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HCV Screening For All One Time, Cost & Health Effective - "Population level outcomes and cost-effectiveness of expanding the recommendation for age-based hepatitis C testing in the United States"
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from Jules: from the very beginning I recognized baby boomer only screening was a big mistake & challenged CDC speakers on this at many conferences & presentations. It was clear they were missing even back then several years ago a significant part of HCV infected groups. Routine screening once a year was my recommendation back then & still is, at least for high risk groups but frankly one time testing is a good start but more testing should follow. . It was obvious even back then that around 30% or more of HCV-infected undiagnosed were under 35 years old or just outside the baby boomer years. For drug users & HIV+ MSM, MSM, multiple times or annual tests is the way to go...in Europe & globally too !  
"The CDC could address this public health concern by recommending all adults receive a one-time HCV test."  
"We used a simulation model of HCV to investigate the clinical outcomes, costs, and cost-effectiveness of age-based strategies for routine HCV testing that could replace current cohort-based guidance in the U.S. We found that a recommendation for one-time testing of all adults, with continued risk-based testing throughout life, improved clinical outcomes and was cost-effective in the U.S. Routine hepatitis C virus (HCV) testing is recommended for persons born 1945-1965, but HCV incidence has increased among younger adults. . We used simulation modeling to demonstrate that routine testing in adults ≥18 increases lifetime identification, cure rates, and is cost-effective.
Compared to the SOC, the ≥18 strategy resulted in an estimated 256,000 additional infected persons identified, 280,000 additional cures, and an estimated 4400 fewer cases of HCC in the US (assuming an HCC incidence rate of 2.49 per 100 person-years with cirrhosis) [30] over the lifetime of this cohort."  
"one-time HCV testing of persons 18 and older appears to be cost-effective, leads to improved clinical outcomes and identifies more persons with HCV than the current birth cohort recommendations. These findings could be considered for future recommendation revisions."  
"The value of screening all adults lies in the value of early diagnosis. In our base case, routine testing of adults >/=18 years dominated the other age-based strategies by extended dominance. The >/=18 strategy identifies cases sooner than the other strategies, thereby increasing QoL and decreasing costs associated with HCV, since there is disutility and cost for the years that a person lives with HCV, even with early stage disease."  
"The birth cohort recommendation focuses the testing effort among the group that have had the highest HCV prevalence [31]. The HCV epidemic is changing with an increasing proportion of persons with HCV outside of this cohort. The shift is multifactorial, including premature mortality in the birth cohort [32]; persons treated and cured of their infection in the birth cohort [33]; and higher incidence of new HCV infections among younger PWID [6]. A substantial number of undiagnosed cases exist outside of the birth cohort, and might never be diagnosed under the current strategy [8]. Expanding the recommendation for routine testing to include all adults would increase the probability of testing and identify more people with HCV.....Other analyses have demonstrated that HCV testing is cost-effective in high prevalence settings such as among baby boomers [7], in substance use disorder treatment programs [34], or in prisons and jails [35], as well as in subpopulations including adolescents and young adults [36] or HIV-infected men who have sex with men [37]. Our study takes the next step in this evolution of thought and policy about HCV testing to consider routine HCV testing all adults. "
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Population level outcomes and cost-effectiveness of expanding the recommendation for age-based hepatitis C testing in the United States  
06 February 2018 - Clinical Infectious Diseases - 1. Joshua A. Barocas, MD, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
2. Abriana Tasillo, Division of Infectious Diseases, Boston Medical Center, Boston, MA, USA
3. Golnaz Eftekhari Yazdi, MSc, Division of Infectious Diseases, Boston Medical Center, Boston, MA, USA
4. Jianing Wang, MSc, Division of Infectious Diseases, Boston Medical Center, Boston, MA, USA
5. Claudia Vellozzi, MD, MPH, Division of Viral Hepatitis, US Centers for Disease Control and Prevention, Atlanta, GA, USA
6. Susan Hariri, PhD, Division of Viral Hepatitis, US Centers for Disease Control and Prevention, Atlanta, GA, USA
7. Cheryl Isenhour, DVM, MPH, Division of Viral Hepatitis, US Centers for Disease Control and Prevention, Atlanta, GA, USA
8. Liisa Randall, PhD, Massachusetts Department of Public Health, Boston, MA, USA
9. John W. Ward, MD, Division of Viral Hepatitis, US Centers for Disease Control and Prevention, Atlanta, GA, USA
10. Jonathan Mermin, MD, MPH, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, US Centers for Disease Control and Prevention, Atlanta, GA, USA
11. Joshua A. Salomon, PhD,* Stanford University Department of Medicine, Stanford, CA, USA
12. Benjamin P. Linas, MD, MPH,* Division of Infectious Diseases, Boston Medical Center, Boston, USA; Boston University School of Medicine, Boston, MA, USA  
Abstract  
Background  
The U.S. Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend one-time hepatitis C virus (HCV) testing for persons born 1945-1965 and targeted testing for high-risk persons. This strategy targets HCV testing to a prevalent population at high risk for HCV morbidity and mortality, but does not include younger populations with high incidence. To address this gap and improve access to HCV testing, age-based strategies should be considered.  
Methods  
We used a simulation of HCV to estimate the effectiveness and cost-effectiveness of HCV testing strategies: 1) standard of care (SOC) - recommendation for one-time testing for all persons born 1945-1965, 2) recommendation for one-time testing for adults ≥40 years (≥40 strategy), 3) ≥30 years (≥30 strategy), and 4) ≥18 years (≥18 strategy). All strategies assumed targeted testing of high-risk persons. Inputs were derived from national databases, observational cohorts and clinical trials. Outcomes included quality-adjusted life expectancy, costs, and cost-effectiveness.  
Results  
Expanded age-based testing strategies increased U.S. population lifetime case identification and cure rates. Greatest increases were observed in the ≥18 strategy. Compared to the SOC, this strategy resulted in an estimated 256,000 additional infected persons identified and 280,000 additional cures at the lowest cost per QALY gained (ICER = $28,000/QALY).  
Conclusions  
In addition to risk-based testing, one-time HCV testing of persons 18 and older appears to be cost-effective, leads to improved clinical outcomes and identifies more persons with HCV than the current birth cohort recommendations. These findings could be considered for future recommendation revisions.  
INTRODUCTION  
Half of the estimated 3.5 million people with chronic hepatitis C virus (HCV) are unaware of their status [1]. HCV treatments provide cure rates >90% [2], highlighting the importance of diagnosis. Current U.S. HCV testing recommendations by the U.S. Centers for Disease Control and Prevention and U.S. Preventive Services Task Force include routine one-time testing of persons born 1945-1965, 'the birth cohort,' and concurrent targeted testing for high-risk persons [3, 4]. While prevalence remains highest among those in the birth cohort [5], incidence is rising in younger persons [6] exposed primarily through injection drug use (IDU).  
The current strategy targets the high prevalence population with advanced liver disease at near-term risk of HCV-associated mortality and is cost-effective [7], but misses younger, more recently infected persons. Risk-based strategies are currently employed to identify persons with HCV not in the birth cohort. Risk-based testing in addition to birth cohort testing is more effective than either strategy alone [8]. The value of expanding routine HCV testing among adults born after 1965 in the U.S. is unknown. In this study, we used a simulation model of HCV disease to investigate population-level outcomes and cost-effectiveness of expanding HCV testing recommendations to age-based testing that could replace birth cohort testing.  
RESULTS  
In the SOC strategy, 71% of all HCV infected persons were identified and 44% of HCV-infected persons were cured over a lifetime (Figure 1). The proportion of individuals in the total U.S. population diagnosed prior to cirrhosis was 58%, and 32% of those who were HCV-infected ultimately died from liver disease (data not shown). Among HCV-infected persons born outside the birth cohort, 67% of cases were diagnosed prior to developing cirrhosis, and liver-related mortality among HCV-infected persons was 27% (Table 2).  
Clinical outcomes  
Expanded age-based testing strategies increased lifetime case identification and cure rates in the U.S. population, with the greatest increases observed in ≥18 strategy (Figure 1). Compared to the SOC, the ≥18 strategy resulted in an estimated 256,000 additional infected persons identified, 280,000 additional cures, and an estimated 4400 fewer cases of HCC in the US (assuming an HCC incidence rate of 2.49 per 100 person-years with cirrhosis) [30] over the lifetime of this cohort. The average number of lifetime tests increased from 2.35 tests per person to 4.63 in the SOC strategy and the ≥18 strategy, respectively (Supplementary Table 2 and Supplementary Figure 1). Clinical outcomes over different time horizons are included in the Supplementary Appendix (Supplementary Figures 2 and 3).  
Among the HCV-infected population born outside of the birth cohort, case detection rates increased from 74% to 85% and cure rates from 49% to 61%, which resulted in a 31% reduction in the proportion reaching cirrhosis before diagnosis, and a 21% reduction in liver-attributable mortality in the ≥18 strategy compared to the SOC (Table 2).  
The ≥18 strategy resulted in an increase in life expectancy from 67.2 to 68.2 years compared to the SOC in this population (Table 2) and one discounted quality adjusted life day across the general population (Table 3).  
Cost outcomes  
As testing began at younger ages, HCV-related costs comprised a smaller portion of the incremental cost of each strategy compared to the next most inclusive (Figure 2). All strategies resulted in decreased costs related to managing chronic HCV and advanced liver disease including HCC. The cost of HCV testing in the SOC strategy corresponds to approximately $2500 per case diagnosed. In the ≥18 strategy, the cost of testing increases to $4400 per case diagnosed. The additional cost of testing per case diagnosed is $1900.  
Incremental cost-effectiveness ratio  
In the base case, the 18 strategy provided the greatest quality adjusted life expectancy and the lowest cost/QALY gained. This strategy dominated all other expanded testing strategies by extended dominance with an ICER compared to the SOC of $28,000/QALY (Table 3).  
Scenario Analysis  
In the inefficient testing scenario that required twice as much testing among uninfected persons to identify the same cases, the average discounted cost of the 18 strategy increased minimally to $126,170 (from $126,150 in the base case). That strategy remained cost-effective, with an ICER compared to 30 strategy of $44,000. In the treatment restriction scenario, the 18 strategy ICER remained cost effective but increased to $34,000/QALY (Supplementary Tables 22-23).  
Sensitivity Analysis  
In one-way sensitivity analyses, the >/=18 strategy had an ICER less than $100,000/QALY compared to its next best alternative across broad parameter ranges (Supplementary Tables 4-21), except for the scenario when an individual can only link to care when first identified as infected and never again (Supplementary Table 20). In other scenarios, specifically, when there was no improvement in QoL and costs decreased following early stage cure, when cost of early stage disease was $0, and when treatment costs were varied, the >/=30 strategy dominated the >/=40 strategy by extended dominance, but the >/=18 strategy remained cost-effective (Supplementary Tables 6, 12-13, 21). We note that the >/=18 strategy remained cost-effective with an ICER of $30,000 when there was no mortality benefit from SVR (Supplementary Table 8).  
CONCLUSIONS  
We used a simulation model of HCV to investigate the clinical outcomes, costs, and cost-effectiveness of age-based strategies for routine HCV testing that could replace current cohort-based guidance in the U.S. We found that a recommendation for one-time testing of all adults, with continued risk-based testing throughout life, improved clinical outcomes and was cost-effective in the U.S.  
The birth cohort recommendation focuses the testing effort among the group that have had the highest HCV prevalence [31]. The HCV epidemic is changing with an increasing proportion of persons with HCV outside of this cohort. The shift is multifactorial, including premature mortality in the birth cohort [32]; persons treated and cured of their infection in the birth cohort [33]; and higher incidence of new HCV infections among younger PWID [6]. A substantial number of undiagnosed cases exist outside of the birth cohort, and might never be diagnosed under the current strategy [8]. Expanding the recommendation for routine testing to include all adults would increase the probability of testing and identify more people with HCV.  
Other analyses have demonstrated that HCV testing is cost-effective in high prevalence settings such as among baby boomers [7], in substance use disorder treatment programs [34], or in prisons and jails [35], as well as in subpopulations including adolescents and young adults [36] or HIV-infected men who have sex with men [37]. Our study takes the next step in this evolution of thought and policy about HCV testing to consider routine HCV testing all adults.  
The value of screening all adults lies in the value of early diagnosis. In our base case, routine testing of adults >/=18 years dominated the other age-based strategies by extended dominance. The >/=18 strategy identifies cases sooner than the other strategies, thereby increasing QoL and decreasing costs associated with HCV, since there is disutility and cost for the years that a person lives with HCV, even with early stage disease. When we assume no QoL improvement or cost decrease associated with treating early stage HCV, the >/=18 strategy no longer dominates the >/=30 strategy, but does prevent enough liver-attributable morbidity and mortality to remain cost-effective. Ultimately, the cost-effectiveness of expanding testing to >/=18 is driven by reductions in cirrhosis and liver-related mortality including HCC while the reason it dominates other strategies is driven by QoL improvements and cost reductions associated with treating early stage HCV. New recommendations should continue to include targeted testing among PWID, which effectively serves as a "backstop" to catch later incident cases missed by the >/=18 strategy.  
Findings from our alternative scenarios deserve discussion. First, while an argument against routine testing is that it is a resource intensive effort to find a small number of cases, our findings demonstrate that routine testing is cost-effective even when we test twice as much to find the same number of cases. Second, though testing in our treatment restriction scenario was cost-effective, this conclusion is not an endorsement of these restrictive policies. Rather, this scenario recognizes the status quo in many states and demonstrates that even if patients are treated only once they reach advanced fibrosis, it remains cost-effective to test all adults.  
There were limitations to our study. First, the use of cohort studies and large national databases to derive estimates may not be representative of the overall U.S. population; however, our detailed analysis of testing rates in Marketscan [24] are in line with previously published reports [38-40]. Second, there is relatively little evidence on the cost of early-stage HCV and the magnitude of the change in health-related utilities derived from treating early-stage HCV. Our sensitivity analyses demonstrated that earlier testing remained cost-effective even in the setting in which treating early stage disease had no implications for cost or QoL. Third, differences between strategies are small and could be suspected to reflect Monte Carlo variance. We anticipated this because the life expectancy change in the general population attributable to expanded HCV testing is expected to be small even at a high general population prevalence of 3% because the majority remain uninfected and get no benefit from testing. We minimized Monte Carlo error in our results with a variance reduction strategy outlined in the methods and supplementary appendix. We empirically assessed the degree of variance between runs to ensure that the differences between strategies expected from random variance is smaller than the difference in outcomes seen between strategies (Supplementary Figures 4-12). Fourth, we use a closed cohort, but allowed individuals who are <18 to age into guidance. Using a closed cohort in this way will be biased by omitting some future consequences of different screening strategies. Because the omitted consequences occur two decades or more into the future, the impact of the omission will be relatively small compared to the overall magnitude of the population-level cumulative outcomes, especially given uncertainties about long-term changes in demography and HCV epidemiology, and in the presence of a positive discount rate, as in our main analyses. Fifth, the rate of fibrosis progression with HCV is uncertain. We used one appropriate estimate of fibrosis progression rates and performed sensitivity analyses to ensure that such uncertainty did not have a major impact on the qualitative conclusions. Finally, while we did not incorporate incident infection explicitly related to factors such as tattoos, HCV incidence in the US due to these risk factors is small in comparison to IDU [6]. We explored the impact of non-drug use related HCV on cost-effectiveness conclusions and our results remained robust.  
In conclusion, in addition to risk-based testing, routine, one-time HCV testing of persons 18 years and older is cost-effective, could lead to improved clinical outcomes and is likely to identify more persons with HCV than the current birth cohort recommendations. These findings should be considered for future recommendation revisions.
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