratios as well as years of life lost due to late presentation and early discontinuation of antiretroviral therapy (ART) for HIV infection. Data from the national HIV Research Network, stratified by gender and race/ethnicity, were used for estimating CD4 counts at ART initiation.

Results

In HIV-uninfected persons in the US with risk profiles similar to those with HIV, the projected life expectancy starting at age 33 was 34.58 years, compared to 42.91 years for the general US population. Those with HIV lost an additional 11.92 years if they received HIV care concordant with guidelines; late treatment initiation resulted in 2.60 additional years of life lost, while premature ART discontinuation led to 0.70 more years of life lost. Losses from late initiation and early discontinuation were greatest for Hispanics (3.90 years).

Conclusions

The high-risk profile of HIV-infected persons, HIV infection itself, as well as late initiation and early discontinuation of care, all lead to substantial decreases in life expectancy. Survival disparities from late initiation and early discontinuation are most pronounced for Hispanic HIV-infected men and women. Interventions focused on risk behaviors as well as earlier linkage and better retention in care will lead to improved survival of HIV-infected persons in the US.

Background

In France, roughly 40,000 HIV-infected persons are unaware of their HIV infection. Although previous studies have evaluated the cost-effectiveness of routine HIV screening in the United States, differences in both the epidemiology of infection and HIV testing behaviors warrant a setting-specific analysis for France.

Methods/Principal Findings

We estimated the life expectancy (LE), cost and cost-effectiveness of alternative HIV screening strategies in the French general population and high-risk sub-populations using a computer model of HIV detection and treatment, coupled with French national clinical and economic data. We compared risk-factor-based HIV testing (“current practice”) to universal routine, voluntary HIV screening in adults aged 18–69. Screening frequencies ranged from once to annually. Input data included mean age (42 years), undiagnosed HIV prevalence (0.10%), annual HIV incidence (0.01%), test acceptance (79%), linkage to care (75%) and cost/test (€43). We performed sensitivity analyses on HIV prevalence and incidence, cost estimates, and the transmission benefits of ART. “Current practice” produced LEs of 242.82 quality-adjusted life months (QALM) among HIV-infected persons and 268.77 QALM in the general population. Adding a one-time HIV screen increased LE by 0.01 QALM in the general population and increased costs by €50/person, for a cost-effectiveness ratio (CER) of €57,400 per quality-adjusted life year (QALY). More frequent screening in the general population increased survival, costs and CERs. Among injection drug users (prevalence 6.17%; incidence 0.17%/year) and in French Guyana (prevalence 0.41%; incidence 0.35%/year), annual screening compared to every five years produced CERs of €51,200 and €46,500/QALY.

Conclusions/Significance

One-time routine HIV screening in France improves survival compared to “current practice” and compares favorably to other screening interventions recommended in Western Europe. In higher-risk groups, more frequent screening is economically justifiable.

Background

The combination of tenofovir and emtricitabine (TDF/FTC) shows promise as HIV pre-exposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, risk of resistance and toxicity, behavioral disinhibition, and drug costs.

Methods

We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP in high-risk (1.6% average annual HIV incidence) men who have sex with men (MSM) in the United States. Base case assumptions included: 50% PrEP efficacy and $753 monthly TDF/FTC costs. We used sensitivity analyses to examine the stability of results and to identify critical input parameters.

Results

In a cohort with mean age 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased average life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted, quality-adjusted life-years or QALYs). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio (ICER) of $298,000 per QALY gained. Markedly larger reductions in lifetime infection risk (from 43.5% to 5.8%) were observed assuming greater (90%) PrEP efficacy. More favorable ICERs were obtained by targeting younger, higher-incidence populations and with improvements in the efficacy and cost of PrEP.

Conclusions

PrEP could substantially reduce HIV transmission in high-risk populations in the United States. Although it is unlikely to confer sufficient benefits to justify current TDF/FTC costs, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger or higher-risk populations. Given recent disappointments in HIV prevention and vaccine development, further study of PrEP-based HIV prevention is warranted.

Objective

Meniscal tears and osteoarthritis (OA) frequently coexist, but to our knowledge, no data exist to identify who will benefit from arthroscopic partial meniscectomy (APM) versus nonoperative management. Our objective was to evaluate the capability of preoperative information to predict APM outcomes in OA.

Methods

Using a mathematical model and published data, we combined 2 clinical (mechanical symptoms and pain pattern) and 2 magnetic resonance imaging (tear type and bone marrow lesions) indicators into 36 possible combinations and ranked each combination according to the likelihood of having primarily tear- versus OA-related pain in individuals ages 45–65 years with knee pain, OA, and meniscal tears. By considering alternative thresholds for performing APM, we identified the cutoff rank that maximized the overall population International Knee Documentation Committee (IKDC) score (0–100 scale).

Results

Rank 1 (e.g., displaced tear, locking, increased pain, no bone marrow lesions) represented the highest likelihood of APM benefit; rank 36 (e.g., oblique tear, no mechanical symptoms, static pain, severe bone marrow lesions) represented the lowest likelihood of APM benefit. Indeterminate middle ranks included individuals with mixed findings (i.e., 2 findings consistent with high and 2 with low likelihood of APM benefit). APM thresholds between ranks 17 and 23 resulted in >82% of the population receiving treatment producing the greatest possible IKDC improvement, with mean incremental gains in IKDC score of >24 points. Findings were robust across a broad range of indicator assumptions, but were sensitive to outcome assumptions.

Conclusion

Among individuals with degenerative meniscal tears and OA, easily obtainable clinical information can differentiate those who are more likely to benefit from APM.

Background

Total knee arthroplasty (TKA) relieves pain and improves quality of life for persons with advanced knee osteoarthritis. However, to our knowledge, the cost-effectiveness of TKA and the influences of hospital volume and patient risk on TKA cost-effectiveness have not been investigated in the United States.

Methods

We developed a Markov, state-transition, computer simulation model and populated it with Medicare claims data and cost and outcomes data from national and multinational sources. We projected lifetime costs and quality-adjusted life expectancy (QALE) for different risk populations and varied TKA intervention and hospital volume. Cost-effectiveness of TKA was estimated across all patient risk and hospital volume permutations. Finally, we conducted sensitivity analyses to determine various parameters’ influences on cost-effectiveness.

Results

Overall, TKA increased QALE from 6.822 to 7.957 quality-adjusted life years (QALYs). Lifetime costs rose from $37 100 (no TKA) to $57 900 after TKA, resulting in an incremental cost-effectiveness ratio of $18 300 per QALY. For high-risk patients, TKA increased QALE from 5.713 to 6.594 QALY, yielding a cost-effectiveness ratio of $28 100 per QALY. At all risk levels, TKA was more costly and less effective in low-volume centers than in high-volume centers. Results were insensitive to variations of key input parameters within policy-relevant, clinically plausible ranges. The greatest variations were seen for the quality of life gain after TKA and the cost of TKA.

Conclusions

Total knee arthroplasty appears to be cost-effective in the US Medicare-aged population, as currently practiced across all risk groups. Policy decisions should be made on the basis of available local options for TKA. However, when a high-volume hospital is available, TKAs performed in a high-volume hospital confer even greater value per dollar spent than TKAs performed in low-volume centers.

Based on data from West Africa, Elena Losina and colleagues predict that interventions to reduce dropout rates from HIV treatment programs (such as eliminating copayments) will be cost-effective.

Background

Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa.

Methods and Findings

We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of <3× gross domestic product per capita (3× GDP per capita = US$2,823 for Côte d'Ivoire) as a plausible threshold for “cost-effectiveness.” The main results are based on a reported 18% 1-y LTFU rate. With full retention in care, projected per-person discounted life expectancy starting from age 37 y was 144.7 mo (12.1 y). Survival losses from LTFU within 1 y of ART initiation ranged from 73.9 to 80.7 mo. The intervention costing US$22/person/year (e.g., eliminating ART co-payment) would be cost-effective with an efficacy of at least 12%. An intervention costing US$77/person/year (inclusive of all the components described above) would be cost-effective with an efficacy of at least 41%.

Conclusions

Interventions that prevent LTFU in resource-limited settings would substantially improve survival and would be cost-effective by international criteria with efficacy of at least 12%–41%, depending on the cost of intervention, based on a reported 18% cumulative incidence of LTFU at 1 y after ART initiation. The commitment to start ART and treat HIV in these settings should include interventions to prevent LTFU.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981. Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. Two-thirds of people infected with HIV live in sub-Saharan Africa. HIV infects and destroys immune system cells, thereby weakening the immune system and rendering infected individuals susceptible to infection. There is no cure for HIV/AIDS. Combination antiretroviral therapy (ART), a mixture of antiretroviral drugs that suppress the replication of the virus in the body, is used to treat and prevent HIV infection. ART is expensive but major international efforts by governments, international organizations, and funding bodies have increased ART availability. According to World Health Organization (WHO) estimates, at least 9.7 million people in low- and middle-income countries need ART and as of 2007, 3 million of those people had reliable access to the drugs.

Why Was This Study Done?

Although ART is an effective treatment for HIV, a large number of individuals who initiate ART do not receive long-term follow-up care. These patients are generally sicker and have a worse long-term outcome than those who receive follow-up care. Loss to follow up (LTFU) is a significant problem that can undermine the benefits of expanding ART availability. Strategies to improve follow up concentrate on bringing lost patients back into the health care system, but such patients often die before they can be contacted. Prevention of LTFU might be a better strategy to improve HIV care after ART initiation, but there is little information available on which specific interventions might best accomplish this goal.

What Did the Researchers Do and Find?

Given the lack of reported data on the actual costs and effectiveness of LTFU prevention, the researchers used a model to estimate the clinical impact and cost-effectiveness of several possible strategies to prevent LTFU in HIV-infected persons receiving ART in Côte d'Ivoire, West Africa. The researchers used the previously developed Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model and combined it with data from a program of ART delivery in Abidjan, Côte d'Ivoire. They then projected the clinical benefits and the cost required to attain a given level of benefit (cost-effectiveness ratio) of different LTFU-prevention strategies from the perspective of the payer (the organization that pays all the medical costs to provide care). Several interventions were considered, including reducing costs to patients (eliminating patient co-payments and paying for transportation) and increasing services to patients at their visits (improving staff training in HIV care, and providing meals at clinic times). LTFU was predicted to cause a 54.3%–58.3% reduction in the estimated life expectancy beyond age 37; patients continuing HIV care were predicted to live a further 144.7 months whie those lost to follow up by 1 year after ART initiation were predicted to live only for a further 73.9–80.7 months. LTFU-prevention strategies in the Côte d'Ivoire were deemed to be cost-effective if they cost less than $2,823 (which is 3× gross domestic product per capita) per year of life saved. The efficacy and cost of the different LTFU-prevention strategies varied in the analyses; stopping ART co-payment alone would be cost-effective at a cost of $22/person/year if it reduced LTFU rates by 12%, while including all the LTFU-prevention strategies described would be cost-effective at $77/person/year if they reduced LTFU-rates by 41%.

What Do These Findings Mean?

The findings suggest that moderately effective strategies for preventing LTFU in resource-limited settings would improve survival, provide good value for money, and should be used to improve HIV treatment programs. Although modeling is valuable to explore the costs and effectiveness of LTFU-prevention strategies it cannot replace the need for more reported data to shed light on problems leading to LTFU and the prevention strategies required to combat it. Also, Côte d'Ivoire might not be representative of all West African countries or resource-limited settings. A similar analysis using data from other ART programs in different countries would be useful to provide better understanding of the impact of LTFU in HIV treatment programs. Finally, the research highlights the cost of second-line ART (a new antiretroviral drug combination for patients in whom first-line treatment fails) as a crucial issue. It is estimated that 5% of all people receiving ART in low- and middle-income countries receive second-line ART and these numbers are expected to increase. Second-line ART had major effects on cost-effectiveness, and a reduction in the cost of this treatment is critical in order to guarantee continued access to HIV treatment.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000173.

This study is further discussed in a PLoS Medicine Perspective by Gregory Bisson and Jeffrey Stringer

WHO provides information on disease prevention, treatment, and HIV/AIDS programs and projects

The UN Millennium Development Goals project site contains information on worldwide efforts to halt the spread of HIV/AIDS

aidsmap, a nonprofit, nongovernmental organization, provides information on HIV and supporting those living with HIV