Papers in Press. Published October 10, 2017 as doi:10.1373/clinchem.2016.266569 The latest version is at http://hwmaint.clinchem.aaccjnls.org/cgi/doi/10.1373/clinchem.2016.266569
Q&A
Clinical Chemistry 63:12 000 – 000 (2017)
New Therapies for Treating Hepatitis C Virus: Impact on Laboratory Testing Recommendations and Clinical Management Moderators: Nicole V. Tolan1* and Gary L. Horowitz2 Experts: Camilla S. Graham,3 David Hillyard,4 William Osburn,5 and Stuart Ray6
Hepatitis C infection affects close to 150 million people worldwide. In the US, it is estimated that as many as 5 million people have been infected with the hepatitis C virus (HCV),7 many of whom are unaware of their infection. Some individuals clear the infection on their own, but the overwhelming majority of patients (approximately 75%) develop chronic infection, which can be asymptomatic for many years. Ultimately, chronic HCV infection can lead to cirrhosis, and potentially liver failure and hepatocellular carcinoma. In the US, HCV is now the most common indication for liver transplantation, and it accounts for more deaths each year than all other reportable infectious diseases combined, including HIV. The latest generation of direct-acting antivirals (DAA) has the potential to cure the disease in at least 95% of patients. Although the cost of these medications is slowly declining, they are still expensive (⬃$30000 –$100 000 per case), and states have varying health-care coverage limitations as to who can be treated. That said, the first step in eliminating the virus is identifying those with infection. To this end, the CDC has recommended onetime baby-boomer cohort screening as the prevalence of infection is highest in those born between 1945–1965. More recently, we have seen an increase in the rate of infection in individuals 20 – 40 years of age, which has been associated with increased injection drug use in the current US opioid epidemic. The currently recommended laboratory testing algorithm involves first screening for HCV antibodies (HCV Ab) via immunoassay. For those patients with positive
1 Department of Laboratory Medicine and Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 2 Department of Pathology and Laboratory Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, MA; 3 Assistant Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA; 4 Professor of Pathology, University of Utah; Medical Director of the Molecular Hepatitis and Retrovirus and Molecular Infectious Diseases laboratories and the Molecular Infectious Diseases and Molecular Hepatitis/ Retrovirus sections, ARUP, Salt Lake City, UT; 5 Assistant Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 6 Professor of Medicine and Vice-Chair of Medicine for Data Integrity and Analytics, Johns Hopkins University School of Medicine, Baltimore, MD.
HCV Ab results, follow-up HCV RNA testing is necessary to differentiate those who have spontaneously cleared the infection from those who have become chronically infected and need further medical care. Studies have shown that, even with a successful screening program, many patients do not get the necessary follow-up HCV RNA testing. Those patients with detectable HCV RNA may require genotyping to determine their treatment course (type of therapy and dose/duration). Furthermore, monitoring of treatment requires additional HCV RNA testing to assess for a sustained virologic response (SVR). A small number of patients with positive HCV Ab and undetectable RNA have “biologic false-positive” antibody results. These are antibodies directed against nonHCV antigens that cross-react with some HCV Ab immunoassays. Current recommendations emphasize that physicians inform all patients with such results, whether they represent “biologic false positives” or cleared infections, that they have no current HCV infection. In older recommendations, the HCV recombinant immunoblot assay was recommended to help make that distinction, but that test is no longer available, proved to be nondiagnostic in many cases, and did little more than delay and complicate diagnosis and treatment. All of these issues present intriguing considerations for physicians and clinical laboratories. We have invited four experts in the field, with diverse backgrounds, to help us better understand how to handle the changing landscape of HCV testing and treatment strategies.
* Address correspondence to this author at: Beth Israel Deaconess Medical Center, 500 Old Connecticut Path, Yamins 309, Framingham, MA 01701. Fax 508-383-7880; e-mail [email protected]. Received August 17, 2017; accepted August 28, 2017. © 2017 American Association for Clinical Chemistry 7 Nonstandard abbreviations: HCV, hepatitis C virus; DAA, direct-acting antivirals; HCV ab, HCV antibodies; SVR, sustained virologic response; PWID, persons who inject drugs; ED, emergency departments; POC, point-of-care; VL, viral load.
1
Copyright (C) 2017 by The American Association for Clinical Chemistry
Q&A The CDC has issued several guidelines over the past few years regarding HCV screening, but it appears there is still room for improvement in how to best find individuals with HCV infections. What are the major challenges that we face and how should we approach identifying those with infection? David Hillyard: Twentyfive years after the discovery of HCV and documentation of its strong association with cirrhosis and HCC, efforts to identify chronically infected individuals and prevent new infections have matured and intensified. Although not all individuals with long-standing HCV infection progress to cirrhosis and HCC, significant numbers do, and bringing them to medical attention is a critical public health issue. The availability of advanced testing methods, highly effective DAA drugs, and development of linkage to care infrastructures now make eradication of HCV infection in well-resourced countries a realistic goal. While the 2012 initiative to screen the US “baby boomer” cohort has greatly improved rates of diagnosis, a large population remains undiagnosed and at risk for HCV-related morbidities. In addition to screening the high-risk baby-boomer population, efforts to identify and interrupt a new wave of transmission secondary to the current injection drug epidemic are intensifying. Public health measures are accordingly focused on removing barriers to diagnosis and treatment, as well as developing strategies to break the cycle of infection and reinfection among persons who inject drugs (PWID). This population is also at risk for coinfection with HIV and hepatitis B virus, which accelerate HCV morbidities. Identification of coinfected patients is therefore another important priority. The approach of universal screening for HIV, which has been in place since 2012, has not been applied to HCV, in part due to its much lower efficiency of sexual transmission and restriction to narrower risk groups. The current CDC testing strategy has seen great success, but recent studies predict upwards of a million remaining cases of chronic HCV for the US in 2020 and that most of these individuals will be unaware of their infection. The case for one-time universal HCV testing, at least in the setting of high-risk patients presenting to Emergency Departments (ED), is supported by recent studies suggesting that as many as 25% of HCV cases may be missed with use of existing guidelines for testing. 2
Clinical Chemistry 63:12 (2017)
Stuart Ray and William Osburn: While birthcohort screening has improved our ability to detect HCV-infected individuals, considerable challenges remain for them and for persons not included in that cohort. Access to care is a substantial hurdle that limits the benefit of any large-scale HCV screening program. Also, gaps in physician knowledge may result in inappropriate or less effective screening in primary care settings. Since the implementation of tissue and blood product HCV testing, the risk of HCV infection from a blood transfusion in the US has decreased from 33% to ⬍0.1%, essentially eliminating a major risk that impacted the baby-boomer cohort. Rather than general population screening, it would seem more efficient to now focus additional screening efforts on individuals with known risk factors for HCV infection, such as PWID or high-risk men who have sex with men with HIV coinfection. That said, the continuum of HCV care has several key weak links, the first of which is that many high-risk people are not getting tested at all. Many HCV-infected persons are not baby boomers, and their clinicians may not be aware of their risk behaviors. So, if our goal is to eliminate HCV infection, birth-cohort and risk-based screening may not suffice. In addition, the current opioid epidemic facing the US has resulted in a recent upsurge in cases of HCV infection. The principal problem with increasing the number of populations who warrant screening, aside from the cost, is the need to then remove barriers to treatment, so that increased screening results in positive outcomes. Considering that HCV causes more deaths in the US than all other notifiable diseases combined, this expense may be well justified. Screening of the baby-boomer birth cohort in combination with risk-based screening in the ED has proven to be an effective strategy for identifying previously undocumented infections. As noted by Hsieh and Lyons, broader screening in the ED (beyond birth-cohort and risk-based screening) would substantially increase the number of HCV infections detected, at least in some locales. However, screening in the ED does not overcome
Hepatitis C Testing
Q&A
the challenge of linking infected patients to care, which is notoriously challenging. A more comprehensive approach to support the continuum of care requires accurate testing, counseling, and linkage to curative treatment in the shortest period of time. Such an approach would greatly increase the effectiveness of birth-cohort screening in delivering necessary health care, beyond identifying those who have been exposed to the virus at some point in their lifetime. The current screening guidelines dictate the use of an HCV Ab test for screening, which has high sensitivity but poor specificity for active HCV infection. An HCV RNA molecular screening test is needed since approximately 30% of infected individuals will have spontaneously cleared the virus without treatment. While point-of-care (POC) HCV Ab tests are commercially available, HCV RNA molecular tests are currently performed only in central labs, resulting in a delay in reporting results. This delay increases the likelihood that a patient will not be linked to necessary care and therefore lost to follow-up. Further, mandating reflex testing of HCV Abpositive specimens to HCV RNA testing might improve the rate of detection and treatment. This is already occurring in some clinical laboratories, but reimbursement issues present hurdles to broad implementation of mandated reflex testing. Importantly, performing the initial screening with a highly sensitive and specific HCV RNA molecular test would completely eliminate the need for follow-up testing. However, these changes may not have any effect on linking infected patients with care, unless they are incorporated into a more comprehensive testand-treat strategy.
• Poor recognition of the burden of liver disease and death attributable to HCV. • Reluctance to test individuals who then cannot access HCV treatment due to the high prices of HCV regimens and rationing of treatment by certain health plans. • Patients who do not access regular primary care.
Camilla Graham: The recommendation for onetime baby-boomer cohort screening sounds simple: perform a HCV Ab test for all persons in the US who were born from 1945 through 1965. This onetime recommendation is for individuals without known, ongoing risks for HCV acquisition, such as injection drug use, and recognizes that most affected individuals in the birth cohort were exposed to HCV during the 1960s to 1980s when up to 250 000 persons a year were infected. However, several barriers exist to executing these screening guidelines, including:
Camilla Graham: Although evidence suggests that 53% of newly diagnosed baby boomers had evidence of severe fibrosis or cirrhosis, there has been reluctance to implement comprehensive baby-boomer testing, so I doubt a recommendation for testing all adults over age 18 would be followed. At a minimum, all states that have a recognized increase in HCV infections in younger adults should perform testing of all adults, and I think the CDC needs to update their testing recommendations to reflect the evolving epidemiology of HCV infection.
• Overburdened physicians do not prioritize HCV testing and most care settings do not have medicaldecision support prompts to help facilitate testing.
At Beth Israel Deaconess, we found that a simple prompt in the hospital’s electronic medical record, reminding clinicians to perform HCV Ab testing in baby boomers who had not previously been tested, resulted in an immediate 300% increase in baby-boomer testing, and this initiative was well received by clinicians and patients. In Massachusetts, in 2015, the diagnosis of HCV was reported to the state department of public health for 4659 persons age ⬍40 years and 4404 persons age ⱖ40 years. This bimodal distribution reflects a recent increase in newly acquired HCV through injection drug use. These younger people would not be identified in a babyboomer testing program. Any state that has demonstrated an increase in HCV infections in persons under age 40 should implement testing of all adults over age 18. Testing individuals in EDs should be an effective strategy to identify individuals who do not receive regular primary care. However, centers that implement HCV testing need to provide the additional resources to ensure that these patients are linked into care. This has been a key challenge with current pilot programs. Should we screen everyone for HCV infection, akin to HIV testing in some states?
Studies have shown that even with successful screening programs, many individuals with positive HCV antibody tests do not get the appropriate follow-up HCV viral load (VL) testing necessary to determine infection status. What are the practical issues limiting us (clinicians and laboratorians) from following the 2013 CDC Recommended Sequence (1) for HCV screening and VL testing? Stuart Ray and William Osburn: In addition to problems reaching persons with limited access to health care Clinical Chemistry 63:12 (2017) 3
Q&A and obtaining treatment for persons diagnosed with HCV infection, the major limitation of the 2013 CDCrecommended testing sequence is that one-third of persons who are positive for HCV Ab are not currently HCV infected. The major practical issue with successfully following this algorithm is the necessity for follow-up RNA testing with positive HCV Ab results. Nonintegrated medical record systems contribute to fragmentation in medical care and further complicate the ability to practically implement and follow the recommended testing sequence. The requirement for an additional clinical visit will always result in some individuals being lost to follow-up testing, counseling, and linkage to treatment. The strength of POC HCV Ab screening occurring today is that the antibody tests being used are rapid and have good negative predictive value; both characteristics are important for screening. However, screening with an HCV RNA molecular test would be a more efficient approach if a sufficiently sensitive, specific, and affordable molecular assay were available. The primary challenge is to identify persons with HCV viremia and to test multiple times in those at greatest risk. David Hillyard: For populations well connected to health-care services, the use of reflex testing from a single sample is an effective and widely available option. For patients who are typically lost to follow-up, rapid testing for diagnosis may have great value. The growing introduction of high-quality near POC qualitative RNA tests for other pathogens into hospitals and clinics in the US may eventually include HCV RNA tests. These technologies could provide a rapid RNA-only testing capacity for the ED and clinics where the risk of loss to follow-up is high. Use of rapid RNA-only testing at any HCV healthcare interface could improve efficiencies and decrease barriers to diagnosis and care for all patients. It may not be necessary for these tests to have the same performance characteristics as currently approved assays. The best scenario would be equivalent sensitivity. However, an extremely rapid, affordable, HCV nucleic acid test with somewhat lower sensitivity (perhaps even a finger stick method) could have great value in POC settings, as has been shown for developing countries. Finally, exclusion of HCV Ab testing from the diagnostic algorithm would have no adverse impact on patient care since individuals who experience spontaneous viral clearance are not at risk for HCV-driven disease progression. Camilla Graham: As indicated earlier, the most common testing approach currently requires individuals who are HCV Ab reactive to return for HCV RNA testing to determine the presence of active infection. There are many reasons why only about 60% of these individuals actually have HCV RNA testing performed. Patients 4
Clinical Chemistry 63:12 (2017)
simply may not return for testing. They may have had HCV Ab testing performed by POC in a screening site that did not have on-site phlebotomy or the ability to process a sample for HCV RNA testing. Additionally, programs that pay for HCV Ab testing may not be able to afford HCV RNA testing. One straightforward solution would be to implement reflex HCV RNA testing for all samples that are HCV Ab reactive. The current prices for HCV Ab and RNA testing make generalized screening an unaffordable strategy in most regions of the world. For example, in the US, one needs to test 100 baby boomers to find 3 that are HCV Ab reactive and need RNA testing. If the actual laboratory cost for HCV Ab is $5 and HCV RNA is $50, sequential testing of a hypothetical 100-person cohort would cost $650, while performing HCV RNA testing on everyone would cost $5000. There would be substantial advantages to having a low cost POC test that directly detected HCV RNA or HCV antigens. However, this test would need to cost less than $6.50 (650/100) in the above example to be competitive with the cost of the current sequential testing strategy. Considering the new emphasis on detecting response to therapy and maintaining a sustained virologic response (SVR), what are the current issues related to HCV VL testing? David Hillyard: The current generation of HCV Ab and RNA tests are the products of years of test improvement and are among the most reliable assays in the clinical laboratory. Most RNA testing is performed by use of advanced generation quantitative tests that target the well-conserved 5⬘ NTR region of the HCV genome. They are used both to confirm positive HCV Ab serologic results and assess response to therapy. An exhaustive literature describes the excellent accuracy and concordance of HCV RNA testing. The three Food and Drug Administration-approved quantitative HCV RNA tests are highly sensitive and specific and are calibrated to a WHO standard material, which has led to a dramatic improvement in interassay concordance over the past decade. Results are reported in IU, facilitating harmonization across platforms and standardization of algorithms for diagnosis and monitoring. Currently, almost all HCV RNA testing is quantitative and is performed in centralized facilities, leading to a delay in confirmation of positive serologic results. Issues of cost, turn-around-time, and access to testing will have increasing importance for patients, laboratories, and test developers. Another measure of the ongoing success of HCV RNA-test calibration is the experience from proficiency surveys involving hundreds of laboratories in the US and Europe. Interassay and intraassay variation at low, me-
Hepatitis C Testing
dium, and high VL is small and consistent year after year. These results bolster the view that results from different HCV VL assays are largely commutable, thus allowing meaningful clinical comparison of data derived from different assays. However, in a small subset of cases, variation in individual virus sequence and other factors may still lead to interassay differences. With the introduction of DAA drugs in 2011, the use of quantitative HCV RNA testing for responseguided therapy began to change, and recently its relevance for clinical management has come into question. The first generation DAA drugs boceprevir and telaprevir were used in combination with interferon and ribavirin, and treatment required quantitative assessment at fixed time points of therapy. The current generation of more effective DAA therapies do not require assessment of RNA levels during therapy. Following diagnosis and initiation of treatment, RNA testing can minimally be done 12 weeks after therapy to assess SVR. More commonly, therapeutic RNA testing is done at 4 weeks to assess patient compliance, at end-of-therapy to determine therapeutic response, and 3 months later to determine SVR. This represents a great simplification in testing and invites a discussion of the very need for quantitative HCV RNA testing. Although quantitative tests can perhaps give a more nuanced insight into therapeutic compliance, they are essentially being used to provide qualitative detected or not detected information in current algorithms. Going forward, all HCV NATs will be expected to have sensitivities in the range of 10 IU/mL, and small sensitivity differences in this range will likely not be relevant for determination of SVR for patients on new highly active therapies. Stuart Ray and William Osburn: Testing should be done at baseline (to establish need for treatment, and in some situations guide regimen selection) and after end of treatment (12 and 24 weeks) to determine relapse vs SVR. Current recommendations include testing at week 4 of treatment to assess response to therapy. The observed precision level of current assays is sufficient for clinical management. Current therapies have made assay precision far less important because viremia has become almost binary— high when untreated, many orders of magnitude lower when treated. However, it’s still important to establish baseline viremia and to test for relapse, but it is much less subtle than it once was. Rapid loss of HCV RNA detectability is typically observed during treatment with DAAs. In the case of treatment failures, HCV RNA plasma concentrations rapidly return to pretreatment values (⬎1000 IU/mL in 99.8% of infected patients). Camilla Graham: Until recently, we had responseguided therapy, which required a highly sensitive HCV
Q&A RNA test be performed at week four of treatment. If a patient’s VL decline was insufficient, they received a prolonged course of treatment, with all the concomitant adverse effects. Now, we have numerous all-oral HCV treatment regimens in clinical use and more in development. Only one regimen (sofosbuvir plus ledipasvir) in one of the 6 genotypes (genotype 1) uses the quantitative HCV RNA result to determine treatment management. In this case, patients who have no previous HCV treatment history, do not have cirrhosis, and have a baseline HCV RNA concentration ⬍6 million IU/mL can be considered to receive 8 weeks of sofosbuvir plus ledipasvir. All other patients receive 12 weeks with or without ribavirin. Even with this guidance, only 40% of patients who qualify for 8 weeks receive it (everyone else receives 12 weeks because clinicians prefer longer treatment). For all other regimens, whether a patient has a VL of 6000 IU/ML or 60 million IU/mL, the treatment is identical. So, for most HCV treatment decisions, a qualitative HCV test (RNA or antigen detection) is adequate. Almost all chronically infected patients have HCV RNA concentrations above 1000 IU/mL, and after treatment, by the SVR timepoint, most patients who relapse will have HCV RNA concentrations above 1000 IU/mL as well. So, a less sensitive qualitative test that is more affordable would be an important addition to our testing options. What is your recommendation for reporting results, considering that some laboratories have been slow to transition away from absolute IUs? Stuart Ray and William Osburn: The calibration of HCV RNA tests to WHO standards (in IU/mL) did much to harmonize assays; this was very important when modestly effective interferon-based treatment responses had to be assessed in terms of a log10-decrease in HCV RNA from baseline. Because HCV VLs span a many-log spectrum, reporting the log10 is recommended, although many laboratories report both IU and log10 IU. Further, all HCV testing guidelines refer to IUs; HCV copy number reporting is no longer appropriate. Reporting results in log10 reduces interpretative error because clinically important changes are in terms of log10 and clinicians often have trouble parsing all of the zeros in a number like 1700000. Numbers like 6.2 really aren’t ambiguous. We will admit that we are in the minority on this opinion— clinicians are used to nominal values (IU/mL). The limit of detection should be the lowest reportable value. Quantitative results in the low end of the range have limited clinical significance in the age of DAA regimens. A result of 20 IU/mL is not significantly different clinically from 30 IU/mL. While low-level viremia during and after treatment was clinically important durClinical Chemistry 63:12 (2017) 5
Q&A ing interferon-based treatment regimens (which were less potent), this is very rarely observed after treatment with DAAs. It is estimated that up to 30% of individuals infected with HCV will spontaneously clear the virus on their own, and even with chronic infection not all patients will progress to liver failure. These facts present a number of additional challenges in the era of these new effective treatments. Should all individuals with a current infection be genotyped at the time of diagnosis, and do you believe all patients should be treated? What factors should play a role in the decision to treat? Camilla Graham: The fact that up to 30% of persons who are HCV Ab positive will have negative HCV RNA results points to the need to use HCV screening assays that directly detect the presence of the virus (nucleic acid or antigen detection). Studies have suggested that one specific HCV genotype, genotype 3, is associated with an increased risk of liver damage due to its direct interactions with hepatic lipid metabolism. Since I believe we will be moving to universal treatment, regardless of extent of liver damage, I think genotyping should be done once someone is linked into care, regardless of treatment. Patients who are actively infected with HCV have other complications in addition to liver damage. Many patients have nonspecific, yet potentially debilitating symptoms such as fatigue, difficulty concentrating, and depression that will often improve as patients are started on antiviral treatment and clear viremia. HCV is associated with lymphoma, kidney disease, arthritis, rashes, and other extrahepatic complications as well. In addition, patients with HCV infection suffer from stigma and shame, and may reduce their contact with others due to a fear of inadvertently transmitting the virus. Similar to the rationale for HIV treatment-asprevention, with HCV we can embark on “cure-asprevention” in persons with a high risk of transmitting infection, such as PWID. There are mathematical models that demonstrate the reduction in overall HCV prevalence when HCV treatment is combined with other harm-reduction activities. It is for all of these reasons that most HCV caregivers advocate that everyone with active infection be treated and cured. Both WHO and the US National Academies of Sciences, Engineering, and Medicine have issued reports describing actions countries can take to achieve the goal of eliminating HCV as a public health hazard by 2030. These agencies acknowledge significant barriers to achieving these goals but assert that elimination is feasible. For example, all patients with HCV infection in the state of Massachusetts currently have access to HCV 6
Clinical Chemistry 63:12 (2017)
treatment without restrictions (except for patients in Corrections due to arcane regulations around drug pricing) so negotiating around drug pricing and access is possible. The foundation of any elimination strategy is identifying persons who are infected and that is why laboratory medicine is so critical to these efforts. Stuart Ray and William Osburn: Many of the current DAA regimens have variable potency for some genotypes, but others do not. For now, genotyping is recommended about 12 weeks before planned treatment initiation, to guide therapy. Because mixed genotypes may be detected with careful study, and because increasingly potent regimens are becoming available, genotype assignment may not be necessary in the long term. Recently infected persons have the lowest burden of liver disease among persons with HCV and tend to have the lowest access to care, but they are the easiest to cure and have the highest rate of transmission to others; therefore, there are balancing considerations. Current guidelines (hcvguidelines.org) recommend treatment of all infected persons, with personalized considerations for comorbidities, drug interactions, etc. Trials that demonstrate effectiveness of shorter courses of treatment during early infection would provide a basis for early treatment in PWID, which would reduce transmission. Other considerations that might limit access to cure must be weighed against downstream morbidity and cost. David Hillyard: Before initiating therapy, taxonomic genotyping is used to determine optimal therapy and in some situations duration of treatment. Although new pan-genotypic DAAs are now ready for clinical use, it is likely that genotyping will remain relevant especially for hard-to-treat patients for some time. The decision to genotype is dependent purely on intention to treat because outcomes of chronic infection for different HCV types do not vary significantly. Therefore, HCV genotyping can be performed as part of a reflex panel that includes antibody and RNA testing if immediate treatment is anticipated, or it can be delayed until the time of treatment. The slow and unpredictable progression of HCVrelated disease raises the question of which of the many newly identified patients with chronic HCV should be treated. The multidecade experience in managing chronic HCV provides a wealth of evidence to guide this decision. These perspectives are clearly outlined in the 2016 American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines section “When and in Whom to initiate HCV Therapy.” This document recommends treatment “for all patients with chronic HCV infection, except those with short life expectancies that cannot be remedied by treating HCV infection, by transplantation, or by other directed therapy.” The panel amended earlier recommendations to
Hepatitis C Testing
prioritize treatment first to those with greatest risk, recognizing that accumulated studies show a benefit for all populations except those with “life expectancy ⬍12 months owing to nonliver-related comorbid conditions.” The continuing barriers to treatment (including price of drugs, access to care, insurance coverage, etc.) increase the numbers of potentially diagnosed cases that in reality will not receive therapy. However, from medical, ethical, and public health perspectives this should not be a mitigating factor in deciding to identify all individuals with chronic HCV with diagnostic testing. Individuals with identified HCV infection, even if they have no indicators of liver damage or active inflammation or have no resource for treatment, can benefit from an early cure of disease or inclusion as part of an identified cohort in need of resource recruitment. At this point in time, the window for useful intervention to help patients with long-standing HCV infection is steadily shrinking. New initiatives must be practical and implementable in the near future. It may be that development of entirely new capabilities for rapid and affordable one-step diagnosis of HCV will not have priority for commercial developers. Nevertheless, these tools will have a continuing important value for developing countries and for US populations at risk for new HCV infection. Meanwhile, use of existing tools repurposed for rapid HCV detection will hopefully be prioritized. Suitable platforms are now available and are CLIA waived for testing of other pathogens. An important bar-
Q&A rier to test deployment has been the requirement for full clinical validation of new tests that have existing predicate devices in widespread use. In the case of HCV RNA testing, the required analytic performance for a new test is well understood. Efforts should be made to encourage regulators to simplify the approval process through an approach that relies solely on rigorous analytic validation.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: G. Horowitz, Clinical Chemistry, AACC; C.S. Graham, Trek Therapeutics PBC. Consultant or Advisory Role: D. Hillyard, Roche Diagnostics. Stock Ownership: C.S. Graham, Trek Therapeutics PBC. Honoraria: None declared. Research Funding: S. Ray, MiDiagnostics Inc. Expert Testimony: None declared. Patents: S. Ray, US Patent 8168771, 9512183, PCT/US2015/ 059403, PCT/US2015/059402.
Previously published online at DOI: 10.1373/clinchem.2016.266569
Clinical Chemistry 63:12 (2017) 7
Q&A
Clinical Chemistry 63:12 000 – 000 (2017)
New Therapies for Treating Hepatitis C Virus: Impact on Laboratory Testing Recommendations and Clinical Management Moderators: Nicole V. Tolan1* and Gary L. Horowitz2 Experts: Camilla S. Graham,3 David Hillyard,4 William Osburn,5 and Stuart Ray6
Hepatitis C infection affects close to 150 million people worldwide. In the US, it is estimated that as many as 5 million people have been infected with the hepatitis C virus (HCV),7 many of whom are unaware of their infection. Some individuals clear the infection on their own, but the overwhelming majority of patients (approximately 75%) develop chronic infection, which can be asymptomatic for many years. Ultimately, chronic HCV infection can lead to cirrhosis, and potentially liver failure and hepatocellular carcinoma. In the US, HCV is now the most common indication for liver transplantation, and it accounts for more deaths each year than all other reportable infectious diseases combined, including HIV. The latest generation of direct-acting antivirals (DAA) has the potential to cure the disease in at least 95% of patients. Although the cost of these medications is slowly declining, they are still expensive (⬃$30000 –$100 000 per case), and states have varying health-care coverage limitations as to who can be treated. That said, the first step in eliminating the virus is identifying those with infection. To this end, the CDC has recommended onetime baby-boomer cohort screening as the prevalence of infection is highest in those born between 1945–1965. More recently, we have seen an increase in the rate of infection in individuals 20 – 40 years of age, which has been associated with increased injection drug use in the current US opioid epidemic. The currently recommended laboratory testing algorithm involves first screening for HCV antibodies (HCV Ab) via immunoassay. For those patients with positive
1 Department of Laboratory Medicine and Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; 2 Department of Pathology and Laboratory Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, MA; 3 Assistant Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA; 4 Professor of Pathology, University of Utah; Medical Director of the Molecular Hepatitis and Retrovirus and Molecular Infectious Diseases laboratories and the Molecular Infectious Diseases and Molecular Hepatitis/ Retrovirus sections, ARUP, Salt Lake City, UT; 5 Assistant Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 6 Professor of Medicine and Vice-Chair of Medicine for Data Integrity and Analytics, Johns Hopkins University School of Medicine, Baltimore, MD.
HCV Ab results, follow-up HCV RNA testing is necessary to differentiate those who have spontaneously cleared the infection from those who have become chronically infected and need further medical care. Studies have shown that, even with a successful screening program, many patients do not get the necessary follow-up HCV RNA testing. Those patients with detectable HCV RNA may require genotyping to determine their treatment course (type of therapy and dose/duration). Furthermore, monitoring of treatment requires additional HCV RNA testing to assess for a sustained virologic response (SVR). A small number of patients with positive HCV Ab and undetectable RNA have “biologic false-positive” antibody results. These are antibodies directed against nonHCV antigens that cross-react with some HCV Ab immunoassays. Current recommendations emphasize that physicians inform all patients with such results, whether they represent “biologic false positives” or cleared infections, that they have no current HCV infection. In older recommendations, the HCV recombinant immunoblot assay was recommended to help make that distinction, but that test is no longer available, proved to be nondiagnostic in many cases, and did little more than delay and complicate diagnosis and treatment. All of these issues present intriguing considerations for physicians and clinical laboratories. We have invited four experts in the field, with diverse backgrounds, to help us better understand how to handle the changing landscape of HCV testing and treatment strategies.
* Address correspondence to this author at: Beth Israel Deaconess Medical Center, 500 Old Connecticut Path, Yamins 309, Framingham, MA 01701. Fax 508-383-7880; e-mail [email protected]. Received August 17, 2017; accepted August 28, 2017. © 2017 American Association for Clinical Chemistry 7 Nonstandard abbreviations: HCV, hepatitis C virus; DAA, direct-acting antivirals; HCV ab, HCV antibodies; SVR, sustained virologic response; PWID, persons who inject drugs; ED, emergency departments; POC, point-of-care; VL, viral load.
1
Copyright (C) 2017 by The American Association for Clinical Chemistry
Q&A The CDC has issued several guidelines over the past few years regarding HCV screening, but it appears there is still room for improvement in how to best find individuals with HCV infections. What are the major challenges that we face and how should we approach identifying those with infection? David Hillyard: Twentyfive years after the discovery of HCV and documentation of its strong association with cirrhosis and HCC, efforts to identify chronically infected individuals and prevent new infections have matured and intensified. Although not all individuals with long-standing HCV infection progress to cirrhosis and HCC, significant numbers do, and bringing them to medical attention is a critical public health issue. The availability of advanced testing methods, highly effective DAA drugs, and development of linkage to care infrastructures now make eradication of HCV infection in well-resourced countries a realistic goal. While the 2012 initiative to screen the US “baby boomer” cohort has greatly improved rates of diagnosis, a large population remains undiagnosed and at risk for HCV-related morbidities. In addition to screening the high-risk baby-boomer population, efforts to identify and interrupt a new wave of transmission secondary to the current injection drug epidemic are intensifying. Public health measures are accordingly focused on removing barriers to diagnosis and treatment, as well as developing strategies to break the cycle of infection and reinfection among persons who inject drugs (PWID). This population is also at risk for coinfection with HIV and hepatitis B virus, which accelerate HCV morbidities. Identification of coinfected patients is therefore another important priority. The approach of universal screening for HIV, which has been in place since 2012, has not been applied to HCV, in part due to its much lower efficiency of sexual transmission and restriction to narrower risk groups. The current CDC testing strategy has seen great success, but recent studies predict upwards of a million remaining cases of chronic HCV for the US in 2020 and that most of these individuals will be unaware of their infection. The case for one-time universal HCV testing, at least in the setting of high-risk patients presenting to Emergency Departments (ED), is supported by recent studies suggesting that as many as 25% of HCV cases may be missed with use of existing guidelines for testing. 2
Clinical Chemistry 63:12 (2017)
Stuart Ray and William Osburn: While birthcohort screening has improved our ability to detect HCV-infected individuals, considerable challenges remain for them and for persons not included in that cohort. Access to care is a substantial hurdle that limits the benefit of any large-scale HCV screening program. Also, gaps in physician knowledge may result in inappropriate or less effective screening in primary care settings. Since the implementation of tissue and blood product HCV testing, the risk of HCV infection from a blood transfusion in the US has decreased from 33% to ⬍0.1%, essentially eliminating a major risk that impacted the baby-boomer cohort. Rather than general population screening, it would seem more efficient to now focus additional screening efforts on individuals with known risk factors for HCV infection, such as PWID or high-risk men who have sex with men with HIV coinfection. That said, the continuum of HCV care has several key weak links, the first of which is that many high-risk people are not getting tested at all. Many HCV-infected persons are not baby boomers, and their clinicians may not be aware of their risk behaviors. So, if our goal is to eliminate HCV infection, birth-cohort and risk-based screening may not suffice. In addition, the current opioid epidemic facing the US has resulted in a recent upsurge in cases of HCV infection. The principal problem with increasing the number of populations who warrant screening, aside from the cost, is the need to then remove barriers to treatment, so that increased screening results in positive outcomes. Considering that HCV causes more deaths in the US than all other notifiable diseases combined, this expense may be well justified. Screening of the baby-boomer birth cohort in combination with risk-based screening in the ED has proven to be an effective strategy for identifying previously undocumented infections. As noted by Hsieh and Lyons, broader screening in the ED (beyond birth-cohort and risk-based screening) would substantially increase the number of HCV infections detected, at least in some locales. However, screening in the ED does not overcome
Hepatitis C Testing
Q&A
the challenge of linking infected patients to care, which is notoriously challenging. A more comprehensive approach to support the continuum of care requires accurate testing, counseling, and linkage to curative treatment in the shortest period of time. Such an approach would greatly increase the effectiveness of birth-cohort screening in delivering necessary health care, beyond identifying those who have been exposed to the virus at some point in their lifetime. The current screening guidelines dictate the use of an HCV Ab test for screening, which has high sensitivity but poor specificity for active HCV infection. An HCV RNA molecular screening test is needed since approximately 30% of infected individuals will have spontaneously cleared the virus without treatment. While point-of-care (POC) HCV Ab tests are commercially available, HCV RNA molecular tests are currently performed only in central labs, resulting in a delay in reporting results. This delay increases the likelihood that a patient will not be linked to necessary care and therefore lost to follow-up. Further, mandating reflex testing of HCV Abpositive specimens to HCV RNA testing might improve the rate of detection and treatment. This is already occurring in some clinical laboratories, but reimbursement issues present hurdles to broad implementation of mandated reflex testing. Importantly, performing the initial screening with a highly sensitive and specific HCV RNA molecular test would completely eliminate the need for follow-up testing. However, these changes may not have any effect on linking infected patients with care, unless they are incorporated into a more comprehensive testand-treat strategy.
• Poor recognition of the burden of liver disease and death attributable to HCV. • Reluctance to test individuals who then cannot access HCV treatment due to the high prices of HCV regimens and rationing of treatment by certain health plans. • Patients who do not access regular primary care.
Camilla Graham: The recommendation for onetime baby-boomer cohort screening sounds simple: perform a HCV Ab test for all persons in the US who were born from 1945 through 1965. This onetime recommendation is for individuals without known, ongoing risks for HCV acquisition, such as injection drug use, and recognizes that most affected individuals in the birth cohort were exposed to HCV during the 1960s to 1980s when up to 250 000 persons a year were infected. However, several barriers exist to executing these screening guidelines, including:
Camilla Graham: Although evidence suggests that 53% of newly diagnosed baby boomers had evidence of severe fibrosis or cirrhosis, there has been reluctance to implement comprehensive baby-boomer testing, so I doubt a recommendation for testing all adults over age 18 would be followed. At a minimum, all states that have a recognized increase in HCV infections in younger adults should perform testing of all adults, and I think the CDC needs to update their testing recommendations to reflect the evolving epidemiology of HCV infection.
• Overburdened physicians do not prioritize HCV testing and most care settings do not have medicaldecision support prompts to help facilitate testing.
At Beth Israel Deaconess, we found that a simple prompt in the hospital’s electronic medical record, reminding clinicians to perform HCV Ab testing in baby boomers who had not previously been tested, resulted in an immediate 300% increase in baby-boomer testing, and this initiative was well received by clinicians and patients. In Massachusetts, in 2015, the diagnosis of HCV was reported to the state department of public health for 4659 persons age ⬍40 years and 4404 persons age ⱖ40 years. This bimodal distribution reflects a recent increase in newly acquired HCV through injection drug use. These younger people would not be identified in a babyboomer testing program. Any state that has demonstrated an increase in HCV infections in persons under age 40 should implement testing of all adults over age 18. Testing individuals in EDs should be an effective strategy to identify individuals who do not receive regular primary care. However, centers that implement HCV testing need to provide the additional resources to ensure that these patients are linked into care. This has been a key challenge with current pilot programs. Should we screen everyone for HCV infection, akin to HIV testing in some states?
Studies have shown that even with successful screening programs, many individuals with positive HCV antibody tests do not get the appropriate follow-up HCV viral load (VL) testing necessary to determine infection status. What are the practical issues limiting us (clinicians and laboratorians) from following the 2013 CDC Recommended Sequence (1) for HCV screening and VL testing? Stuart Ray and William Osburn: In addition to problems reaching persons with limited access to health care Clinical Chemistry 63:12 (2017) 3
Q&A and obtaining treatment for persons diagnosed with HCV infection, the major limitation of the 2013 CDCrecommended testing sequence is that one-third of persons who are positive for HCV Ab are not currently HCV infected. The major practical issue with successfully following this algorithm is the necessity for follow-up RNA testing with positive HCV Ab results. Nonintegrated medical record systems contribute to fragmentation in medical care and further complicate the ability to practically implement and follow the recommended testing sequence. The requirement for an additional clinical visit will always result in some individuals being lost to follow-up testing, counseling, and linkage to treatment. The strength of POC HCV Ab screening occurring today is that the antibody tests being used are rapid and have good negative predictive value; both characteristics are important for screening. However, screening with an HCV RNA molecular test would be a more efficient approach if a sufficiently sensitive, specific, and affordable molecular assay were available. The primary challenge is to identify persons with HCV viremia and to test multiple times in those at greatest risk. David Hillyard: For populations well connected to health-care services, the use of reflex testing from a single sample is an effective and widely available option. For patients who are typically lost to follow-up, rapid testing for diagnosis may have great value. The growing introduction of high-quality near POC qualitative RNA tests for other pathogens into hospitals and clinics in the US may eventually include HCV RNA tests. These technologies could provide a rapid RNA-only testing capacity for the ED and clinics where the risk of loss to follow-up is high. Use of rapid RNA-only testing at any HCV healthcare interface could improve efficiencies and decrease barriers to diagnosis and care for all patients. It may not be necessary for these tests to have the same performance characteristics as currently approved assays. The best scenario would be equivalent sensitivity. However, an extremely rapid, affordable, HCV nucleic acid test with somewhat lower sensitivity (perhaps even a finger stick method) could have great value in POC settings, as has been shown for developing countries. Finally, exclusion of HCV Ab testing from the diagnostic algorithm would have no adverse impact on patient care since individuals who experience spontaneous viral clearance are not at risk for HCV-driven disease progression. Camilla Graham: As indicated earlier, the most common testing approach currently requires individuals who are HCV Ab reactive to return for HCV RNA testing to determine the presence of active infection. There are many reasons why only about 60% of these individuals actually have HCV RNA testing performed. Patients 4
Clinical Chemistry 63:12 (2017)
simply may not return for testing. They may have had HCV Ab testing performed by POC in a screening site that did not have on-site phlebotomy or the ability to process a sample for HCV RNA testing. Additionally, programs that pay for HCV Ab testing may not be able to afford HCV RNA testing. One straightforward solution would be to implement reflex HCV RNA testing for all samples that are HCV Ab reactive. The current prices for HCV Ab and RNA testing make generalized screening an unaffordable strategy in most regions of the world. For example, in the US, one needs to test 100 baby boomers to find 3 that are HCV Ab reactive and need RNA testing. If the actual laboratory cost for HCV Ab is $5 and HCV RNA is $50, sequential testing of a hypothetical 100-person cohort would cost $650, while performing HCV RNA testing on everyone would cost $5000. There would be substantial advantages to having a low cost POC test that directly detected HCV RNA or HCV antigens. However, this test would need to cost less than $6.50 (650/100) in the above example to be competitive with the cost of the current sequential testing strategy. Considering the new emphasis on detecting response to therapy and maintaining a sustained virologic response (SVR), what are the current issues related to HCV VL testing? David Hillyard: The current generation of HCV Ab and RNA tests are the products of years of test improvement and are among the most reliable assays in the clinical laboratory. Most RNA testing is performed by use of advanced generation quantitative tests that target the well-conserved 5⬘ NTR region of the HCV genome. They are used both to confirm positive HCV Ab serologic results and assess response to therapy. An exhaustive literature describes the excellent accuracy and concordance of HCV RNA testing. The three Food and Drug Administration-approved quantitative HCV RNA tests are highly sensitive and specific and are calibrated to a WHO standard material, which has led to a dramatic improvement in interassay concordance over the past decade. Results are reported in IU, facilitating harmonization across platforms and standardization of algorithms for diagnosis and monitoring. Currently, almost all HCV RNA testing is quantitative and is performed in centralized facilities, leading to a delay in confirmation of positive serologic results. Issues of cost, turn-around-time, and access to testing will have increasing importance for patients, laboratories, and test developers. Another measure of the ongoing success of HCV RNA-test calibration is the experience from proficiency surveys involving hundreds of laboratories in the US and Europe. Interassay and intraassay variation at low, me-
Hepatitis C Testing
dium, and high VL is small and consistent year after year. These results bolster the view that results from different HCV VL assays are largely commutable, thus allowing meaningful clinical comparison of data derived from different assays. However, in a small subset of cases, variation in individual virus sequence and other factors may still lead to interassay differences. With the introduction of DAA drugs in 2011, the use of quantitative HCV RNA testing for responseguided therapy began to change, and recently its relevance for clinical management has come into question. The first generation DAA drugs boceprevir and telaprevir were used in combination with interferon and ribavirin, and treatment required quantitative assessment at fixed time points of therapy. The current generation of more effective DAA therapies do not require assessment of RNA levels during therapy. Following diagnosis and initiation of treatment, RNA testing can minimally be done 12 weeks after therapy to assess SVR. More commonly, therapeutic RNA testing is done at 4 weeks to assess patient compliance, at end-of-therapy to determine therapeutic response, and 3 months later to determine SVR. This represents a great simplification in testing and invites a discussion of the very need for quantitative HCV RNA testing. Although quantitative tests can perhaps give a more nuanced insight into therapeutic compliance, they are essentially being used to provide qualitative detected or not detected information in current algorithms. Going forward, all HCV NATs will be expected to have sensitivities in the range of 10 IU/mL, and small sensitivity differences in this range will likely not be relevant for determination of SVR for patients on new highly active therapies. Stuart Ray and William Osburn: Testing should be done at baseline (to establish need for treatment, and in some situations guide regimen selection) and after end of treatment (12 and 24 weeks) to determine relapse vs SVR. Current recommendations include testing at week 4 of treatment to assess response to therapy. The observed precision level of current assays is sufficient for clinical management. Current therapies have made assay precision far less important because viremia has become almost binary— high when untreated, many orders of magnitude lower when treated. However, it’s still important to establish baseline viremia and to test for relapse, but it is much less subtle than it once was. Rapid loss of HCV RNA detectability is typically observed during treatment with DAAs. In the case of treatment failures, HCV RNA plasma concentrations rapidly return to pretreatment values (⬎1000 IU/mL in 99.8% of infected patients). Camilla Graham: Until recently, we had responseguided therapy, which required a highly sensitive HCV
Q&A RNA test be performed at week four of treatment. If a patient’s VL decline was insufficient, they received a prolonged course of treatment, with all the concomitant adverse effects. Now, we have numerous all-oral HCV treatment regimens in clinical use and more in development. Only one regimen (sofosbuvir plus ledipasvir) in one of the 6 genotypes (genotype 1) uses the quantitative HCV RNA result to determine treatment management. In this case, patients who have no previous HCV treatment history, do not have cirrhosis, and have a baseline HCV RNA concentration ⬍6 million IU/mL can be considered to receive 8 weeks of sofosbuvir plus ledipasvir. All other patients receive 12 weeks with or without ribavirin. Even with this guidance, only 40% of patients who qualify for 8 weeks receive it (everyone else receives 12 weeks because clinicians prefer longer treatment). For all other regimens, whether a patient has a VL of 6000 IU/ML or 60 million IU/mL, the treatment is identical. So, for most HCV treatment decisions, a qualitative HCV test (RNA or antigen detection) is adequate. Almost all chronically infected patients have HCV RNA concentrations above 1000 IU/mL, and after treatment, by the SVR timepoint, most patients who relapse will have HCV RNA concentrations above 1000 IU/mL as well. So, a less sensitive qualitative test that is more affordable would be an important addition to our testing options. What is your recommendation for reporting results, considering that some laboratories have been slow to transition away from absolute IUs? Stuart Ray and William Osburn: The calibration of HCV RNA tests to WHO standards (in IU/mL) did much to harmonize assays; this was very important when modestly effective interferon-based treatment responses had to be assessed in terms of a log10-decrease in HCV RNA from baseline. Because HCV VLs span a many-log spectrum, reporting the log10 is recommended, although many laboratories report both IU and log10 IU. Further, all HCV testing guidelines refer to IUs; HCV copy number reporting is no longer appropriate. Reporting results in log10 reduces interpretative error because clinically important changes are in terms of log10 and clinicians often have trouble parsing all of the zeros in a number like 1700000. Numbers like 6.2 really aren’t ambiguous. We will admit that we are in the minority on this opinion— clinicians are used to nominal values (IU/mL). The limit of detection should be the lowest reportable value. Quantitative results in the low end of the range have limited clinical significance in the age of DAA regimens. A result of 20 IU/mL is not significantly different clinically from 30 IU/mL. While low-level viremia during and after treatment was clinically important durClinical Chemistry 63:12 (2017) 5
Q&A ing interferon-based treatment regimens (which were less potent), this is very rarely observed after treatment with DAAs. It is estimated that up to 30% of individuals infected with HCV will spontaneously clear the virus on their own, and even with chronic infection not all patients will progress to liver failure. These facts present a number of additional challenges in the era of these new effective treatments. Should all individuals with a current infection be genotyped at the time of diagnosis, and do you believe all patients should be treated? What factors should play a role in the decision to treat? Camilla Graham: The fact that up to 30% of persons who are HCV Ab positive will have negative HCV RNA results points to the need to use HCV screening assays that directly detect the presence of the virus (nucleic acid or antigen detection). Studies have suggested that one specific HCV genotype, genotype 3, is associated with an increased risk of liver damage due to its direct interactions with hepatic lipid metabolism. Since I believe we will be moving to universal treatment, regardless of extent of liver damage, I think genotyping should be done once someone is linked into care, regardless of treatment. Patients who are actively infected with HCV have other complications in addition to liver damage. Many patients have nonspecific, yet potentially debilitating symptoms such as fatigue, difficulty concentrating, and depression that will often improve as patients are started on antiviral treatment and clear viremia. HCV is associated with lymphoma, kidney disease, arthritis, rashes, and other extrahepatic complications as well. In addition, patients with HCV infection suffer from stigma and shame, and may reduce their contact with others due to a fear of inadvertently transmitting the virus. Similar to the rationale for HIV treatment-asprevention, with HCV we can embark on “cure-asprevention” in persons with a high risk of transmitting infection, such as PWID. There are mathematical models that demonstrate the reduction in overall HCV prevalence when HCV treatment is combined with other harm-reduction activities. It is for all of these reasons that most HCV caregivers advocate that everyone with active infection be treated and cured. Both WHO and the US National Academies of Sciences, Engineering, and Medicine have issued reports describing actions countries can take to achieve the goal of eliminating HCV as a public health hazard by 2030. These agencies acknowledge significant barriers to achieving these goals but assert that elimination is feasible. For example, all patients with HCV infection in the state of Massachusetts currently have access to HCV 6
Clinical Chemistry 63:12 (2017)
treatment without restrictions (except for patients in Corrections due to arcane regulations around drug pricing) so negotiating around drug pricing and access is possible. The foundation of any elimination strategy is identifying persons who are infected and that is why laboratory medicine is so critical to these efforts. Stuart Ray and William Osburn: Many of the current DAA regimens have variable potency for some genotypes, but others do not. For now, genotyping is recommended about 12 weeks before planned treatment initiation, to guide therapy. Because mixed genotypes may be detected with careful study, and because increasingly potent regimens are becoming available, genotype assignment may not be necessary in the long term. Recently infected persons have the lowest burden of liver disease among persons with HCV and tend to have the lowest access to care, but they are the easiest to cure and have the highest rate of transmission to others; therefore, there are balancing considerations. Current guidelines (hcvguidelines.org) recommend treatment of all infected persons, with personalized considerations for comorbidities, drug interactions, etc. Trials that demonstrate effectiveness of shorter courses of treatment during early infection would provide a basis for early treatment in PWID, which would reduce transmission. Other considerations that might limit access to cure must be weighed against downstream morbidity and cost. David Hillyard: Before initiating therapy, taxonomic genotyping is used to determine optimal therapy and in some situations duration of treatment. Although new pan-genotypic DAAs are now ready for clinical use, it is likely that genotyping will remain relevant especially for hard-to-treat patients for some time. The decision to genotype is dependent purely on intention to treat because outcomes of chronic infection for different HCV types do not vary significantly. Therefore, HCV genotyping can be performed as part of a reflex panel that includes antibody and RNA testing if immediate treatment is anticipated, or it can be delayed until the time of treatment. The slow and unpredictable progression of HCVrelated disease raises the question of which of the many newly identified patients with chronic HCV should be treated. The multidecade experience in managing chronic HCV provides a wealth of evidence to guide this decision. These perspectives are clearly outlined in the 2016 American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines section “When and in Whom to initiate HCV Therapy.” This document recommends treatment “for all patients with chronic HCV infection, except those with short life expectancies that cannot be remedied by treating HCV infection, by transplantation, or by other directed therapy.” The panel amended earlier recommendations to
Hepatitis C Testing
prioritize treatment first to those with greatest risk, recognizing that accumulated studies show a benefit for all populations except those with “life expectancy ⬍12 months owing to nonliver-related comorbid conditions.” The continuing barriers to treatment (including price of drugs, access to care, insurance coverage, etc.) increase the numbers of potentially diagnosed cases that in reality will not receive therapy. However, from medical, ethical, and public health perspectives this should not be a mitigating factor in deciding to identify all individuals with chronic HCV with diagnostic testing. Individuals with identified HCV infection, even if they have no indicators of liver damage or active inflammation or have no resource for treatment, can benefit from an early cure of disease or inclusion as part of an identified cohort in need of resource recruitment. At this point in time, the window for useful intervention to help patients with long-standing HCV infection is steadily shrinking. New initiatives must be practical and implementable in the near future. It may be that development of entirely new capabilities for rapid and affordable one-step diagnosis of HCV will not have priority for commercial developers. Nevertheless, these tools will have a continuing important value for developing countries and for US populations at risk for new HCV infection. Meanwhile, use of existing tools repurposed for rapid HCV detection will hopefully be prioritized. Suitable platforms are now available and are CLIA waived for testing of other pathogens. An important bar-
Q&A rier to test deployment has been the requirement for full clinical validation of new tests that have existing predicate devices in widespread use. In the case of HCV RNA testing, the required analytic performance for a new test is well understood. Efforts should be made to encourage regulators to simplify the approval process through an approach that relies solely on rigorous analytic validation.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: G. Horowitz, Clinical Chemistry, AACC; C.S. Graham, Trek Therapeutics PBC. Consultant or Advisory Role: D. Hillyard, Roche Diagnostics. Stock Ownership: C.S. Graham, Trek Therapeutics PBC. Honoraria: None declared. Research Funding: S. Ray, MiDiagnostics Inc. Expert Testimony: None declared. Patents: S. Ray, US Patent 8168771, 9512183, PCT/US2015/ 059403, PCT/US2015/059402.
Previously published online at DOI: 10.1373/clinchem.2016.266569
Clinical Chemistry 63:12 (2017) 7
