Faculty Bibliography

ABSTRACT: BACKGROUND: Updated World Health Organization guidelines have amplified debate about how resource constraints should impact monitoring strategies for HIV-infected persons on combination antiretroviral therapy (cART). We estimated the incremental benefit and cost effectiveness of alternative monitoring strategies for east Africans with known HIV infection. METHODS: Using a validated HIV computer simulation based on resource-limited data (USAID and AMPATH) and circumstances (east Africa), we compared alternative monitoring strategies for HIV-infected persons newly started on cART. We evaluated clinical, immunologic and virologic monitoring strategies, including combinations and conditional logic (e.g., only perform virologic testing if immunologic testing is positive). We calculated incremental cost-effectiveness ratios (ICER) in units of cost per quality-adjusted life year (QALY), using a societal perspective and a lifetime horizon. Costs were measured in 2008 US dollars, and costs and benefits were discounted at 3%. We compared the ICER of monitoring strategies with those of other resource-constrained decisions, in particular earlier cART initiation (at CD4 counts of 350 cells/mm3 rather than 200 cells/mm3). RESULTS: Monitoring strategies employing routine CD4 testing without virologic testing never maximized health benefits, regardless of budget or societal willingness to pay for additional health benefits. Monitoring strategies employing virologic testing conditional upon particular CD4 results delivered the most benefit at willingness-to-pay levels similar to the cost of earlier cART initiation (approximately $2600/QALY). Monitoring strategies employing routine virologic testing alone only maximized health benefits at willingness-to-pay levels (> $4400/QALY) that greatly exceeded the ICER of earlier cART initiation. CONCLUSIONS: CD4 testing alone never maximized health benefits regardless of resource limitations. Programmes routinely performing virologic testing but deferring cART initiation may increase health benefits by reallocating monitoring resources towards earlier cART initiation

Many consumers and clinicians incorrectly believe that the Food and Drug Administration (FDA) approval of a new therapeutic implies that its benefits have been proven to exceed its harms. While the FDA could require proof that benefits exceed harms prior to approval, it has been argued that this approach would be infeasible because of prohibitively large sample sizes. One possible alternative would be for the FDA to supplement its standard 'label' denoting 'safe and effective' with a secondary 'label' denoting benefits have been demonstrated to exceed harms, which would be granted only after sufficient post-marketing data had accumulated to prove that its benefits exceeded its harms. This secondary label would not necessarily be linked to marketing restrictions or other commercial prohibitions but, rather, would be only information for consumers and clinicians. Strengths, weaknesses, and feasibility challenges of this approach are discussed

BACKGROUND: Early, aggressive treatment of rheumatoid arthritis (RA) improves outcomes but confers increased risk. Risk stratification to target aggressive treatment of high-risk individuals with early RA is considered important to optimize outcomes while minimizing clinical and monetary costs. Some advocate the addition of magnetic resonance imaging (MRI) to standard RA risk stratification with clinical markers for patients early in the disease course. Our objective was to determine the incremental cost-effectiveness of adding MRI to standard risk stratification in early RA. METHODS: Using a decision analysis model of standard risk stratification with or without MRI, followed by escalated standard treatment protocols based on treatment response, we estimated 1-year and lifetime quality-adjusted life-years, RA-related costs, and incremental cost-effectiveness ratios (with MRI vs without MRI) for RA patients with fewer than 12 months of disease and no baseline radiographic erosions. Inputs were derived from the published literature. We assumed a societal perspective with 3.0% discounting. RESULTS: One-year and lifetime incremental cost-effectiveness ratios for adding MRI to standard testing were $204,103 and $167,783 per quality-adjusted life-year gained, respectively. In 1-way sensitivity analyses, model results were insensitive to plausible ranges for every variable except MRI specificity, which published data suggest is below the threshold for MRI cost-effectiveness. In probabilistic sensitivity analyses, most simulations produced lifetime incremental cost-effectiveness ratios in excess of $100,000 per quality-adjusted life-year gained, a commonly cited threshold. CONCLUSION: Under plausible clinical conditions, adding MRI is not cost-effective compared with standard risk stratification in early-RA patients

Brief physician interventions can reduce alcohol consumption. Physicians may not have the time to provide brief interventions, and it is unclear whether nonphysicians can do so effectively. We conducted a systematic review and meta-analysis to examine the efficacy of brief interventions by nonphysician clinicians for unhealthy alcohol use. We searched the English-language literature in MEDLINE and other databases covering the domains of alcohol problems, primary care, nonphysician, and brief interventions. Studies of brief interventions delivered at least in part by nonphysicians in primary care and examining drinking outcomes were included. Sensitivity analyses examined the effect of excluding studies that contributed disproportionately to the heterogeneity of results. Thirteen studies, conducted 1996-2008, met our criteria. Seven studies with a total of 2,633 patients were included in the meta-analysis. Nonphysician interventions were associated with 1.7 (95% confidence interval [CI]=-.03 to -3.5) fewer standard drinks per week than control conditions (p = .054). Excluding the one study that increased heterogeneity, the effect was smaller but reached statistical significance; nonphysician counseling was associated with 1.4 (95% CI = .3- 2.4) fewer standard drinks per week compared to control (p = .012). Nonphysician brief interventions are modestly effective at reducing drinking in primary care patients with unhealthy alcohol use. (Am J Addict 2011;00:1-14)

While some media reports offer accurate interpretations of clinical research, other reports are misleading. The uneven accuracy of medical reporting may act in concert with its sheer volume to confuse the lay public about which health messages are most important and evidence-based. I outline one possible step towards a solution: medical journals can embed quality of evidence ratings in article summaries and create incentives for inclusion of these ratings in lay media reports

BACKGROUND: Some have recommended against routine screening for colorectal cancer (CRC) among patients >/=75 years of age, while others have suggested that screening colonoscopy (SC) is less beneficial for women than men. We estimated the expected benefits (decreased mortality from CRC) and harms (SC-related mortality) of SC based on sex, age, and comorbidity. OBJECTIVE: To stratify older patients according to expected benefits and harms of SC based on sex, age, and comorbidity. DESIGN: Retrospective study using Medicare claims data. PARTICIPANTS: Medicare beneficiaries 67-94 years old with and without CRC. MAIN MEASURES: Life expectancy, CRC- and colonoscopy-attributable mortality rates across strata of sex, age, and comorbidity, pay-off time (i.e. the minimum time until benefits from SC exceeded harms), and life-years saved for every 100,000 SC. KEY RESULTS: Increasing age and comorbidity were associated with lower CRC-attributable mortality. Due to shorter life expectancy and CRC-attributable mortality, the benefits associated with SC were substantially lower among patients with greater comorbidity. Among men aged 75-79 years with no comorbidity, the number of life-years saved was 459 per 100,000 SC, while men aged 67-69 with >/=3 comorbidities had 81 life-years saved per 100,000 SC. There was no evidence that SC was less effective in women. Among men and women 75-79 with no comorbidity, number of life-years saved was 459 and 509 per 100,000 SC, respectively; among patients with >/=3 comorbidities, there was no benefit for either men or women. CONCLUSIONS: Although the effectiveness of SC was equivalent for men and women, there was substantial variation in SC effectiveness within age groups, arguing against screening recommendations based solely on age

Background: Prasugrel is effective at decreasing cardiovascular events compared to clopidogrel, but increases the risk of bleeding. In 2010, the FDA issued a black box warning to consider genetic testing in clopidogrel users. Our aims were to evaluate (1) the balance of potential benefits and harms and (2) the cost-effectiveness that would result from adopting a genotype-guided strategy of dual anti-platelet therapy following PCI for ACS vs. no testing strategies of prasugrel plus aspirin (prasugrel) or clopidogrel plus aspirin (clopidogrel). Methods: A Markov state transition model was used to conduct a decision analysis and compare strategies. Probabilities of adverse outcomes were derived from TRITON-TIMI 38 trial. Event rates on clopidogrel for carriers of CYP2C19*2 vs. wild-type were derived from the TRITON genetic substudy and a recent meta-analysis. Costs are expressed in January 2011 US dollars and estimated based on Medicare reimbursements for diagnosis-related group codes. Medication costs were used from the net wholesale price for prasugrel ($5.45/d) and a generic estimate for clopidogrel ($1/d). Results: In base case analyses, the genetic testing guided strategy yielded more benefits than harms, and was less costly compared to both 'no testing' strategies. Over 15 months, total costs were $83.8 ($1200.9 at 10 yrs) lower with a gain of 0.0007 QALY (0.0216 QALY at 10 yrs) in the genotype-guided strategy compared to prasugrel. Compared to clopidogrel, it was $0.38 ($2168.8 at 10 yrs) lower with a gain of 0.0036 QALY (0.112 QALY at 10 yrs). The strongest predictor of the preferred strategy was the relative risk (RR) of a thrombotic event occurring in CYP2C19*2 carriers versus wild-type. Below a RR of 1.5, a genotype-guided strategy is no longer more effective (but is less expensive) when compared to prasugrel. Compared to clopidogrel, below a RR of 1.3 a genotype-guided strategy is no longer cost effective (>$100,000/QALY). Clopidogrel costs ($1-$4/d) did not alter our results. Conclusions: Among ACS patients undergoing PCI, a genotype-guided strategy is economically favorable in determining which anti-platelet regimen is used, assuming that the risk of thrombotic events in CYP2C19*2 carriers is approximately 30-50% higher than wild type patients

BACKGROUND: In HIV care, it is difficult to decide when to initiate therapy, which drugs to use for initial treatment, and which drugs to use if drug resistance develops. With hundreds of possible drug regimens available and variable patterns of drug resistance, randomized controlled trials cannot answer all HIV treatment decisions. Mechanistic models of HIV infection can be used to conduct virtual therapeutic trials with the goal of predicting outcomes, some of which are long-term and may not fall within the time frame of a typical therapeutic trial. METHODS: We used a previously developed and validated model of HIV infection to replicate 2 arms of an HIV initial treatment trial (ACTG A5142) and predict long-term outcomes. The model incorporated data about biologic processes involved in the development of drug resistance. RESULTS: The model reproduced the proportion that developed AIDS (0.04 and 0.05 for the efavirenz arm and lopinavir arms, respectively, vs. 0.04 and 0.06 for the trial), the development of virologic failure (0.27 and 0.33 for the Efavirenz arm and lopinavir arms, respectively, vs. 0.24 and 0.37 for the trial), and drug resistance. The hazard ratio for the time to treatment failure, a combination of resistance and other causes (0.96 for the model vs. 0.75 for the trial; 95% confidence interval, 0.57-0.98), and changes in CD4 cell count, were less accurate. The model estimated longer-term life expectancy, quality-adjusted life expectancy, and HIV-related deaths. CONCLUSIONS: Mechanistic models of HIV infections have the potential to be useful in comparative effectiveness research.

BACKGROUND: Evidence suggests that cost sharing (i.e.,copayments and deductibles) decreases health expenditures but also reduces essential care. Value-based insurance design (VBID) has been proposed to encourage essential care while controlling health expenditures. Our objective was to estimate the impact of broader diffusion of VBID on US health care benefits and costs. METHODS AND FINDINGS: We used a published computer simulation of costs and life expectancy gains from US health care to estimate the impact of broader diffusion of VBID. Two scenarios were analyzed: (1) applying VBID solely to pharmacy benefits and (2) applying VBID to both pharmacy benefits and other health care services (e.g., devices). We assumed that cost sharing would be eliminated for high-value services (<$100,000 per life-year), would remain unchanged for intermediate- or unknown-value services ($100,000-$300,000 per life-year or unknown), and would be increased for low-value services (>$300,000 per life-year). All costs are provided in 2003 US dollars. Our simulation estimated that approximately 60% of health expenditures in the US are spent on low-value services, 20% are spent on intermediate-value services, and 20% are spent on high-value services. Correspondingly, the vast majority (80%) of health expenditures would have cost sharing that is impacted by VBID. With prevailing patterns of cost sharing, health care conferred 4.70 life-years at a per-capita annual expenditure of US$5,688. Broader diffusion of VBID to pharmaceuticals increased the benefit conferred by health care by 0.03 to 0.05 additional life-years, without increasing costs and without increasing out-of-pocket payments. Broader diffusion of VBID to other health care services could increase the benefit conferred by health care by 0.24 to 0.44 additional life-years, also without increasing costs and without increasing overall out-of-pocket payments. Among those without health insurance, using cost saving from VBID to subsidize insurance coverage would increase the benefit conferred by health care by 1.21 life-years, a 31% increase. CONCLUSION: Broader diffusion of VBID may amplify benefits from US health care without increasing health expenditures.