Intended for healthcare professionals

Analysis

Is widespread screening for hepatitis C justified?

BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.g7809 (Published 13 January 2015) Cite this as: BMJ 2015;350:g7809

HCV Testing Makes Public Health Sense

In their recent publication, Koretz and colleagues questioned the rationale for hepatitis C virus (HCV) testing, care, and treatment in the United States. The article raised important issues; however, it did not address the full range of benefits associated with HCV testing linked to care, and treatment, and made incorrect assumptions regarding the safety and effectiveness of HCV therapies. We would like to set the record straight on a number of key points.
The CDC and USPSTF recommendations for one-time testing of persons born during 1945-1965 are based on sound evidence that HCV testing linked to care is beneficial for patients, cost effective, and with the potential of averting over 120,000 deaths from HCV (1,2) (http://www.cdc.gov/hepatitis. In the United States, hepatitis C is considered an urgent public health issue. At least 50% of the approximately 3 million persons living with HCV infection remain unaware of their infection; persons born during 1945-1965 have a prevalence of HCV infection five times higher than other adults (1). HCV-related mortality is rising in the United States; from 1999 through 2007, deaths from HCV rose 50% climbing to 17,000 HCV associated deaths reported in 2010 (3). True numbers of deaths are much higher, as only one in four deaths from HCV-related liver disease or hepatocellular carcinoma (HCC) is recorded on a death certificate (4). HCV incidence is also increasing as a consequence of an epidemic of opioid abuse including injection of prescription narcotics and heroin (5).
Koretz et al. suggests that HCV screening among persons born during 1945-1965 is not justified because patients infected with HCV exhibit variable rates of disease progression, with many never succumbing to end-stage outcomes of the disease. However, there are considerable benefits to case identification, linkage to care, and clinical evaluation. Many HCV-infected persons have silent progressive liver disease; in one assessment, 29% of HCV-infected persons in the birth cohort had cirrhosis at the time of their diagnosis (6). In the absence of diagnosis, care, and treatment, over one in three HCV infected persons are expected to die of HCV-associated conditions (1). The goal of routine birth-cohort based HCV screening recommendations is for all persons infected with HCV to become aware of their infection status and be linked to care—ideally early in the course of infection to maximize the benefits of care and treatment services including counseling and drug treatment aimed at reducing transmission, managing co-factors (e.g., alcohol abuse), protecting the liver (e.g., hepatitis A and B vaccination), and assessing the severity of liver disease(1), in addition to direct antiviral treatment. Treatment decisions are aided by guidance from clinician-centered professional associations (i.e., the Infectious Diseases Society of America [IDSA]/American Association for the Study of Liver Diseases [AASLD]).
The authors criticize sustained virologic response (SVR) as a surrogate measure of benefit of HCV therapy. Studies with longer-term follow-up data for the recently licensed HCV agents are needed and are underway (6); however, the preponderance of current evidence shows SVR reduces the risk of liver-related mortality, and HCC by 70-80% (7). Residual HCV is rarely detected after SVR (8). For practically all patients successfully treated, SVR represents a cure of HCV infection.
The authors express concern that persons can develop HCC after achieving an SVR. Risk for HCC is greatest when treatment is delayed until the onset of severe fibrosis or cirrhosis -- prerequisites for development of HCC in persons with HCV infection. Thus, this evidence reveals the benefits of early detection of infection and treatment to achieve virologic cure, thereby reducing risk for HCC: the earlier the treatment, the less fibrosis, and the lower the risk for HCC. In the comparison provided in the author’s analysis, HCC incidence of 1% per year in a treated cohort versus 1.4%-3.3% in an untreated cohort translates to a 29%-70% reduction in liver cancer for HCV-infected persons who receive treatment.
The authors provide cautionary warnings of substantial harms of HCV treatment. However, these concerns largely pertain to earlier interferon-based regimens of long duration, which are no longer recommended as first line HCV therapy, or included agents no longer used in the United States (e.g., telapravir). In the study comparing sofosbuvir versus peginterferon plus ribavirin cited in the analysis, persons receiving peginterferon were eleven-fold more likely to discontinue treatment because of an adverse event (9). Although severe adverse effects can occur, current therapies for HCV are clearly safer than those they have replaced.
As with any therapeutic intervention, treatment decisions are best informed by data regarding potential treatment-related harms balanced against benefits of treatment adverting adverse health outcomes associated with HCV infection including cirrhosis, liver failure, and severe extra-hepatic complications (e.g., cryoglobulinemia) (10). Current HCV treatment guidelines prioritize therapy for persons with evidence of moderate to severe disease and with co-factors that accelerate disease progression (www.hcvguidelines.org/). Based on experience with HIV therapy, indications for HCV treatment may evolve to include a larger proportion of infected persons, depending on additional data and formal risk-benefit analyses of safety and effectiveness.
For a large number of currently undiagnosed persons, the benefits of HCV care and treatment would be lost if implementation of the CDC and USPSTF recommendations were delayed pending results of the 4-6 year study proposed by the authors. Moreover, the proposed study faces a number of challenges including unbiased recruitment of participants for the intervention and control arms, and ethical concerns as the mortality among untested persons in the control arm could have been prevented.
Given what is known about the course of HCV disease, the merits of HCV testing, benefits of care, and availability of safe, curative therapies, missed opportunities for providing these services needlessly compromise the health of HCV infected persons and perpetuate the public’s burden of HCV transmission and disease. Rather than delays to reconsider recommendations, now is the time to garner the public health and clinical care capacity necessary to assure equitable access to HCV testing, care and treatment for all persons infected with HCV.
* The findings and conclusions from this review are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

1. CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR 2012; 61(RR-4): 1-32.
2. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 3;159(5):349-57.
3. Ly KN, Xing , Klevens RM, Jiles RB, Holmberg SD. Causes of death and characteristics of decedents with viral hepatitis, United States, 2010. Clin Infect Dis. 2014 Jan;58(1):40-9.
4. Mahajan R1, Xing J, Liu SJ, et al. Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006-2010.Clin Infect Dis. 2014 Apr;58(8):1055-61.
5. Suryaprasad AG, White JZ, Xu F, et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014 59(10):1411-9.
6. Moorman AC1, Xing J, Ko S, Rupp LB, et al. Late diagnosis of hepatitis C virus infection in the Chronic Hepatitis Cohort Study (CHeCS): Missed opportunities for intervention. Hepatology. 2014 Aug 13. doi: 10.1002/hep.27365. [Epub ahead of print].
7. Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol. 2010 Mar;8(3):280-8, 288.
8. Hedenstierna M, Weiland O, Brass A, et al. Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure. Aliment Pharmacol Ther. 2015 Jan 28. doi: 10.1111/apt.13096. [Epub ahead of print].
9. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-87.
10. Gragnani L, Fognani E, Piluso A, et al. Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: A prospective, controlled, open-label, cohort study. Hepatology. 2014 Nov 27. doi: 10.1002/hep.27623. [Epub ahead of print].

Competing interests: No competing interests

06 March 2015
John W Ward
Medical Epidemiologists
Mermin, Johnathan H
US Centers for Disease Control and Prevention
1600 Clifton Road, Atlanta Georgia