Screening for Hepatitis C Virus (HCV) in Adults

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The Centers for Medicare & Medicaid Services (CMS) has determined the following: The evidence is adequate to conclude that screening for Hepatitis C Virus (HCV), consistent with the grade B recommendations by the U.S. Preventive Services Task Force (USPSTF), is reasonable and necessary for the prevention or early detection of an illness or disability and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B, as described below. Therefore, CMS will cover screening for HCV with the appropriate U.S. Food and Drug Administration (FDA) approved/cleared laboratory tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations, when ordered by the beneficiary's primary care physician or practitioner within the context of a primary care setting, and performed by an eligible Medicare provider for these services, for beneficiaries who meet either of the following conditions. A screening test is covered for adults at high risk for Hepatitis C Virus infection. “High risk” is defined as persons with a current or past history of illicit injection drug use; and persons who have a history of receiving a blood transfusion prior to 1992. Repeat screening for high risk persons is covered annually only for persons who have had continued illicit injection drug use since the prior negative screening test. A single screening test is covered for adults who do not meet the high risk as defined above, but who were born from 1945 through 1965. The determination of “high risk for HCV” is identified by the primary care physician or practitioner who assesses the patient's history, which is part of any complete medical history, typically part of an annual wellness visit and considered in the development of a comprehensive prevention plan. The medical record should be a reflection of the service provided. For the purposes of this national coverage determination (NCD), a primary care setting is defined by the provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients, and practicing in the context of family and community. Emergency departments, inpatient hospital settings, ambulatory surgical centers, independent diagnostic testing facilities, skilled nursing facilities, inpatient rehabilitation facilities, clinics providing a limited focus of health care services, and hospice are examples of settings not considered primary care settings under this definition. For the purposes of this NCD, a “primary care physician” and “primary care practitioner” will be defined consistent with existing sections of the Social Security Act (§1833(u)(6), §1833(x)(2)(A)(i)(I) and §1833(x)(2)(A)(i)(II)). §1833(u) (6) Physician Defined.—For purposes of this paragraph, the term “physician” means a physician described in section 1861(r)(1) and the term “primary care physician” means a physician who is identified in the available data as a general practitioner, family practice practitioner, general internist, or obstetrician or gynecologist. §1833(x)(2)(A)(i) (I) is a physician (as described in section 1861(r)(1)) who has a primary specialty designation of family medicine, internal medicine, geriatric medicine, or pediatric medicine; or (II) is a nurse practitioner, clinical nurse specialist, or physician assistant (as those terms are defined in section 1861(aa)(5));

Decision Memo: TO: Administrative File: (CAG-00436N) FROM: Tamara Syrek Jensen, JD Acting Director Coverage and Analysis Group Lori Ashby Acting Director Division of Medical and Surgical Services Lori Paserchia, MD Lead Medical Officer Deirdre O'Connor Lead Analyst Division of Medical and Surgical Services SUBJECT: Decision Memorandum for Screening for Hepatitis C Virus (HCV) in Adults DATE: June 2, 2014 I. Decision The Centers for Medicare & Medicaid Services (CMS) has determined the following: The evidence is adequate to conclude that screening for Hepatitis C Virus (HCV), consistent with the grade B recommendations by the U.S. Preventive Services Task Force (USPSTF), is reasonable and necessary for the prevention or early detection of an illness or disability and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B, as described below. Therefore, CMS will cover screening for HCV with the appropriate U.S. Food and Drug Administration (FDA) approved/cleared laboratory tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations, when ordered by the beneficiary's primary care physician or practitioner within the context of a primary care setting, and performed by an eligible Medicare provider for these services, for beneficiaries who meet either of the following conditions. A screening test is covered for adults at high risk for Hepatitis C Virus infection. “High risk” is defined as persons with a current or past history of illicit injection drug use; and persons who have a history of receiving a blood transfusion prior to 1992. Repeat screening for high risk persons is covered annually only for persons who have had continued illicit injection drug use since the prior negative screening test. A single screening test is covered for adults who do not meet the high risk as defined above, but who were born from 1945 through 1965. The determination of “high risk for HCV” is identified by the primary care physician or practitioner who assesses the patient's history, which is part of any complete medical history, typically part of an annual wellness visit and considered in the development of a comprehensive prevention plan. The medical record should be a reflection of the service provided. For the purposes of this national coverage determination (NCD), a primary care setting is defined by the provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients, and practicing in the context of family and community. Emergency departments, inpatient hospital settings, ambulatory surgical centers, independent diagnostic testing facilities, skilled nursing facilities, inpatient rehabilitation facilities, clinics providing a limited focus of health care services, and hospice are examples of settings not considered primary care settings under this definition. For the purposes of this NCD, a “primary care physician” and “primary care practitioner” will be defined consistent with existing sections of the Social Security Act (§1833(u)(6), §1833(x)(2)(A)(i)(I) and §1833(x)(2)(A)(i)(II)). §1833(u) (6) Physician Defined.—For purposes of this paragraph, the term “physician” means a physician described in section 1861(r)(1) and the term “primary care physician” means a physician who is identified in the available data as a general practitioner, family practice practitioner, general internist, or obstetrician or gynecologist. §1833(x)(2)(A)(i) (I) is a physician (as described in section 1861(r)(1)) who has a primary specialty designation of family medicine, internal medicine, geriatric medicine, or pediatric medicine; or (II) is a nurse practitioner, clinical nurse specialist, or physician assistant (as those terms are defined in section 1861(aa)(5)); II. Background The following acronyms are used throughout this document. For the readers convenience they are listed here in alphabetical order. AAFP – American Academy of Family Physicians AASLD – American Association for the Study for Liver Diseases ACG – American College of Gastroenterology AHRQ – Agency for Health Research and Quality CDC – Centers for Disease Control and Prevention CLIA – Clinical Laboratory Improvement Act DAA – direct-acting antiviral agent ESRD – end stage renal disease FDA – U.S. Food and Drug Administration HAV – Hepatitis A virus HBV – Hepatitis B virus HCV – Hepatitis C virus HCC – Hepatocellular carcinoma HIV – Human immunodeficiency virus IDSA – Infectious Disease Society of America IOM – Institute of Medicine MMWR – Morbidity and Mortality Weekly Report NANBH – non-A, non-B viral Hepatitis NAT – nucleic acid test NCA – National Coverage Analysis NCD – National Coverage Decision PR – pegylated interferon plus ribavirin QALY – quality adjusted life years RR – relative risk SAE – serious adverse events SVR – sustained virologic response USPSTF – United States Preventive Services Task Force Based upon publication of updated HCV screening guidelines by the USPSTF, CMS initiated this national coverage analysis (NCA) to evaluate the existing evidence on HCV screenings for adults. The scope of this NCA includes a review of the existing evidence and a determination if the body of evidence is sufficient for Medicare coverage of screening for HCV in adults, which is recommended with a grade B by the USPSTF. “The USPSTF recommends screening for hepatitis C virus (HCV) infection in persons at high risk for infection. The USPSTF also recommends offering one-time screening for HCV infection to adults born between 1945 and 1965.” (http://www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm) For the purposes of this NCA, we are furnishing information on viral hepatitis as an inflammation of the liver caused by hepatitis A, B, C, D, or E viruses. We are not discussing hepatitis arising from other viral agents, e.g. Epstein-Barr virus (EBV) or cytomegalovirus (CMV). The identification of non-A, non-B viral hepatitis (NANBH) followed the 1975 advent of serological testing for hepatitis A (HAV) and B (HBV) and the realization that HAV and HBV did not account for most cases of transfusion-associated hepatitis. (Houghton 2009) By 1988, the hepatitis C virus (HCV) had been identified and was shown to be the principal cause of parenterally transmitted NANBH. (Houghton 2009) While the basic structure is common to all HCVs, there are at least six different genotypes of the virus. (Rosen 2011) Genotype 1 is the most common in the U.S. (Chou, Hartung 2013) HCV is an infection that attacks the liver and leads to inflammation. The infection is often asymptomatic and can go undiagnosed for decades. It is difficult for the human immune system to eliminate the HCV and it is a major cause of chronic liver disease. The presence of HCV in the liver initiates a response from the immune system which in turn causes inflammation. Inflammation over long periods of time (usually decades) can cause scarring, called cirrhosis. A cirrhotic liver fails to perform the normal functions of the liver, which leads to liver failure. Cirrhotic livers are more prone to become cancerous and liver failure leads to serious complications, even death. HCV is reported to be the leading cause of chronic hepatitis, cirrhosis and liver cancer and a primary indication for liver transplant in the Western World. (Rosen 2011) “The morbidity and mortality associated with chronic HCV are mainly attributable to its progression toward cirrhosis and hepatocellular carcinoma.” (Rauch 2010) About 80% of people exposed to HCV develop chronic infection and of these three to 11% will develop liver cirrhosis within 20 years. (Nelson 2011) The natural history and chronicity rates for people infected with the HCV vary. The possible outcomes of HCV are diagramed below. (Figure 3: Outcome of HCV infection, Maheshwari et al. 2011) Risk HCV is a bloodborne infection and risks for transmission are primarily associated with exposures to contaminated blood or blood products via transfusions, shared needles and reused medical supplies. “Sexual and mother-to-child transmission is much less likely than for HIV. In developed nations, most new infections occur in injection-drug users.” (Gravitz 2011) By 1992 serologic assays for the testing of the blood supply had been developed. This allowed for effective screening of blood donors. The USPSTF identified the most important risk factors for HCV infection as past or current injection drug use or the receipt of a blood transfusion before 1992. (USPSTF Screening for Hepatitis C Virus in Adults 2013) The Centers for Disease Control and Prevention (CDC) noted that in 1998 the highest prevalence of HCV was identified among persons with substantial or repeated direct percutaneous exposures, such as people who inject drugs, those who receive blood from infected donors, and persons with hemophilia. (CDC MMWR Vol. 61/No. 4 August 17, 2012) In the United States, for the population already infected with HCV, veterans and baby boomers (those born between 1946 and 1964) are most at risk for becoming symptomatic. Veterans have an infection rate at least three times that of the general population and baby boomers, who make up about 30% of the U.S. population, account for two-thirds of the people with HCV in the US. (Gravitz 2011) Epidemiology Infection with HCV affects more than 180 million people globally. In 2010, the CDC estimated that 2.7 to 3.9 million persons in the United States were living with HCV. (CDC MMWR/Vol.61/No. 4 August 17, 2012) A safer blood supply along with safer injection practices among intravenous drug users contributed to a decline in the number of reported cases of HCV from 1999 – 2008. (CDC MMWR/Vol61/No. 4 August 17, 2012) “While the incidence of new hepatitis C virus cases has decreased, the prevalence of infection will not peak until the year 2040. In addition, as the duration of infection increases, the proportion of new patients with cirrhosis will double by 2020 in an untreated patient population.” (Rodriguez-Luna and Douglas 2004) Screening “Screening for HCV infection could identify persons at earlier stages of disease, before they develop serious or irreversible liver damage, and lead to treatments to improve clinical outcomes or reduce transmission risk. Up to three quarters of HCV-infected persons are unaware of their status.” (USPSTF Screening for HCV, Systematic Review 2012 http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcscrart.htm) The CDC recommended HCV testing be initiated with an FDA – approved test for antibody HCV followed by an HCV nucleic acid test (NAT) for persons who test positive. (CDC MMWR Vol. 61/No. 4 August 2012) The USPSTF stated that anti-HCV antibody testing followed by polymerase chain reaction testing (a type of NAT) is accurate for identifying patients with chronic HCV infection. (USPSTF Screening for HCV, Systematic Review 2012 http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcscrart.htm) Treatment The goal of treatment of HCV in adults is to eradicate the virus and prevent long-term complications such as cirrhosis, liver failure and hepatocellular carcinoma (Chou, Hartung 2013). In the medical literature, 100% eradication of the virus from the blood is referred to as a sustained virologic response (SVR). Very recently, another type of genotype named IL-28B has been identified as a predictor of response to treatment. The presence of IL-28B is associated with a two-fold greater SVR in European, African American and Hispanic populations. Its presence or absence is used to determine whether to initiate treatment. The standard treatment for many years consisted of a combination of pegylated interferon and ribavirin (a.k.a., dual therapy). However, this two-drug regimen leads to numerous side effects (Gravitz 2011), which can result in discontinuation of treatment prior to completing the full course. In addition, this regimen is less effective for genotype 1, which is the predominant genotype in the U.S. (about 75% of cases) and the more difficult genotype to treat. (Chou, Hartung 2013) However, treatment of HCV for adults continues to evolve. In the past several years, FDA approved two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), for the treatment of genotype 1 infection. These antivirals are commonly referred to as direct acting antivirals (DAAs). Thus, the new standard of care for previously untreated (treatment naïve) patients with genotype 1 HCV infection is 12 – 32 weeks of boceprevir or telaprevir in combination with 24 – 48 weeks of pegylated interferon and ribavirin. (Lawitz 2013) The exact duration of treatment is dictated by the patient's response to therapy as well as the stage of hepatic fibrosis. (Lawitz 2013) The use of a DAA in combination with interferon and ribavirin is commonly referred to as triple therapy. On November 22, 2013 FDA approved a third antiviral called simeprevir (Olysio), which is a protease inhibitor indicated for HCV genotype 1 infection. Simeprevir is to be administered in combination with pegylated interferon and ribavirin. (http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm377234.htm) On December 6, 2013 FDA approved sofosbuvir (Sovaldi), which is a nucleotide analog HCV NS5B polymerase inhibitor indicated for use for HCV infection due to genotypes 1, 2, 3 or 4. The FDA recommended regimens for patients with genotype 1 or 4 infection is sofosbuvir with pegylated interferon and ribavirin and for patients with genotype 2 or genotype 3 infection is sofosbuvir with ribavirin. (http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm377920.htm) III. History of Medicare Coverage Pursuant to §1861(ddd) of the Social Security Act, the Secretary may add coverage of "additional preventive services" if certain statutory requirements are met. Our regulations provide: §410.64 Additional preventive services (a) Medicare Part B pays for additional preventive services not described in paragraph (1) or (3) of the definition of “preventive services” under §410.2, that identify medical conditions or risk factors for individuals if the Secretary determines through the national coverage determination process (as defined in section 1869(f)(1)(B) of the Act) that these services are all of the following: (1) Reasonable and necessary for the prevention or early detection of illness or disability. (2) Recommended with a grade of A or B by the United States Preventive Services Task Force. (3) Appropriate for individuals entitled to benefits under part A or enrolled under Part B. (b) In making determinations under paragraph (a) of this section regarding the coverage of a new preventive service, the Secretary may conduct an assessment of the relation between predicted outcomes and the expenditures for such services and may take into account the results of such an assessment in making such national coverage determinations. Currently, screening for HCV is not covered by Medicare. IV. Timeline of Recent Activities Date Action September 5, 2013 CMS initiates opening a NCA for screening for HCV. Initial 30-day public comment period begins. October 5, 2013 Initial public comment period closed. March 4, 2014 Posted PDM. Second 30-day public comment period begins. April 3, 2014 Second public comment period closed. V. Food and Drug Administration (FDA) Status In general, diagnostic laboratory tests are regulated by the FDA. Numerous laboratory tests that can detect the presence of HCV antibody as well as HCV polymerase chain reaction tests are FDA approved/cleared and available. The FDA In Vitro Diagnostics database provides specific information on the approved or cleared tests. VI. General Methodological Principles When making national coverage determinations concerning additional preventive services, CMS applies the statutory criteria in §1861(ddd) of the Social Security Act and evaluates relevant clinical evidence to determine whether or not the service is reasonable and necessary for the prevention or early detection of illness or disability, is recommended with a grade of A or B by the USPSTF, and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B of the Medicare program. Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence A. Introduction Consistent with §1861(ddd)(1)(A) and 42 CFR § 410.64(a)(1), additional preventive services must be reasonable and necessary for the prevention or early detection of illness or disability. With respect to evaluating whether screening tests conducted on asymptomatic individuals are reasonable and necessary for these purposes, the analytic framework involves consideration of different factors compared to either diagnostic tests or therapeutic interventions. Evaluation of screening tests has been largely standardized in the medical and scientific communities, and the "value of a screening test may be assessed according to the following criteria: Simplicity . In many screening programmes more than one test is used to detect one disease, and in a multiphasic programme the individual will be subjected to a number of tests within a short space of time. It is therefore essential that the tests used should be easy to administer and should be capable of use by para-medical and other personnel. Acceptability . As screening is in most instances voluntary and a high rate of co-operation is necessary in an efficient screening programme, it is important that tests should be acceptable to the subjects. Accuracy . The test should give a true measurement of the attribute under investigation. Cost . The expense of screening should be considered in relation to the benefits resulting from the early detection of disease, i.e., the severity of the disease, the advantages of treatment at an early stage and the probability of cure. Precision (sometimes called repeatability) . The test should give consistent results in repeated trials. Sensitivity . This may be defined as the ability of the test to give a positive finding when the individual screened has the disease or abnormality under investigation. Specificity . This may be defined as the ability of the test to give a negative finding when the individual screened does not have the disease or abnormality under investigation." (Cochran and Holland 1971).” As Cochrane and Holland (1971) noted, evidence on health outcomes, i.e., “evidence that screening can alter the natural history of disease in a significant proportion of those screened," is important in the consideration of screening tests since individuals are asymptomatic and "the practitioner initiates screening procedures.” (Cochran and Holland 1971) Four of the seven criteria cited above (Cochrane and Holland 1971) as reasonable and necessary for screening tests (i.e., accuracy, precision, sensitivity and specificity) reflect a screening test's ability to minimize the harm of testing inaccuracy, especially from false positive or false negative results. Screening test compliance with these criteria is within the scope of FDA review of in-vitro diagnostic devices and the FDA has only reviewed evidence on the approved label indications for these tests. Primary Care and USPSTF Recommended Preventive Services The USPSTF functions as an independent panel of non-Federal experts in prevention and primary care. The primary audience for the USPSTF's work remains primary care clinicians. From the Preface to 2012 USPSTF Clinical Preventive Services Guide (available at http://www.ahrq.gov/clinic/pocketgd1011/pocketgd1011.pdf, pp. v-vi): “Preface Since being codified by Congress, the U.S. Preventive Services Task Force (USPSTF) has been fulfilling its charge to conduct rigorous reviews of scientific evidence to create evidence-based recommendations for preventive services that should be provided in the primary care setting.… Our Procedure Manual, which can be found at http://www.USPreventiveServicesTaskForce.org/uspstf08/methods/procmanual.htm, outlines our updated process for evaluating the quality and strength of the evidence for a service, determining the net health benefit (benefits minus harms) associated with the service, and judging the level of certainty that providing these services will be beneficial in primary care.” The Institute of Medicine (IOM) has provided a definition of primary care based on the function which states: “Primary care is the provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients , and practicing in the context of family and community (IOM. Primary Care: America's Health in a New Era 1996).” In discussing the value of primary care, one of the elements cited supporting this definition is that primary care “…opens opportunities for disease prevention and health promotion as well as early detection of disease….” (IOM Primary Care: America's Health in a New Era 1996) The Agency for Healthcare Research and Quality (AHRQ) has adopted the IOM definition of primary care in their primary care practice based research networks (PBRNs) (http://pbrn.ahrq.gov/portal/server.pt/community/practice_based_research_networks_%28pbrn%29__about/852). Many preventive services are discussed within the context of the primary care setting and the USPSTF reviews preventive services that should be provided in the primary care setting. Primary care providers are thought of as the initial contact for patients within a complicated health system. Primary care providers are often identified as the conduit for identifying the need for preventive services by assessing the patient's individual risk factors and developing a comprehensive prevention plan that directs patients in a coordinated manner to appropriate services to address their individual health risks and provide the most efficient utilization of health care services. B. USPSTF Grade Definitions The U.S. Preventive Services Task Force (USPSTF) assigns one of five letter grades to each of its recommendations (A, B, C, D, I). In July of 2012, the grade definitions were updated to reflect the change in definition of and suggestions for practice for the grade C recommendation. The following tables from the USPSTF website provide the current grade definitions and descriptions of levels of certainty. (http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm) Grade Definitions After July 2012 Grade Definition Suggestions for Practice A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. I Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. Level of Certainty Description High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: The number, size, or quality of individual studies. Inconsistency of findings across individual studies. Limited generalizability of findings to routine primary care practice. Lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies. Important flaws in study design or methods. Inconsistency of findings across individual studies. Gaps in the chain of evidence. Findings not generalizable to routine primary care practice. Lack of information on important health outcomes. More information may allow estimation of effects on health outcomes. * The USPSTF defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service. C. U.S. Preventive Services Task Force Recommendations for HCV–(link provided http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm) The USPSTF recommends screening for HCV infection in persons at high risk for infection. (Grade: B recommendation) The USPSTF also recommends offering 1-time screening for HCV infection to adults born between 1945 and 1965. (Grade: B recommendation). “In 1998, the highest prevalence rates of the anti-HCV antibody occurred in persons with significant direct percutaneous exposures, such as injection drug users and persons with hemophilia (60% to 90%); persons with less significant percutaneous exposures involving smaller amounts of blood, such as patients receiving hemodialysis (10% to 30%), had more moderate prevalence rates. Persons engaging in high-risk sexual behaviors (1% to 10%); recipients of blood transfusions (6%); and persons with infrequent percutaneous exposures, such as health care workers (1% to 2%), had the lowest prevalence rates." “In reviewing the prevalence data on high-risk groups and the potential for reduced transmission, the USPSTF concluded that screening in high-risk persons (prevalence ≥50%) and the birth cohort (prevalence of about 3% to 4%) would result in a moderate net benefit.” The evidence supporting these recommendations is considered and summarized in section VII.E of this document. D. Literature Search In addition to the prerequisite USPSTF recommendations, CMS must consider not only whether an additional preventive service is reasonable and necessary for the prevention or early detection of illness or disability, but whether the service is appropriate for individuals entitled to benefits under part A or enrolled under part B of the Medicare program. CMS performed its literature search using PubMed on December 16, 2013 with the search terms “mass screening,” “hepacivirus” and “human.” The following limitations were applied: English, Clinical Trial and a publication within the last ten years. Citations that presented the results of a clinical study were found and reviewed at the abstract level. Numerous studies in which HCV screening was an outcome, rather than an intervention, were judged not relevant to this topic. Four citations were included for further review in the evidence section of this PDM (Moyer 2013; Chou, Cottrell 2013; CDC MMWR Vol.61/No. 4 August 17, 2012; Coffin 2011). Moyer 2013 presents the most recent screening recommendation from the USPSTF. Chou, Cottrell 2013 presents a technology assessment funded by AHRQ. The CDC MMWR 2012 publication presents the recommendations of the CDC. Coffin 2011 presents the results of a cost-effectiveness analysis. An updated search was performed on April 11, 2014 and no new clinical evidence was identified. In addition to the citations found through the literature search, two documents of interest were discovered upon examination of the bibliography of each citation mentioned above. (Liu 2013; Rein 2012) Finally, one practice guideline from the American Association for the Study for Liver Diseases was identified by a public commenter (Ghany 2009). E. Discussion of Evidence Our discussion focuses upon the adequacy of the evidence to draw conclusions about the risks and benefits of screening for HCV for adult Medicare patients, in other words, for those beneficiaries who are 65 years old and older and those who are on Medicare disability or in the End Stage Renal Disease (ESRD) program. CMS searches for and considers literature articles, reports and guidelines that present evidence rather than present a review or a commentary. This evidence usually concerns clinical health outcomes associated with screening for HCV infection that typically are objective in nature, such as mortality and adverse event rates. Consequently, studies that evaluate screening test strategies are not as relevant and are less helpful to CMS. Lastly, when evaluating “additional preventive services,” CMS may conduct an assessment of the relation between predicted outcomes and the expenditures for the service. §1861(ddd)(2); 42 C.F.R. §410.64(b). 1 Questions: The questions of interest for this national coverage analysis are: 1a. Is the evidence sufficient to determine that screening for hepatitis C virus infection in all persons at high risk for infection is recommended with a grade of A or B by the USPSTF? 1b. Is the evidence sufficient to determine that screening for hepatitis C virus infection in all persons at high risk for infection improves outcomes in the prevention or early detection of illness or disability? 1c. Is the evidence sufficient to determine that screening for hepatitis C virus infection in all persons at high risk for infection is appropriate for Medicare beneficiaries? 2a. Is the evidence sufficient to determine that 1-time screening for hepatitis C virus infection in all adults born between 1945 and 1965 is recommended with a grade of A or B by the USPSTF? 2b. Is the evidence sufficient to determine that 1-time screening for hepatitis C virus infection in all adults born between 1945 and 1965 improves outcomes in the prevention or early detection of illness or disability? 2c. Is the evidence sufficient to determine that 1-time screening for hepatitis C virus infection in all adults born between 1945 and 1965 is appropriate for Medicare beneficiaries? 2 External Technology Assessments (TA) CMS did not commission an external TA on this topic. 3 Internal TA Evidence Summary Chou R, Cottrell EB, Wasson N, et al. Screening for hepatitis C virus infection in adults: A systematic review for the U.S. Preventative Services Task Force. Annuals of Internal Medicine 2013;158:101. This article provides a synopsis of a systematic review prepared for the USPSTF by the Oregon Evidence Practice Center, which was under contract to AHRQ. The full report of this systematic review is found at http://www.effectivehealthcare.ahrq.gov/ehc/products/285/1283/CER69_HepatitisCScreening_FinalReport_20121015.pdf. The authors performed a systematic review based on evidence obtained after a search of the medical literature dating from 1947 to May 2012, the Cochrane Library Database, clinical trial registries and reference lists. The review focused on HCV screening in asymptomatic pregnant or non-pregnant adults without known liver enzyme abnormalities and on "research gaps identified in the 2004 USPSTF review and new studies published since that review." Studies of post-transplant patients, HIV-infected patients, patients undergoing hemodialysis and/or people with occupational-related exposure to HCV were excluded. The goals of the review were: to determine if screening for HCV in the target population reduces mortality and morbidity due to HCV infection, affects quality of life or reduces incidence of HCV infection; to determine the effectiveness of different risk- or prevalence-based methods for screening on clinical outcomes; to determine the sensitivity and number needed to screen to identify one case of HCV infection of different risk- or prevalence-based methods for screening; and to assess the harms associated with screening. Study selection criteria limited the review to evidence from randomized trials and cohort, case-control, and cross-sectional studies that assessed yield or clinical outcomes of HCV screening. The “analytic framework focuses on direct evidence that HCV screening improves important health outcomes compared with not screening, as well as the chain of indirect evidence (diagnostic accuracy of screening, clinical utility and harms of subsequent testing in HCV-infected persons, and benefits and harms of treatments) linking screening with improved health outcomes.” Health outcomes assessed were “mortality, end-stage liver disease, cirrhosis, hepatocellular carcinoma, need for transplantation, quality of life, HCV transmission, harms associated with screening (such as anxiety, labeling, and effects on quality of life), and harms associated with liver biopsy (including death, bleeding, and severe pain).” With studies that reported the diagnostic yield of different screening strategies, the authors "computed the number needed to screen to identify 1 case of HCV infection by dividing the number of screening tests performed by the number of HCV cases identified. The proportion screened was the number of patients screened upon application of a particular screening strategy, divided by the total number of patients assessed." The overall strength of the evidence was rated as “high,” “moderate,” “low,” or "insufficient” using AHRQ's methodology (AHRQ April 2012). For goals one and two, the authors did not find any studies that "compared clinical outcomes between individuals screened and not screened for HCV infection or between individuals screened by using different risk- or prevalence-based strategies." For goal three, data for determining the diagnostic accuracy and yield of risk-based screening methods were based on four cross-sectional studies that were rated "Fair" and one case-control study rated as "Poor." Two cross-sectional studies were conducted in sexually-transmitted disease clinics and the remaining cross-sectional studies were conducted in urban primary care clinics. A wide variety of screening strategies were examined within and across each study. The demographic profile of the study population for each study also varied widely. The authors did not perform a subset analysis based on age or report results based on age. However, the authors' evidence table for these five studies (as provided in the full report) indicated that for each study the majority of the patient population was less than 65 years of age. The cross-sectional study with the lower-prevalence population "found that screening based on presence of 1 or more positive items on a 20-item questionnaire was associated with a sensitivity of 90% for identifying persons with HCV infection and a number needed to screen to identify 1 case of HCV infection of 2.4." The "Three cross-sectional studies in higher-prevalence populations found that screening strategies targeting multiple risk factors were associated with sensitivities of more than 90% and numbers needed to screen of 9.3 to 18." The authors noted that "More narrowly targeted screening strategies evaluated in these studies were associated with specificities of more than 95% and numbers needed to screen of less than 2, but missed up to two thirds of infected patients." For goal four, the authors noted that "Data on direct harms of screening were sparse. A large study of percutaneous liver biopsies (n = 2740) in HCV-infected patients with compensated cirrhosis reported no deaths and a 1.1% rate of serious adverse events (primarily bleeding and severe pain)." Limitations of the systematic review identified by the authors included a lack of modeling studies to be assessed and a lack of inclusion into calculations of screening yield of high or unreported proportions of potentially eligible patients in the observational studies due to unknown HCV status. In addition, the authors noted that "The CDC's birth cohort approach was not evaluated in the studies included in our review on the yield of alternative screening strategies. Clinical studies that prospectively evaluate the accuracy, yield, and outcomes of alternative HCV screening strategies, including the birth cohort approach, are needed." The authors noted that similar to the 2004 USPSTF review, "we found no direct evidence on effects of HCV screening versus no screening on clinical outcomes, or on the comparison of clinical effects of alternative screening strategies." It was further noted that "In the absence of direct evidence on clinical outcomes associated with screening, an indirect chain of evidence showing the availability of accurate diagnostic tests and effective treatments could link screening with improvements in clinical outcomes. The 2004 USPSTF review found HCV antibody testing to be highly accurate. Much of the benefits from screening are likely to be based on the effectiveness of antiviral treatments, including newly approved direct-acting antiviral agents, which are addressed in a separate review. Therefore, screening recommendations should be based on the evidence for screening and treatment in totality. Studies showing that screening or subsequent interventions are associated with decreased transmission risk could also significantly affect estimates of potential benefits, but these are not yet available." The authors concluded that “Although screening tests can accurately identify adults with chronic HCV infection, targeted screening strategies based on the presence of risk factors misses some patients with HCV infection. Well-designed prospective studies are needed to better understand the effects of different HCV screening strategies on diagnostic yield and clinical outcomes.” Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for Hepatitis C Virus Infection in Adults: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine September 2013. Volume 159 • Number 5, Pages 349-358. ( Summary of Evidence for USPSTF Recommendation for Screening) The USPSTF presented its recommendation statement, which “applies to all asymptomatic adults without known liver disease or functional abnormalities,” in an article published in the medical literature. (Moyer 2013) The USPSTF stated in this article that: "The USPSTF found adequate evidence that anti-HCV antibody testing followed by confirmatory polymerase chain reaction testing accurately detects chronic HCV infection." "In screening strategies targeting persons with risk factors for HCV infection (such as past or present injection drug use, sex with an injection drug user, or blood transfusion before 1992), anti-HCV antibody testing is associated with high sensitivity ( > 90%) and small numbers needed to screen to identify 1 case of HCV infection ( < 20 persons). Anti-HCV antibody testing remains highly accurate in low-prevalence populations, although the numbers needed to screen to detect 1 case of HCV infection are higher." "The USPSTF also found adequate evidence that various noninvasive tests have good to very good diagnostic accuracy in diagnosing fibrosis or cirrhosis." "The USPSTF found no direct evidence on the benefit of screening for HCV infection in asymptomatic adults in reducing morbidity and mortality. However, the USPSTF found adequate evidence that antiviral regimens result in sustained virologic response (SVR) and improved clinical outcomes." "The USPSTF found inadequate evidence that counseling or immunization of patients with HCV infection against other infections improves health outcomes, reduces transmission of HCV, or changes high-risk behaviors. The USPSTF found inadequate evidence that knowledge of positive status for HCV infection reduces high-risk behaviors. The USPSTF also found inadequate evidence that labor management and breastfeeding strategies in HCV-positive women are effective at reducing risk for mother-to-child transmission." “Given the accuracy of the screening test and the availability of effective interventions for HCV infection, the USPSTF concludes that screening is of moderate benefit for populations at high risk for infection. The USPSTF concludes that 1-time screening in all adults in the United States born between 1945 and 1965 is also of moderate benefit.” “The USPSTF found limited evidence on the harms of screening for HCV. Potential harms of screening include anxiety, patient labeling, and feelings of stigmatization.” “The USPSTF found adequate evidence on the harms associated with the diagnostic evaluation used to guide treatment decisions (liver biopsy). These harms include bleeding, infection, and severe pain in approximately 1% of persons who had a liver biopsy and death in less than 0.2%. However, the use of liver biopsy to guide treatment decisions is declining, and noninvasive tests have sufficient accuracy to diagnose fibrosis and cirrhosis. Thus, the absolute risk to persons who currently receive a diagnosis of HCV infection and subsequent treatment is probably declining.” “The USPSTF found adequate evidence that antiviral therapy regimens are associated with a high rate of harms, such as fatigue, headache, flu-like symptoms, hematologic events, and rash. However, antiviral therapy is given for a defined duration, serious adverse events are uncommon, and adverse events are self-limited and typically resolve after treatment is discontinued. The USPSTF found adequate evidence that these harms of treatment are small.” “The USPSTF concludes with moderate certainty that screening for HCV infection in adults at increased risk for infection and 1-time screening in adults in the 1945 – 1965 birth cohort has moderate net benefit.” CDC MMWR - Smith BD, Morgan RL, Beckert GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945 – 1965. MMWR August 17, 2012. Vol. 61, No. 4, pages 1 - 32. This report presents the CDC's recommendation to expand its 1998 HCV testing guidelines. The CDC formed a team of experts from within and outside the Federal Government called the HCV Birth Cohort Testing Work Group (Work Group). Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, the Work Group performed a comprehensive systematic review of the literature to determine the availability and quality of the evidence regarding HCV infection prevalence as well as the health benefits and harms associated with one-time HCV testing for persons unaware of their status. Outcomes of interest included all-cause mortality, HCC, SVR, serious adverse events (SAEs), quality of life (QoL) and HCV transmission. The CDC's Division of Viral Hepatitis developed the proposed and, after peer-review by external experts and a public comment period, the final recommendation. The report noted that "CDC considered various birth cohorts with increased HCV prevalence. For each proposed birth cohort, CDC determined the weighted, unadjusted anti-HCV prevalence and the size of the population. On the basis of HCV prevalence and disease burden, the 1945 - 1965 birth cohort was selected as the target population." The prevalence of anti-HCV in this target population is 3.25%. The authors noted that "evidence was found in the literature for all-cause mortality, HCC, SVR, SAEs, QoL" but not for HCV transmission. For the QoL outcome, the authors judged the quality of evidence to be "low" due to limited availability and study design. For all-cause mortality, the authors identified 22 relevant articles however 21 of these did not meet the inclusion criteria due to "insufficient sample sizes, unrepresentative study population, and other sources of confounding." Only one (Backus 2011) was directly applicable to the targeted birth cohort. Backus 2011 reported "that treatment-related SVR was associated with a reduction in risk for mortality among persons who had HCV infection diagnosed (Relative risk [RR] = 0.45; 95% CI = 0.41 - 0.51)." However, the authors noted that "this study only compares persons who responded to therapy with those who did not respond and does not address a screened population or an untreated population. Differences in stage of liver disease between the groups had the potential to bias these finds, but those data were not available. Therefore, the confidence in the estimate of effect was deemed to be low, and no change in rating of the quality of evidence was performed despite a large estimated treatment effect." The Working Group assessed 12 observational studies that investigated the incidence of HCC in individuals achieving an SVR compared to those who did not respond to treatment. The authors stated that "Treatment-related SVR was associated with a reduced risk for HCC ( > 75%) among persons at all stages of fibrosis (RR = 0.24; 95% CI = 0.18 - 0.31)." Regarding SVR, the authors noted that the combination of pegylated interferon plus ribavirin (PR) and first generation direct-acting antiviral agents (DAA) "increases the rate of SVR in treated persons with hepatitis C genotype 1 when compared with PR alone. Pooled estimates comparing boceprevir- and telaprevir-based regimens with PR suggest that these regimens are associated with 28% increases in SVR rates (RR = 0.28, 95% CI = 0.24 - 0.32). Although SVR was initially judged by the Work Group to be directly associated with patient-important outcomes (e.g., reduced viral transmission), further deliberation resulted in SVR being defined as an intermediary outcome that is predictive of a reduction in morbidity and mortality, particularly from HCC." Regarding SAEs, the CDC report noted that "Treatment for HCV infection with PR can result in serious adverse events (SAEs). In May 2011, triple-drug therapy with PR and DAA became the standard of care for patients with HCV genotype 1, but limited data are available for systematic reviews on SAEs for regimens including these new agents." The authors added that "Although the addition of boceprevir and telaprevir to standard treatment with PR increases the rate of SVR in persons with HCV genotype 1, it also has been shown to result in an increased rate of adverse events that are severe enough to lead to treatment discontinuation (RR = 1.34; 95% CI = 0.95 - 1.87)." The CDC concluded with a recommendation that “Adults born during 1945 – 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk.” This recommendation was assessed as a "Strong Recommendation, Moderate Quality of Evidence." Cost-effectiveness of HCV Screening A number of authors have addressed the question of cost for HCV screening. Several of the most recent publications are presented below. Liu SL, Cipriano LE, Holodniy M and Goldhaber-Fiebert JD. Cost-effectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS ONE 2013;8:e58975. The authors performed decision analysis/Markov modeling to evaluate various screening strategies (including risk-based and birth cohort-based strategies) and various treatment strategies (including dual therapy, triple therapy and IL-28B guided therapy strategies) in asymptomatic 40 - 74 year old (base case age, 50 years) adults in the U.S. who were unaware of their HCV infection status. Cohorts were stratified by age, sex, race, risk history, HCV infection status, HCV genotype, treatment eligibility, IL-28B genotype and initial liver fibrosis stage. National Health and Nutrition Examination Survey (NHANES) data were used to provide prevalence of risk factors and mortality rates. Screening-related costs were estimated using the 2010 Medicare fee schedule. Costs were inflation-adjusted to 2010 U.S. dollars. The primary outcomes were lifetime costs and quality-adjusted life years (QALYs). A societal perspective was used. The authors found that "In the base case, risk-factor guided and birth-cohort screening of individuals who are currently 50 years of age, respectively, averted 4 - 7 and 10 - 15 liver transplants, 13 - 27 and 35 - 56 liver cancers, and gained 181 - 450 and 483 - 950 QALYs per 100,000 people compared to no screening, depending on the HCV treatment strategy used and assuming 30 - 40% treatment uptake and 70% treatment adherence. Risk-factor guided and birth-cohort screening, respectively, increased costs by $17 - 30 million and $35 - 57 million per 100,000 people compared to no screening. Birth-cohort screening yielded greater health benefits per dollar spent than risk-factor guided screening in all cases largely because risk factors for HCV are