Mehlika Toy

All Publications

• Population Health And Economic Impacts Of Reaching Chronic Hepatitis B Diagnosis And Treatment Targets In The US. Health affairs (Project Hope) Toy, M., Hutton, D. W., So, S. 2018; 37 (7): 1033–40

  Abstract

  The National Academies of Sciences, Engineering, and Medicine have concluded that eliminating the public health problem of chronic hepatitis B is feasible. We examined the economic and public health impact of reaching the World Health Organization targets of having 90percent of chronic hepatitis B cases diagnosed and 80percent being treated by 2030 in the United States with an annual incremental increase in screening and treatment rates. To reach the targets by 2030 would require screening approximately 14.5million adults in at-risk populations to diagnose an estimated 870,000 undiagnosed cases and would result in substantial health gains: an increase of 16.5million quality-adjusted life-years (QALYs), and reductions in liver-related deaths of 37percent and in cases of compensated cirrhosis of 24percent, decompensated liver cirrhosis of 51percent, and liver cancer of 35percent. Achieving the targets by 2030 would be highly cost-effective at $103 per QALY and would be cost-saving if the antiviral drug price were no more than $114 per month. Achieving them by 2025 would be cost-saving and would reduce liver-related deaths by 47percent.

  View details for DOI 10.1377/hlthaff.2018.0035

  View details for PubMedID 29985701

• Racial/ethnic- and county-specific prevalence of chronic hepatitis B and its burden in California Hepatology, Medicine and Policy Toy, M., Wei, B., Virdi, T. S., Le, A., Trinh, H., Li, J., Zhang, J., Hsing, A. W., So, S. K., Nguyen, M. H. 2018; 3 (6)

  View details for DOI 10.1186/s41124-018-0034-7

• Prevalence and predictors of hepatitis B immunization in adults without immunity for hepatitis B from 1999-2014: a population-based study of 27,713 adults in the US Le, M. H., Toy, M., Gane, E. J., So, S., Nguyen, M. H. WILEY. 2017: 1004A

  View details for Web of Science ID 000412089802249

• Suboptimal rates, trends and predictors of hepatitis B vaccination in a population-based sample of children and adolescents in the United States (US) between 1999 and 2014 Le, M. H., Toy, M., Gane, E. J., So, S., Nguyen, M. H. WILEY. 2017: 1003A

  View details for Web of Science ID 000412089802247

• Age and gender-specific disease progression rates to cirrhosis and hepatocellular carcinoma (HCC) in treated and untreated patients with chronic hepatitis B Le, A. K., Toy, M., Yang, H., Trinh, H. N., Zhang, J. Q., Wong, C., Wong, C., Li, J., Nguyen, M. H. WILEY. 2017: 994A

  View details for Web of Science ID 000412089802230

• Population Health Impact and Cost-Effectiveness of Chronic Hepatitis B Diagnosis, Care, and Treatment in the United States A National Strategy for the Elimination of Hepatitis B and C: Phase Two Report Toy, M. The National Academies of Sciences. 2017: Appendix 1
• Viral Hepatitis Strategic Information and Modelling Reference Group Meeting report 14–16 June 2016 WHO headquarters, Geneva, Switzerland Hutin, Y., Aggarwal, R., Cowie, B., Hallet, T., Hutchinson, S., Razavi, H., Abu-Raddad, L., Toy, M., Chhatwal, J. World Health Organization. 2016
• Emerging Technologies for Point-of-Care Management of HIV Infection ANNUAL REVIEW OF MEDICINE, VOL 66 Shafiee, H., Wang, S., Inci, F., Toy, M., Henrich, T. J., Kuritzkes, D. R., Demirci, U. 2015; 66: 387-405

  Abstract

  The global HIV/AIDS pandemic has resulted in 39 million deaths to date, and there are currently more than 35 million people living with HIV worldwide. Prevention, screening, and treatment strategies have led to major progress in addressing this disease globally. Diagnostics is critical for HIV prevention, screening and disease staging, and monitoring antiretroviral therapy (ART). Currently available diagnostic assays, which include polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and western blot (WB), are complex, expensive, and time consuming. These diagnostic technologies are ill suited for use in low- and middle-income countries, where the challenge of the HIV/AIDS pandemic is most severe. Therefore, innovative, inexpensive, disposable, and rapid diagnostic platform technologies are urgently needed. In this review, we discuss challenges associated with HIV management in resource-constrained settings and review the state-of-the-art HIV diagnostic technologies for CD4(+) T lymphocyte count, viral load measurement, and drug resistance testing.

  View details for DOI 10.1146/annurev-med-092112-143017

  View details for Web of Science ID 000348560300026

  View details for PubMedID 25423597

• Cost-Effectiveness and Cost Thresholds of Generic and Brand Drugs in a National Chronic Hepatitis B Treatment Program in China. PloS one Toy, M., Hutton, D. W., So, S. K. 2015; 10 (11)

  Abstract

  Chronic liver disease and liver cancer associated with chronic hepatitis B (CHB) are leading causes of death among adults in China. Although newborn hepatitis B immunization has successfully reduced the prevalence of CHB in children, about 100 million Chinese adults remain chronically infected. If left unmanaged, 15-25% will die from liver cancer or liver cirrhosis. Antiviral treatment is not necessary for all patients with CHB, but when it is indicated, good response to treatment would prevent disease progression and reduce disease mortality and morbidity, and costly complications. The aim of this study is to analyze the cost-effectiveness of generic and brand antiviral drugs for CHB treatment in China, and assessing various thresholds at which a highly potent, low resistance antiviral drug would be cost-saving and/or cost-effective to introduce in a national treatment program. We developed a Markov simulation model of disease progression using effectiveness and cost data from the medical literature. We measured life-time costs, quality adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. The no treatment strategy incurred the highest health care costs ($12,932-$25,293) per patient, and the worst health outcomes, compared to the antiviral treatment strategies. Monotherapy with either entecavir or tenofovir yielded the most QALYs (14.10-19.02) for both HBeAg-positive and negative patients, with or without cirrhosis. Threshold analysis showed entercavir or tenofovir treatment would be cost saving if the drug price is $32-75 (195-460 RMB) per month, highly cost-effective at $62-110 (379-670 RMB) per month and cost-effective at $63-120 (384-734 RMB) per month. This study can support policy decisions regarding the implementation of a national health program for chronic hepatitis B treatment in China at the population level.

  View details for DOI 10.1371/journal.pone.0139876

  View details for PubMedID 26536626

• Recent advances in micro/nanotechnologies for global control of hepatitis B infection BIOTECHNOLOGY ADVANCES Yildiz, U. H., Inci, F., Wang, S., Toy, M., Tekin, H. C., Javaid, A., Lau, D. T., Demirci, U. 2015; 33 (1): 178-190

  Abstract

  The control of hepatitis B virus (HBV) infection is a challenging task, specifically in developing countries there is limited access to diagnostics and antiviral treatment mainly due to high costs and insufficient healthcare infrastructure. Although the current diagnostic technologies can reliably detect HBV, they are relatively laborious, impractical and require expensive resources that are not suitable for resource-limited settings. Advances in micro/nanotechnology are pioneering the development of new generation methodologies in diagnosis and screening of HBV. Owing to combination of nanomaterials (metal/inorganic nanoparticles, carbon nanotubes, etc.) with microfabrication technologies, utilization of miniaturized sensors detecting HBV and other viruses from ultra-low volume of blood, serum and plasma is realized. The state-of-the-art microfluidic devices with integrated nanotechnologies potentially allow for inexpensive HBV screening at low cost. This review aims to highlight recent advances in nanotechnology and microfabrication processes that are employed for developing point-of-care (POC) HBV assays.

  View details for DOI 10.1016/j.biotechadv.2014.11.003

  View details for Web of Science ID 000351321400013

  View details for PubMedID 25450190

• Population Health Impact and Cost-Effectiveness of Monitoring Inactive Chronic Hepatitis B and Treating Eligible Patients in Shanghai, China HEPATOLOGY Toy, M., Salomon, J. A., Jiang, H., Gui, H., Wang, H., Wang, J., Richardus, J. H., Xie, Q. 2014; 60 (1): 46-55

  Abstract

  Inactive chronic hepatitis B (CHB) carriers make up the largest group of hepatitis B virus-infected patients, and China bears the largest total CHB burden of any country. We therefore assessed the population health impact and cost-effectiveness of a strategy of lifelong monitoring for inactive CHB and treatment of eligible patients in Shanghai, China. We used a computer simulation model to project health outcomes among a population cohort of CHB based on age-specific prevalence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and cirrhosis. Using a Markov model we simulated patients' progression through a discrete series of health states, and compared current practice to a monitor and treat (M&T) strategy. We measured lifetime costs and quality-adjusted life years (QALYs) (both discounted at 3% per year), incremental cost-effectiveness ratios (ICERs), and clinical outcomes such as development of hepatocellular carcinoma (HCC). We estimated that there are 1.5 million CHB-infected persons in Shanghai. The M&T strategy costs US$20,730 per patient and yields a discounted QALY of 15.45, which represents incremental costs and health benefits of US$275 and 0.10 QALYs compared to current practice, and an ICER of US$2,996 per QALY gained. In the base case, we estimated that the M&T strategy will reduce HCC and CHB-related mortality by only around 1%. If variables such as adherence to monitoring and treatment could be substantially improved the M&T strategy could reduce HCC by 70% and CHB-related mortality by 83%.Lifelong monitoring of inactive CHB carriers is cost-effective in Shanghai according to typical benchmarks for value for money, but achieving substantial population-level health gains depends on identifying more CHB-infected cases in the population, and increasing rates of treatment, monitoring, and treatment adherence.

  View details for DOI 10.1002/hep.26934

  View details for Web of Science ID 000337969000010

  View details for PubMedID 24990105

• Cost-effective interventions in the control of chronic hepatitis B infection European Medical Journal: Hepatology Toy, M. 2014; 1: 71-76
• Preventing hepatocellular carcinoma: the crucial role of chronic hepatitis B monitoring and antiviral treatment Hepatic Oncology Toy, M., Demirci, U., So, S. 2014; 1 (3): 255-257
• Cost-effectiveness of viral hepatitis B & C treatment BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY Toy, M. 2013; 27 (6): 973-985

  Abstract

  With the availability of effective antiviral therapies for chronic viral hepatitis B and C, cost-effectiveness studies have been performed to assess the outcomes and costs of these therapies to support health policy. It is now accepted that treatment of active CHB is cost-effective versus no treatment, although there are a variety of options. And with the new developments around CHC treatment and diagnostic tools it is of interest to both the clinician and policy makers to know both the costs and effects of these choices. The purpose of this article is to provide the reader with an insight into the recent treatment developments and cost-effectiveness issues related to chronic hepatitis B and C treatment, and an overview of recent cost-effectiveness studies evolving around HBV and HCV therapy.

  View details for DOI 10.1016/j.bpg.2013.08.020

  View details for Web of Science ID 000327806500013

  View details for PubMedID 24182615

• A Mathematical Approach for Evaluating Markov Models in Continuous Time without Discrete-Event Simulation MEDICAL DECISION MAKING van Rosmalen, J., Toy, M., O'Mahony, J. F. 2013; 33 (6): 767-779

  Abstract

  Markov models are a simple and powerful tool for analyzing the health and economic effects of health care interventions. These models are usually evaluated in discrete time using cohort analysis. The use of discrete time assumes that changes in health states occur only at the end of a cycle period. Discrete-time Markov models only approximate the process of disease progression, as clinical events typically occur in continuous time. The approximation can yield biased cost-effectiveness estimates for Markov models with long cycle periods and if no half-cycle correction is made. The purpose of this article is to present an overview of methods for evaluating Markov models in continuous time. These methods use mathematical results from stochastic process theory and control theory. The methods are illustrated using an applied example on the cost-effectiveness of antiviral therapy for chronic hepatitis B. The main result is a mathematical solution for the expected time spent in each state in a continuous-time Markov model. It is shown how this solution can account for age-dependent transition rates and discounting of costs and health effects, and how the concept of tunnel states can be used to account for transition rates that depend on the time spent in a state. The applied example shows that the continuous-time model yields more accurate results than the discrete-time model but does not require much computation time and is easily implemented. In conclusion, continuous-time Markov models are a feasible alternative to cohort analysis and can offer several theoretical and practical advantages.

  View details for DOI 10.1177/0272989X13487947

  View details for Web of Science ID 000327813000004

  View details for PubMedID 23715464

• Cost-effectiveness of Augmenting Universal Hepatitis B Vaccination With Immunoglobin Treatment PEDIATRICS Chen, S. C., Toy, M., Yeh, J. M., Wang, J., Resch, S. 2013; 131 (4): E1135-E1143

  Abstract

  To compare the cost-effectiveness of hepatitis B virus (HBV) control strategies combining universal vaccination with hepatitis B immunoglobulin (HBIG) treatment for neonates of carrier mothers.Drawing on Taiwan's experience, we developed a decision-analytic model to estimate the clinical and economic outcomes for 4 strategies: (1) strategy V-universal vaccination; (2) strategy S-V plus screening for hepatitis B surface antigen (HBsAg) and HBIG treatment for HBsAg-positive mothers' neonates; (3) strategy E-V plus screening for hepatitis B e-antigen (HBeAg), HBIG for HBeAg-positive mothers' neonates; (4) strategy S&E-V plus screening for HBsAg then HBeAg, HBIG for all HBeAg-positive, and some HBeAg-negative/HBsAg-positive mothers' neonates.Strategy S averted the most infections, followed by S&E, E, and V. In most cases, the more effective strategies were also more costly. The willingness-to-pay (WTP) above which strategy S was cost-effective rose as carrier rate declined and was <$4000 per infection averted for carrier rates >5%. The WTP below which strategy V was optimal also increased as carrier rate declined, from $1400 at 30% carrier rate to $3100 at 5% carrier rate. Strategies involving E were optimal for an intermediate range of WTP that narrowed as carrier rate declined.HBIG treatment for neonates of HBsAg carrier mothers is likely to be a cost-effective addition to universal vaccination, particularly in settings with adequate health care infrastructure. Targeting HBIG to neonates of higher risk HBeAg-positive mothers may be preferred where WTP is moderate. However, in very resource-limited settings, universal vaccination alone is optimal.

  View details for DOI 10.1542/peds.2012-1262

  View details for Web of Science ID 000318269500012

  View details for PubMedID 23530168

• High disease progression and medical costs if not detected in a high endemic chronic hepatitis B region: a cost-effectiveness analysis Journal of Antivirals and Antiretrovirals Li, S., Onder, F. O., Xie, Q., Liu, Y., Toy, M. 2013; 5: 154-159
• The cost-effectiveness of treating chronic hepatitis B patients in a median endemic and middle income country EUROPEAN JOURNAL OF HEALTH ECONOMICS Toy, M., Onder, F. O., Idilman, R., Kabacam, G., Richardus, J. H., Bozdayi, M., Akdogan, M., Kuloglu, Z., Kansu, A., Schalm, S., Yurdaydin, C. 2012; 13 (5): 663-676

  Abstract

  Chronic hepatitis B (CHB) infection is a serious public health problem due to its potential liver disease sequelae and highly expensive medical costs such as the need for liver transplantation. The aim of this study was to quantify the burden of active CHB in terms of mortality and morbidity, the eligibility of antiviral treatment and to assess various treatment scenarios and possible salvage combinations for cost-effectiveness.A population cohort from a large data base of chronic hepatitis B patients was constructed and stratified according to 10-year age groups, the prevalence of HBsAg, HBV DNA level, ALT level, HBeAg status and the presence of cirrhosis. An age-specific Markov model for disease progression and cost-effectiveness analysis was constructed and calibrated for the specific population setting.Of about 3.2 million estimated HBsAg carriers, 25% are eligible for treatment. If the active cohort remains untreated, 31% will die due to liver related complications. Within a 20-year period, 11% will have developed decompensated cirrhosis, 12% liver cancer and 6% will need liver transplantation. Quality adjusted life years (QALYs) for the no treatment scenario ranged from 9.3 to 14.0. For scenarios with antiviral treatment, QALYs ranged from 9.9 to 14.5 for lamivudine, 13.0-17.5 for salvage therapy, and 16.6-19.0 for the third generation drugs entecavir and tenofovir.In a country with considerable amount of active CHB patients, monotherapy with a highly potent third generation drug has the most health-gain, and is cost-effective in both HBeAg-positive and negative in all stages of liver disease.

  View details for DOI 10.1007/s10198-012-0413-8

  View details for Web of Science ID 000308029500013

  View details for PubMedID 22815098

• Age- and region-specific hepatitis B prevalence in Turkey estimated using generalized linear mixed models: a systematic review BMC INFECTIOUS DISEASES Toy, M., Onder, F. O., Woermann, T., Bozdayi, A. M., Schalm, S. W., Borsboom, G. J., van Rosmalen, J., Richardus, J. H., Yurdaydin, C. 2011; 11

  Abstract

  To provide a clear picture of the current hepatitis B situation, the authors performed a systematic review to estimate the age- and region-specific prevalence of chronic hepatitis B (CHB) in Turkey.A total of 339 studies with original data on the prevalence of hepatitis B surface antigen (HBsAg) in Turkey and published between 1999 and 2009 were identified through a search of electronic databases, by reviewing citations, and by writing to authors. After a critical assessment, the authors included 129 studies, divided into categories: 'age-specific'; 'region-specific'; and 'specific population group'. To account for the differences among the studies, a generalized linear mixed model was used to estimate the overall prevalence across all age groups and regions. For specific population groups, the authors calculated the weighted mean prevalence.The estimated overall population prevalence was 4.57, 95% confidence interval (CI): 3.58, 5.76, and the estimated total number of CHB cases was about 3.3 million. The outcomes of the age-specific groups varied from 2.84, (95% CI: 2.60, 3.10) for the 0-14-year olds to 6.36 (95% CI: 5.83, 6.90) in the 25-34-year-old group.There are large age-group and regional differences in CHB prevalence in Turkey, where CHB remains a serious health problem.

  View details for DOI 10.1186/1471-2334-11-337

  View details for Web of Science ID 000300063800001

  View details for PubMedID 22151620

• Screening and Early Treatment of Migrants for Chronic Hepatitis B Virus Infection Is Cost-Effective GASTROENTEROLOGY Veldhuijzen, I. K., Toy, M., Hahne, S. J., de Wit, G. A., Schalm, S. W., de Man, R. A., Richardus, J. H. 2010; 138 (2): 522-530

  Abstract

  Persons with chronic hepatitis B virus (HBV) infection are at risk of developing cirrhosis and hepatocellular carcinoma. Early detection of chronic HBV infection through screening and treatment of eligible patients has the potential to prevent these sequelae. We assessed the cost-effectiveness in The Netherlands of systematically screening migrants from countries that have high and intermediate HBV infection levels.Epidemiologic data of the expected numbers of patients with active chronic HBV infection in the target population and information about the costs of a screening program were used in a Markov model and used to determine costs and quality-adjusted life years (QALY) for patients who were and were not treated.Compared with the status quo, a 1-time screen for HBV infection can reduce mortality of liver-related diseases by 10%. Using base case estimates, the incremental cost-effectiveness ratio (ICER) of screening, compared with not screening, is euros (euro) 8966 per QALY gained. The ICER ranged from euro7936 to euro11,705 based on univariate sensitivity analysis, varying parameter values of HBV prevalence, participation rate, success in referral, and treatment compliance. Using multivariate sensitivity analysis for treatment effectiveness, the ICER ranged from euro7222 to euro15,694; for disease progression, it ranged from euro5568 to euro60,418.Early detection and treatment of people with HBV infection can have a large impact on liver-related health outcomes. Systematic screening for chronic HBV infection among migrants is likely to be cost-effective, even using low estimates for HBV prevalence, participation, referral, and treatment compliance.

  View details for DOI 10.1053/j.gastro.2009.10.039

  View details for Web of Science ID 000274300900020

  View details for PubMedID 19879275

• Potential Impact of Long-Term Nucleoside Therapy on the Mortality and Morbidity of Active Chronic Hepatitis B HEPATOLOGY Toy, M., Veldhuijzen, I. K., de Man, R. A., Richardus, J. H., Schalm, S. W. 2009; 50 (3): 743-751

  Abstract

  The potential impact of long-term antiviral therapy on the burden of chronic hepatitis B has hardly been documented. The aim of this study was to estimate the effects of prolonged antiviral therapy and antiviral resistance on the mortality and morbidity of active chronic hepatitis B patients. A population cohort of chronic hepatitis B patients in the Netherlands was constructed and stratified according to 10-year age groups, prevalence of hepatitis B surface antigen, hepatitis B virus DNA level, alanine aminotransferase level, hepatitis B e antigen status, and presence of cirrhosis. A Markov model was created to mathematically simulate the cohort's progression through a finite series of health states. The analysis was performed on the basis of four scenarios: natural history, long-term therapy with a high-resistance profile drug without or with salvage, and therapy with a low-resistance profile drug. It has been estimated that there were 64,000 people (0.4%) suffering from chronic hepatitis B infection in the Netherlands in 2005, with 6521 (10%) of them having high viremia and elevated alanine aminotransferase levels. Within a 20-year period, 1725 (26%) of the 6521 patients in the active chronic hepatitis B cohort will die because of liver-related causes. Of the 5685 without cirrhosis at entry, 1671 (29%) will develop cirrhosis. Of those 836 with cirrhosis at entry, 619 (74%) will die within a 20-year period. If this active chronic hepatitis B cohort is fully detected and treated, mortality related to liver disease can be reduced by 80% if a low-resistance profile drug is chosen from the start. The effect is due to both the reduction in complications of cirrhosis and the prevention of the development of cirrhosis.Long-term antiviral therapy with a strategy that minimizes or controls resistance will have a major preventive effect on liver-related mortality and morbidity.

  View details for DOI 10.1002/hep.23061

  View details for Web of Science ID 000269551100013

  View details for PubMedID 19585616

• Transmission routes of hepatitis B virus infection in chronic hepatitis B patients in the Netherlands JOURNAL OF MEDICAL VIROLOGY Toy, M., Veldhuijzen, I. K., Mostert, M. C., de Man, R. A., Richardus, J. H. 2008; 80 (3): 399-404

  Abstract

  The Netherlands is a low endemic country for hepatitis B virus (HBV). Rotterdam, a city in The Netherlands harbors a large group of chronic hepatitis B (CHB) patients of which most are born abroad. The study included 464 consecutive CHB patients who were reported to the Municipal Public Health Service in Rotterdam from January 1, 2002 to September 15, 2005. The HBV genotypes, possible transmission routes of infection and travel history of CHB patients born in The Netherlands, were compared with those CHB patients living in The Netherlands but who were foreign-born, taking into account the ethnicity of the mother. Of the 464 patients with CHB infection, 14% were Dutch-born and 86% were foreign-born. The CHB patients in the Dutch-born group had genotypes A (35%), B (15%), C (11%), D (37%), and G (2%). In the foreign-born group, the distribution of genotypes was A (20%), B (15%), C (11%), D (40%), and E (15%). In the Dutch-born group, sexual transmission accounted for a larger proportion of infections (P < 0.0001) compared to the foreign-born group, whereas perinatal transmission is reported to be higher in the foreign-born group and in the Dutch-born group with a foreign mother. The genotypes of the chronic HBV strains determined corresponded well with the HBV genotypes expected from the countries of origin of the patients or their mothers. Genotypes A and D are predominant in CHB patients in The Netherlands.

  View details for DOI 10.1002/jmv.21098

  View details for Web of Science ID 000252756500004

  View details for PubMedID 18205235