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
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Weiss and Ioannou believe that the evidence that treatment has a favorable impact on hepatitis C infections (presumably on preventing end stage liver disease) is so strong that the trial we proposed is unethical. They do agree with us that comparing those who develop sustained virological responses to those who do not so respond is insufficient evidence. However, after acknowledging that the sustained virological response is not an adequate surrogate outcome, they justify treatment by citing the effect of treatment on another unvalidated surrogate outcome (histology) (1-4), using observations from studies that compared those who developed sustained virological responses to either treated patients who did not develop them or to untreated (and non-comparable) controls. This would also appear to be insufficient evidence. Their argument that the survival in patients who develop sustained virological responses is equivalent to the general population is based on two references that only considered a relatively small number of individuals, and the direction of the effect favored the general population (4, 5), so a type II error cannot be excluded. Since sustained virological responses usually occur in those who are not likely to progress, this would be a predictable finding. Weiss and Ioannou do agree with us that the sustained virological response is not always a cure.
They then go on to state that, even if it is true that it is unclear whether or not treatment yields a net health benefit, a more appropriate randomized trial would be one of antiviral therapy, presumably comparing treatment to no treatment. Their concern about our suggested trial relates to the proposed short duration of the trial (4-6 years), a time that they believe would be inadequate to see an impact of treatment. However, these patients will all be 50-70 years old at the time of screening and will have already been infected for 3-4 decades. If death from other comorbidities (including liver disease not due to hepatitis C) and the failure of hepatitis C to progress to end stage liver disease over the next few years are really issues, what is the justification for proposing screening in the first place?
On the other hand, we do not disagree with their proposal to conduct a randomized trial comparing treatment to no treatment in patients with known hepatitis C, using morbidity and mortality as the outcomes. To date, we have no trial that has shown that any type of antiviral treatment provides such benefits.
1. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127:875-81
2. Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135:821-9
3. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958-65
4. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011; 52:889-900
5. van der Meer AJ, Wedemeyer H, Feld JJ, et al. Life expectancy in patients with chronic HCV infection and cirrhosis compared with a general population. JAMA 2014; 312:1927-8
Competing interests: No competing interests
In response to Dr. Matthews and colleagues:
1. As we reported (1), data were available from eight inception cohort studies and they indicated that, among the individuals who developed chronic infections, no more than 15-20% developed end-stage liver disease after 3-4 decades. This would be enough “optimum” data to be suspicious of other studies that are likely biased and that show much higher progression rates.
2. To the best of our knowledge, there are no studies that have looked for hepatitis C virus in other tissues in patients achieving SVRs with the newer agents. One cannot make any conclusions about the efficacy of treatment by comparing two groups that have both been treated (2). While reinfection may account for the reappearance of virus in some people who achieve SVRs, it cannot be denied that relapse also occurs (3); the respective percentages are not known.
3. The proposed randomized trial would not deny access to diagnosis and treatment to the control group, as Matthews claim. Patients in the control arm who develop symptoms or acquire major risk factors would be screened and (if diagnosed) also treated. If it takes a decade or more to see an effect, it would follow that the implementation of cohort screening is going to be costly, still associated with adverse events, and not very effective or cost-effective.
4. The costs of the screening test and confirmation of chronic HCV infection will not be insignificant in themselves. If the treatments are not effective in preventing liver disease, they are a waste of resources regardless of what they cost. If they are effective, then their cost-effectiveness ought to be first established in the current "high risk" HCV population before expanding eligibility for treatment to millions of additional persons as lower risk of long-term complications.
1. Koretz RL, Lin KW, Ioannidis JP, et al. Is widespread screening for hepatitis C justified? BMJ 2015;350:g7809
2. Hill A, Saleem J, Heath KA, et al. Effects of Sustained virological response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta-analysis of 129 studies in 23,309 patients with Hepatitis C infection. American Association for the Study of Liver Diseases (AASLD) 65th Annual Meeting. Boston, MA, 2014. Oral presentation, Abstract 44. Hepatology 2014; 60(4)
3. Hara K, Rivera MM, Koh C, et al. Sequence analysis of hepatitis C virus from patients with relapse after a sustained virological response: relapse or reinfection? J Infect Dis 2014; 209:38-45
Competing interests: No competing interests
We appreciate the input from Drs. Ward and Mermin into the discussion about hepatitis C screening and treatment, especially since Dr. Ward is the senior author of the paper from the Centers for Disease Control and Prevention that recommended cohort screening (1). Ward and Mermin assert that our paper (2) did not address the full range of benefits of screening and made incorrect assumptions concerning the safety and effectiveness of antiviral treatment.
We agree with them that hepatitis C is a significant clinical problem in the United States as borne out by the epidemiologic data that they cited. However, the issue at hand is whether or not the screening of all individuals born between 1945 and 1965, with subsequent antiviral treatment, will improve those clinical outcomes. Ward and Mermin assert that such screening will have that desired goal. We will address the evidence that they put forth to support their claims.
Ward and Mermin claim that one-third of all individuals with chronic hepatitis C will die of hepatitis C-associated conditions (which we assume means the development of decompensated cirrhosis or hepatocellular carcinoma). This estimate appears to be based on modelling; such models overestimate the rate of progression because the data are obtained from tertiary referral centers (referral bias) (2). Data from inception cohort studies suggest that this rate is lower, namely 15-20% (2).
Ward and Mirman raised concern about hepatitis C not being listed on the death certificate in about 80% of cases of patients who died with such infections (3). However, that observation was based on the absence of that diagnosis on any death certificate, regardless of the cause of death.
Ward and Mermin believe that the optimum time to identify infected individuals is early in the course of the infection. The identification of patients who are already 50-70 years old and have usually had the infection for decades would not seem to accomplish that objective. Similarly they raised concern about a recently-observed rising incidence of hepatitis C (4). However, that event arose in young, nonurban individuals who would not be in the proposed cohort.
Ward and Mermin presented four lines of evidence to support their belief that treatment is effective, namely 1) that treatment is recommended by liver and infectious disease societies; 2) that sustained virological responses decrease the risk of liver-related mortality; 3) that residual hepatitis C virus is rarely detected after sustained virological response; and 4) that such responses represent a cure for practically all patients.
Our original paper (2) discussed the available evidence that was employed by various groups and experts to recommend therapy; we found it to be unconvincing. The reference cited to show that sustained virological responses reduce mortality and cancer by 70-80% (5) was actually a systematic review of trials that compared the outcomes of those who were treated and developed responses to those who were treated but did not develop responses. Such trials are incapable of establishing efficacy of treatment because there is no untreated control group. The one study cited by Ward and Mermin that looked for hepatitis-C-virus-RNA in other body sites of patients who had had sustained virological responses found it in 6% of 54 patients (6); other studies have found it much more frequently, sometimes in > 80% (7, 8). Regardless, for those in whom the virus persists, cure has not been accomplished. Similarly, those who developed decompensated cirrhosis or hepatocellular carcinoma after having a sustained virological response (2) would not view themselves as having been cured.
Ward and Mermin claim that the risk for developing hepatocellular carcinoma is greatest when treatment is delayed until the onset of severe fibrosis; unfortunately they did not provide any references to support their allegation and there are no decades-long followup studies of patients who had sustained virological responses at an earlier stage of liver disease to see if complications have indeed been avoided. However, it does not appear that Ward and Mermin are refuting the fact that these cancers can arise in patients with severe fibrosis in spite of having had a sustained virological response. The reference we employed to document this (9) found an annual incidence of 1%/year. In order to put this number into perspective, we cited a review article by Everson that indicated that the natural history of untreated cirrhosis resulted in annual rates of hepatocellular appearance ranging from 1.4-3.3% (10). It is incorrect to treat these numbers as observations from a randomized trial in order to create risk ratios; the four papers cited in the review article by Everson contained diverse populations. For example, the study that found the highest annual incidence of cancer began with a population in which 18% of the cirrhotic patients were classified as Child’s B.
We agree that the newer agents are likely to be better tolerated than interferon-based regimens. However, we would note that, in one head-to-head comparison of sofosbuvir plus ribavirin to pegylated interferon plus ribavirin (11), while there were more total adverse events in the recipients of the interferon-based therapy (86% [sofosbuvir] versus 96% [interferon]), these events were common in both groups and there was no difference in the incidence of serious ones (3% [sofosbuvir] versus 1% [interferon]). Certainly, long-term clinical benefits still need to be established.
The trial that we proposed would not result in biased recruitment in the two arms. Patients who wanted to participate would be randomized into one of the two groups; randomization avoids the problem of confounding.
Finally, Ward and Mirmen suggest that there are other interventions from screening beside antiviral therapy, such as counseling, substance abuse control, and vaccination against hepatitis A and B. In its 2013 report, the United States Preventive Services Task Force found no studies that evaluated the effects of counseling or immunizations on health outcomes or transmission risk (12). That group did find seven observational studies assessing whether or not knowledge of the hepatitis C status was associated with sustained behavior changes to avoid alcohol or injection drug use, but no consistent relationship was found.
1. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012; 61 (RR-4):1-32.
2. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ 2015; 350: g7809
3. Mahajan R, 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; 58:1055-61
4. 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; 59:1411-9
5. 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; 8:280-8, 288e.1
6. 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; 41: 532–543
7. Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2005;41:106-14
8. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 2004; 78:5867-74
9. van der meer A, Feld J, Hofer H, al. E. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. Abstract 143. Paper presented at: 64th Annual Meeting of the American Association for the Study of Liver Diseases 2013; Washington, DC
10. Everson GT. Management of cirrhosis due to chronic hepatitis C. J Hepatol 2005; 42 (suppl
11. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878-87
12. 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. Ann Intern Med 2013; 159:349-57
Competing interests: No competing interests
Mandal et al believe that targeted case-finding based on risk factors in primary care settings is the optimal way to proceed in the UK and we did not call for a moratorium on such screening. However, we still believe that long-term clinical outcomes with any screening and treating strategy need to be documented. Simply relying on modeling (1) and data comparing subgroups of treated patients (2) is not enough. Modeling (1) starts with the assumption that treatment is effective clinically, so the inferences are circular. While we do not disagree that sustained virological response is a strong prognostic marker, this does not mean necessarily that it is also a strong surrogate of treatment benefit (3, 4). We also agree that effective treatment should hopefully also lead to reduction of transmission of infection (5), but the magnitude of this benefit needs to be documented with evidence. It may be easier to probe this benefit with strategies using targeted screening on high-risk patients, such as people who inject drugs.
To be noted, Mandal et al believe that birth cohort screening would not be useful in the UK. We proposed a randomized trial to test birth cohort screening in the United States because there is a belief by several stakeholders that this is a very good prevention approach. If the numbers of potentially additional detectable cases by birth cohort screening is so small even under optimal circumstances in the UK, no trial is needed; birth cohort screening should simply not be adopted.
Mandal et al called for a trial assessing the role and impact of hepatitis C treatment. Assuming that they were advocating a randomized trial comparing treatment to no treatment and assessing clinical outcomes, we would agree with them.
1. Harris RJ, Thomas B, Griffiths J, et al. Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios. J Hepatol 2014; 61:530-7
2. Innes HA, McDonald SA, Dillon JF, et al. Towards a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. Hepatology 2015; 61(3). DOI: 10.1002/hep.27766 [e-publication ahead of print, accepted February 26, 3015]
3. Koretz RL, Lin KW, Ioannidis JP, et al. Is widespread screening for hepatitis C justified? BMJ 2015;350:g7809
4. Koretz RL, Pleguezuelo M, Arvaniti V, et al. Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. Cochrane Database Syst Rev. 2013;1:CD003617
5. Martin NK, Foster GR, Vilar J, et al. HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact. J Viral Hepat 2015; 22:399-408
Competing interests: No competing interests
Koretz et al suggest that “physicians should resist screening [for hepatitis C virus (HCV) infection] until we have strong evidence that antiviral therapy is clinically effective and the benefits outweigh the harms”. They are concerned that: a) antiviral agents can produce toxicity in some patients; and that b) though some surrogate markers of efficacy (eg sustained virologic response) have clearly been evident in randomized trials of these agents, it is possible that the drugs will not have the same impact on the occurrence of (and mortality due to) serious complications of HCV infection such as cirrhosis, hepatocellular carcinoma, and extra-hepatic conditions (such as cryoglobulinemic vasculitis). As a means of providing the strong evidence that would bear on the question of screening for hepatitis C infection, Koretz et al recommend that a trial be conducted in which persons born during 1945-65 are randomized to be offered screening, with 4-6 year follow-up for mortality related to complications of chronic HCV infection. We believe that: 1. Given the strength of the evidence in support of an overall favorable impact of antiviral therapy for HCV infection, it would not be ethical to conduct a randomized trial in which some persons with occult infections are not identified and treated; and 2. If truly equipoise were present – meaning that (contrary to our opinion) it is unclear whether antiviral treatment yields a net health benefit – then a trial of screening would be less informative than a corresponding 4-6 year trial of antiviral therapy among persons known to be hepatitis C infected.
1. Koretz et al are correct in concluding that the lower incidence of liver disease progression in persons who achieve a sustained virologic response relative to persons who do not achieve such a response is not sufficient evidence of long-term efficacy against clinical outcomes. However, they appear to minimize the importance of other surrogate markers. Eradication of HCV infection has been associated with marked hepatic histological improvement in multiple long-term studies1-3, including 13 such studies described in a systematic review4. Even among HCV-infected patients with advanced fibrosis or cirrhosis (Ishak fibrosis scores 4-6), those who achieved SVR as a result of antiviral treatment had overall survival comparable to the general population whereas those not attaining SVR had reduced survival5, 6 ]We feel that the presence of improved liver structure and function associated with antiviral therapy, in addition to viral eradication, makes it highly likely that treatment of patients with HCV infection by means of antiviral agents will lead to a reduced likelihood of liver disease progression. Of course, no therapy is perfect: as pointed out by Koretz et al, “some” patients in whom a sustained virologic response has occurred have gone on to develop end stage liver disease. And, in patients with advanced structural hepatic changes resulting from chronic HCV infection that are already in place at the outset of treatment, there may well be a high incidence of continued progression despite treatment. But our assessment of the evidence to date is that with respect to long-term clinical outcomes, MANY patients infected with hepatitis C will benefit from receipt of antiviral treatment.
2. Randomized trials of screening are appropriate to conduct only when it is not deemed ethical to withhold treatment from persons who are screened as positive. It would be viewed as unethical to withhold treatment from a woman who has been found to have breast cancer by means of mammographic screening, or a man who has been found to have lung cancer by means of helical CT screening. Therefore, the potential benefit of screening and the treatment that follows requires a comparison of cancer mortality between screened and unscreened persons. However, when the impact of treatment CAN be gauged (typically through randomized trials) separately from that of the performance of the screening modality in identifying ill persons, the most efficient means of estimating the impact of screening in reducing mortality is to combine the results of studies of screening accuracy with those of studies of therapeutic efficacy (Weiss). For example, our knowledge of the impact of screening for hypertension derives largely from studies that documented the predictive ability of high blood pressure for the occurrence of cardiovascular disease, combined with randomized studies of treatment of hypertensive individuals.
If there indeed were equipoise regarding the value of antiviral therapy for HCV infection – as asserted by Koretz et al – it would be ethical to conduct a randomized trial of this form of treatment. Such a trial would restrict enrollment to persons who actually have HCV infection. In a trial of HCV SCREENING efficacy, however, it would not be possible to identify persons with HCV infection among those assigned to the non-screening arm. Included in the analysis of such a trial would be persons in both treatment and control arms who died from end stage liver disease or liver cancer for reasons other than hepatitis C, eg alcoholic liver disease, fatty liver disease or hepatitis B virus infection. Because of the lack of impact of antiviral treatment on these other conditions, the value of screening to prevent long-term complications of HCV infection per se would be underestimated. In addition, the relatively short duration of follow-up of participants in the trial proposed by Koretz et al – 4-6 years – would likely to lead to an underestimate of the absolute impact of HCV screening on liver disease mortality. Persons with clinically evident liver disease - i.e. those most likely to succumb to this disease or its complications in the ensuing 4-6 years – would in most instances already have been tested for HCV, and would not be candidates for participation in a “screening” trial. The trial participants would thus be heavily weighted with persons without clinically-evident liver disease, whose hepatic-related mortality would be expected to be quite small until well after the trial had concluded.
We do not believe that a randomized trial of HCV screening is warranted. Now that the majority of HCV-infected patients can achieve SVR, what is needed is better tools to predict which patients are most likely to benefit from achieving SVR. Given the well-described aging of the HCV-infected population in the USA7, 8, many patients with HCV infection who have not yet developed advanced fibrosis are likely to die of competing comorbidities. On the other end of the spectrum, we need to determine the threshold of severity of HCV-related liver disease beyond which SVR cannot improve liver-related outcomes. These determinations are particularly critical because the current high cost of antiviral therapy means that no healthcare system can afford to treat all HCV-infected patients.
1. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, Kilani A, Areias J, Auperin A, Benhamou JP, Degott C, Erlinger S. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997;127:875-81.
2. Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, Giuily N, Castelnau C, Cardoso AC, Asselah T, Feray C, Nicolas-Chanoine MH, Bedossa P, Marcellin P. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008;135:821-9.
3. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65.
4. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011;52:889-900.
5. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, Duarte-Rojo A, Heathcote EJ, Manns MP, Kuske L, Zeuzem S, Hofmann WP, de Knegt RJ, Hansen BE, Janssen HL. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584-93.
6. van der Meer AJ, Wedemeyer H, Feld JJ, Dufour JF, Zeuzem S, Hansen BE, Janssen HL. Life expectancy in patients with chronic HCV infection and cirrhosis compared with a general population. JAMA 2014;312:1927-8.
7. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513-21, 521 e1-6.
8. Denniston MM, Jiles RB, Drobeniuc J, Klevens M, Ward JW, McQuillan G, Holmberg SD. Chronic hepatitis C infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
Competing interests: No competing interests
Koretz and colleagues raise several important issues on the strength of the evidence base for HCV case finding through widespread screening, HCV treatment and liver disease prevention.
We disagree, however, with their solution of mounting a large scale trial of screening. Such a trial would be expensive, take many years and may still fail to reduce uncertainty about the natural history of HCV, when some of these uncertainties, e.g. liver disease progression after HCV treatment and non-liver disease mortality rates are taken into account in cost-effectiveness models of HCV treatment[2,3], which Koretz and colleagues perfunctorily dismiss.
We agree that there is an important question on whether “birth cohort” screening is the best strategy to identify people with chronic liver disease[4,5]. In England an estimated 0.4% of adults are chronically infected with HCV, equating to approximately 160,000 people, with around 85% of infections acquired through injecting drug use, of which an estimated 89,000 aged 15-59 years are ex-injecting drug users[6,7]. Therefore, the numbers of ex-injectors or people who have never injected with HCV related chronic liver disease in the UK is unlikely to be sufficient to justify a birth cohort screening approach similar to that promoted in the US.
In contrast, the National Institute of Health and Care Excellence (NICE) recommends targeted testing of hepatitis C (and B) in primary care, prisons and immigration removal centres, sexual health and genito-urinary medicine clinics.8 Up to 50% of people who currently inject drugs (PWID) have been infected and so this “case finding” approach is likely to be cost-effective in the UK, and cost-effective in the US[2,9,10] as Koretz and colleagues have highlighted. In fact, sentinel surveillance of anti-HCV testing in England suggests that targeted approaches in primary care settings have a high yield with positivity rates of 9.4% in prisons, 1.7% in GUM clinics, 10.1% in drug services (increasing to 19% if oral fluid and dried blood spot testing are included7), 2.1% in General Practice and 2.6% in Emergency Departments. There is a lack, however, of robust empirical evidence on how to increase case finding in the UK with only one uncontrolled pilot study in primary care and a single trial of dried blood spot testing in prisons and specialist drug treatments.
Increasing the identification of infected individuals so that they can be offered HCV treatment has two potential benefits: reducing HCV related mortality and End Stage Liver Disease (ESLD) and averting HCV infections/future transmission. We know that in the UK there is currently insufficient HCV treatment (estimated at 3% of the infected population each year ) either to slow the rise in HCV related ESLD and hepatocellular cancer (HCC) or reduce HCV prevalence among PWID[14,15]. Continuing with standard treatments at current levels, by the year 2035, England will be facing 1650 cases of HCV-related end stage liver disease and cancer annually; however, without treatment that number could increase to 2290 incident ESLD/HCC cases each year. Increasing the number of people treated could prevent up to 400 of these cases per year with forthcoming, more effective, treatments offering the potential to halve disease burden in 10-20 years depending on how quickly complete treatment coverage can be achieved. Recent studies have demonstrated high SVR rates in those with cirrhosis indicating that more rapid burden reductions are possible.
Koretz and colleagues also question the clinical significance of SVR as an outcome . While this endpoint may need further evaluation, a recent Scottish cohort study of over 3000 patients treated for hepatitis C found that SVR was associated with significant absolute risk reductions for liver mortality, all-cause mortality, severe liver mortality and cardiovascular disease, with the greatest risk reductions in those with non-mild liver disease versus mild liver disease. Additionally, this study also demonstrated an association between SVR and behavioural events, consistent with patients achieving SVR leading healthier lives. These findings do suggest that SVR is a meaningful endpoint and worth aiming for in the short-term.
It is our belief that the UK (and other countries) now need to evaluate the scale-up of HCV treatment among people with severe liver disease and its impact on ESLD and HCV related mortality, together with a trial assessing the role and impact of HCV treatment in primary prevention of HCV, rather than a trial specifically of a form of screening. Of course, establishing a national treatment monitoring and outcome dataset should be an important component of any HCV treatment scale-up and evaluation to ensure equitable access to treatment and efficient use of limited resources.
However, although evidence on the impact of HCV treatment should be accumulated, to have a moratorium on risk-based testing in the interim would be questionable. Chronic HCV infection often has no symptoms or only non-specific symptoms, which are frequently ignored. A large pool of people with undiagnosed infections exists which, in developed countries, mainly affects people who already experience poorer health access and health outcomes. If these individuals are not identified, they may not benefit from behavioural and clinical interventions that reduce their risk of HCV related complications (e.g. diabetes and dyslipidaemia) and that slow down liver disease progression, and they will retain their risk of premature mortality from non-HCV related causes (e.g. opiate overdose). Most crucially, they will continue to be at risk of transmitting HCV infection to others as they are unlikely to benefit from access to safer injecting practices and/or obtain SVR after successful treatment. Whilst Koretz and colleagues are conducting their large scale studies over the next few decades, they may ponder on the resulting infections and deaths that could have been averted.
1. Koretz RL, Lin KW, Ioannidis JP, et al. Is widespread screening for hepatitis C justified? BMJ 2015;350:g7809.
2. Martin NK, Hickman M, Miners A, et al. Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons. BMJ open 2013;3(8).
3. Martin NK, Vickerman P, Miners A, et al. The cost-effectiveness of HCV antiviral treatment for injecting drug user populations. Hepatology 2012;55(1):49-57.
4. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med 2012;156(4):263-70.
5. Coffin PO, Scott JD, Golden MR, et al. Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clin Infect Dis 2012;54(9):1259-71.
6. De Angelis D, Sweeting M, Ades A, et al. An evidence synthesis approach to estimating Hepatitis C prevalence in England and Wales. Stat Methods Med Res 2009;18(4):361-79.
7. Public Health England, Hepatitis C in the UK. 2014 Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...
8. NICE. Hepatitis B and C - ways to promote and offer testing to people at risk of infection. Manchester, 2012.
9. Martin NK, Miners A, Vickerman P. Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: An economic modelling report. London, 2012.
10. Miners AH, Martin NK, Ghosh A, et al. Assessing the cost-effectiveness of finding cases of hepatitis C infection in UK migrant populations and the value of further research. J Viral Hepat 2013.
11. Public Health England. Annual report from the sentinel surveillance study of blood borne virus testing in England: data for January to December 2013. Health Protection Report. Volume 8 Number 29 Published on: 25 July 2014.
12. Cullen BL, Hutchinson SJ, Cameron SO, et al. Identifying former injecting drug users infected with hepatitis C: an evaluation of a general practice-based case-finding intervention. J Public Health (Oxf) 2012;34(1):14-23.
13. Hickman M, McDonald T, Judd A, et al. Increasing the uptake of hepatitis C virus testing among injecting drug users in specialist drug treatment and prison settings by using dried blood spots for diagnostic testing: a cluster randomized controlled trial. J Viral Hepat 2008;15(4):250-54.
14. Harris RJ, Thomas B, Griffiths J, et al. Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios. J Hepatol 2014.
15. Martin NK, Foster GR, Vilar J, et al. HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact. J Viral Hepat 2014.
16. American Association for the Study of Liver Diseases. (2014). Parallel 12: Hepatitis C: New Agents -Part 1. In The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2014 (p. 236A–241A). Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/hep.27461/abstract].
17. Innes HA, McDonald SA, Dillon JF, et al. Towards a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. Hepatology 2015; 61(3). DOI: 10.1002/hep.27766
18. Martin NK, Hickman M, Hutchinson SJ, et al. Combination interventions to prevent HCV transmission among people who inject drugs: modeling the impact of antiviral treatment, needle and syringe programs, and opiate substitution therapy. ClinInfectDis 2013;57 Suppl 2:S39-S45.
Competing interests: No competing interests
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
We understand the passion for treatment exhibited by Dr. Foster and his colleagues in their letter. However, we are concerned about the limitations of the evidence that they presented.
Is treatment effective in preventing end-stage liver disease or improving morbidity or mortality in general? The reference in paragraph three (1) was an editorial that cited seven studies that either compared treated patients to non-randomized untreated patients or compared treated patients who did, or did not, achieve a sustained virological response (SVR). Neither study design can establish efficacy because of confounding variables or the absence of an untreated comparator group.
The basis for the claim that patients with decompensated cirrhosis respond favorably to treatment (improved MELD and Child-Pugh scores) was an abstract describing a randomized trial comparing 12 to 24 weeks of treatment in 108 patients with decompensated cirrhosis (2). There were 10 dropouts (4 transplants, 3 deaths, and 3 adverse events) and 24 serious adverse events (unclear if the 3 who dropped out were part of these 24). No clinical data were provided (although they may have been presented at the meeting), so it is unclear what the magnitude of the “benefit” was; at least 31/108 had detrimental outcomes. Moreover, in the absence of untreated controls, no absolute benefit can be ascertained.
Foster et al propose that the efficacy of treatment is due to reduced inflammation. This hypothesis was tested in the HALT-C trial of pegylated interferon; while SVR rates were low, the treated group had more, but those individuals were also more likely to die (3).
They cite a systematic review showing that the rates of hepatocellular carcinoma are lower in those achieving SVRs (4). That review employed uncontrolled or non-randomized controlled studies. There was no significant association between the use of interferon therapy and the incidences of death or transplantation, but the treated patients did have a significantly lower incidence of hepatocellular carcinoma. However, this latter observation was not confirmed in a number of randomized trials that compared interferon therapy to no treatment (5).
They claim that treatment improves quality of life and neurocognitive function, citing one trial to support this latter assertion (6). Quality of life data cannot be reliably interpreted in unblinded studies, especially when many assume that treatment is effective and SVRs are cures. The cited study (6) compares treated patients who did, or did not, achieve SVRs (no untreated controls) and was an unblinded study that measured a subjective outcome.
They conclude by invoking the support of European and American experts. A required standard for introducing screening is the presence of effective therapy; the available evidence does not meet that standard. Expert opinion is the lowest level of evidence; in 1997, expert opinion recommended interferon treatment for all patients with severe fibrosis (7) but subsequent randomized trials failed to show that it provided any benefit to that very population (5).
While we agree that hepatitis C is a common problem, we disagree over the percentage that will have an adverse outcome. We focused on the inception cohort studies while Foster et al considered models based on natural history studies from tertiary referral centers. The claim that the data from the last 10 years validated the models disregards the fact that the models dramatically disagree with the inception cohort data.
We believe that data from tertiary referral centers overestimate the risk of end-stage liver disease because of selection bias. Foster et al attribute the more benign courses that are depicted in the inception cohort studies to the institution of life-style changes, but they fail to explain why patients in tertiary referral centers are not responsive to those changes. They note that life-style changes can only be recommended if infected patients are identified; in this regard, we do not oppose risk-based screening. If Foster et al really believe that life-style changes can make this dramatic a difference, it is surprising that so many of their comments are instead directed to the use of pharmacologic agents. We actually have no convincing evidence that life-style changes make any difference, but our proposed trial would shed light on this issue.
Foster et al cite two references to support the claim that, over a 30-40 year period, a majority of patients develop liver disease. One paper presented all-cause and disease-specific mortalities in different countries in the world, comparing data from 1990 to 2013 (8). The other reference was cited as “England PH. Hepatitis C in the UK. 2014”; a PubMed search did not identify an author named PH England, so we cannot comment on this reference. The Lancet paper was not designed to address the natural history of hepatitis C; only numbers and age-adjusted rates of deaths in two different years were presented.
Foster et al noted that 20% of infected individuals would have cirrhosis after 20 years of infection (9); however, the endpoint of concern is not histologic cirrhosis but end-stage liver disease. Data from the inception cohort studies indicate that that risk after 20 years is very low and, even after three decades, is less than 5% (10).
Foster et al disagree with us regarding the utility of the SVR as a treatment outcome. They suggest that the virus is eliminated if SVR is achieved; however, we know that there are some individuals with SVRs who have evidence of HCV-RNA in other body tissues and that others will subsequently relapse with the same virus (10).
Foster et al allege that we stated that “viral elimination” (presumably SVR) does not reduce the incidence of cancer, a contention that we did not make. Rather, we noted that an SVR did not remove the risk of cancer. To support this conclusion, we cited a long-term study of patients who, in spite of having severe fibrosis (86% cirrhosis), achieved SVRs (11) to point out that the SVR did not guarantee a cure; hepatocellular carcinoma developed at a rate of 1%/year in these patients. Their comment about comparing a high rate of cancer in a group that achieved SVRs to a “strikingly low rate” in a different untreated group related to the fact that we attempted to put this 1% rate into perspective by noting that the annual rate of cancer development in observational studies was 1.4-3.3%.
Foster et al believe that we did not adequately discuss the newer agents. We did acknowledge that these therapies produce high SVR rates. However, given the facts that not all patients achieving SVRs are cured (10), that SVRs are not always achieved, and that only a minority of infected patients will progress, the SVR is not a meaningful outcome.
We agree that serious adverse events are not always due to the medication. However, if the intervention is not effective, any adverse events are unacceptable.
Foster et al claim that chronic hepatitis C infection is known to cause renal disease, diabetes, and lipid disorders. However, the three cited references (1, 12, 13) only show association; association cannot prove causation. For example, a large epidemiologic study that investigated the relationship between diabetes and hepatitis C indicated that the adjusted odds ratio for both diabetes and prediabetes in those with and without hepatitis C infection was 1.0 (14). The abnormality associated with hepatitis C was the abnormal ALT, and the apparent association reported by others was attributed to ascertainment bias.
Foster et al believe that our estimation of 250 deaths per year is incorrect because the number will increase from year to year. This assertion appears to be based on the models that we believe overestimate the rate of progression. However, since we believe that this trial needs to be done, their concern translates into a trial of shorter duration.
Foster et al note that treatment results in reversal of fibrosis and cite a reference that assessed patients treated with interferon and ribavirin (15).
We would note that this outcome is also an unvalidated surrogate outcome and, like the SVR, is of unknown utility.
Foster et al fault us for not considering the issue of HCV transmission. At this time, we have no data regarding the effect of treatment on transmission; if HCV-RNA persists in other organs, this will still be a problem.
Foster et al make enthusiastic recommendations for the implementation of screening and treatment. We believe that policy decisions should rest on good evidence; such evidence is not currently available to support these recommendations.
Ronald L Koretz, emeritus professor of clinical medicine, David Geffen-UCLA School of Medicine, CA, USA
Kenneth W Lin, associate professor of family medicine, Georgetown University School of Medicine, Washington, DC, USA
John P A Ioannidis, professor of medicine, Stanford University, CA, USA
Jeanne Lenzer, medical investigative journalist, New York, USA
1. van der Meer AJ. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut 2015; 64:364-366
2. Flamm SL, Everson GT, Charlton M et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study. (Abstract 239) Hepatology 2014; 60 (Suppl):320A
3. Di Bisceglie AM, Stoddard AM, Dienstag JL, Shiffman ML, Seeff LB, Bonkovsky HL, et
al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term
peginterferon. Hepatology 2011;53:1100-8
4. Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther. 2010; 32(3): 344-55
5. Koretz RL, Pleguezuelo M, Arvaniti V, Barrera Baena P, Ciria R, Gurusamy KS, et al.
Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C.
Cochrane Database Syst Rev 2013;1:CD003617
6. Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, et al. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013; 58(2): 497-504
7. Management of hepatitis C. NIH consensus statement online 1997;15:1-41. http://
8. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385: 117–71
9. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008; 48(2): 418-31
10. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ 2015; 350: g7809
11. Van der Meer A, Feld J, Hofer H, Almasio PL, Calvaruso V, Fernandez-Rodriguez CM,
et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection
and advanced hepatic fibrosis following sustained virological response: Abstract 143.
64th annual meeting of the American Association for the Study of Liver Diseases,
Washington, DC, 2013.
12. Molnar MZ, Alhourani HM, Wall BM, Lu JL, Streja E, Kalantar-Zadeh K, et al. Association of hepatitis C virus infection with incidence and progression of chronic kidney disease in a large cohort of US veterans. Hepatology 2015; doi: 10.1002/hep.27664
13. Alaei M, Negro F. Hepatitis C virus and glucose and lipid metabolism. Diabetes Metabolism 2008; 34(6 Pt 2): 692-700
14. Ruhl CE, Menke A, Cowie CC, Everhart JE. Relationship of hepatitis C virus infection with diabetes in the U.S. population. Hepatology 2014; 60:1139-49
15. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002; 122(5): 1303-13
Competing interests: No competing interests
We read Koretz’ article 1 on HCV screening with concern. The authors argue that screening for HCV infection should be delayed pending more research. Their arguments are based on a linear impact of HCV infection on fibrosis and mortality, the poor efficacy of current drugs and the lack of evidence that current drugs improve mortality. These assumptions are wrong.
Infection with HCV was common in the 1960-80s, before it was properly identified, when iatrogenic transmission and injecting drug use readily transmitted the virus2. Infection is therefore common in middle age and those infected are growing older. Increasing age increases HCV mortality and deaths from infection are predicted to rise exponentially for the next few years before declining rapidly 3. Data from independent sources 4,5 confirm a recent increase in mortality and during the 4 to 6 years suggested to complete a screening study many will die of treatable infection. Koretz’ assumption that the 250 deaths per year in the screening trial will be constant throughout the trial is wrong – the demographics of the epidemic will ensure that the number of deaths will increase every year. The longer we delay intervening in the epidemic the more deaths will ensue.
The very long term natural history of chronic HCV infection remains to be determined – we agree that an average of 20% of patients develop cirrhosis after 20 years 6 but fibrosis progression accelerates with age 7, 8 and the few studies over a life time of infection show a majority of patients developing liver disease over a 30-40 year time frame4, 5. These higher mortality figures help to explain the observed increases in mortality noted above and the latest Global Burden of Disease estimate of 700,000 deaths globally in 2013. Koretz quotes a Taiwanese study9 showing that patients with chronic HCV die more often from liver disease than uninfected controls and also die more often from nephritis and cardiovascular disease. They conclude that people who are at risk of HCV infection are likely to die of non-liver disorders unrelated to their infection. However, chronic HCV infection is known to cause renal disease 10, diabetes and dyslipidaemia 11, 12 and as effective therapy for HCV reduces all cause mortality (data recently critiqued and reviewed by van der Meer 201512) a more appropriate interpretation of these data is that the non-hepatic effects of HCV are injurious and resolve with effective therapy. In the developing world, where this study was conducted, HCV transmission is often via contaminated medical equipment, chiefly needles used in immunization programs, and the argument that mortality from chronic HCV infection is due to associated Western life-styles rather than the virus is not applicable. Hence epidemiological studies confirm the association of HCV viraemia with early death. We agree with Koretz that disease progression is non-random and lifestyle factors can be modified to improve outcome. Indeed in all of the long term follow up cohorts (cited by Koretz as the best data on natural history of HCV) these lifestyle changes were implemented, probably accounting for the relatively benign natural history seen in these cohorts over 30 years of infection. It is difficult to see how lifestyle changes that prevent HCV progression can be implemented unless such patients are identified and the argument that patients diagnosed with HCV have a slow rate of disease progression following lifestyle interventions is a clear argument in favour of identification, even if therapy can not be made immediately available.
Studies comparing mortality in treated patients who respond to therapy, compared to treated patients who do not respond to therapy all show a benefit from viral clearance 13. Koretz argues that these clear benefits were ‘likely’ due to ‘inherent differences in people who respond’ i.e. people who respond to therapy were those who were not going to develop liver disease. If this were true then patients with cirrhosis (i.e. those who have developed HCV associated liver disease) should almost never respond to therapy. However, up to 50% of patients with cirrhosis who are treated with interferon based regimes do eliminate the virus 14,15and histological follow up studies show fibrosis regression 16. Data from patients with decompensated cirrhosis treated with new anti-viral agents sofosbuvir and ledipasvir show a marked improvement in markers of liver dysfunction and an improvement in MELD and Child-Pugh scores17. There is therefore clear evidence of benefit from therapy in patients with cirrhosis. Given that chronic HCV infection causes liver inflammation and fibrosis and given that viral elimination reduces inflammation and leads to histological regression of fibrosis it is difficult to argue that that treatment has no benefit. Koretz argues that viral elimination does not reduce the risk of liver cancer and compares different studies with different underlying rates of cancer to imply that the rate of cancer is the same in successfully treated and unsuccessfully treated patients. This is misleading – all comparisons within the same cohorts that we are aware of show a reduction in liver cancer rates in treated patients and a meta-analysis of such studies 18 confirms this. To take the highest cancer rate reported from a population who were treated and compare it to a single, selected, untreated population with a strikingly low rate of malignancy and thereby conclude that treatment has no effect is invalid and does the authors little credit.
It is disappointing that the authors do not adequately discuss current therapies for HCV. In countries with the resources to support a screening campaign the current standard of care no longer involves interferon but uses all oral therapies, either sofosbuvir/ledipasvir19 or parataprevir, ombitasvir and dasabuvir20. These drugs eliminate virus in >95% of treated patients, albeit with some lower response rates in less common viral strains. The authors are selective in their review of drug safety data – they intersperse data from telaprevir (no longer recommended in the USA) with the latest drugs (sofosbuvir plus ledipasvir) and they quote an SAE rate of 2% for the later combination. An appropriate analysis of safety data from sofosbuvir/ledipasvir21 shows that of the 10 SAEs reported in 647 treated patients most (if not all) were from conditions not associated with the medication (for example road traffic accident, lung or pituitary cancer, bile duct stone). We would not wish to minimize the need for close monitoring of newly licensed drugs nor the potential for unanticipated safety concerns but it is inappropriate to selectively cite adverse events and misleading to create the impression that current therapies have the disadvantages of the drugs that they replace.
Throughout their discussion the authors do not comment on the transmission of HCV, which remains high in injection drug users and is not negligible in pregnant mothers, nor do they cite the large body of work indicating that chronic HCV infection reduces quality of life and is associated with objective neuro-cognitive dysfunction, which improve post therapy22.
Koretz’ proposal for a trial of screening will, without doubt, delay the introduction of global policies to eliminate chronic HCV infection. The authors’ timetable of 4-6 years for a trial will lead to large numbers of preventable deaths. In an epidemic with an ageing cohort of patients increasingly reaching an age at which complications will ensue we must not allow calls for delay to allow further data collection to derail intervention. Multiple models from different sources all agree that there will be an increase in HCV mortality over the next decade. The data from the last 10 years confirm the accuracy of the earlier models validating the approach used. We know that patients under clinical review can change their life style to reduce disease progression; we know that patients who have been treated successfully die less often than those who have not cleared virus and we know that patients who do not have virus feel better and do not transmit their virus to others. Independent experts from Europe and the US have reviewed these data and conclude that more testing, more screening is the right response. We agree. The development of new, highly effective, all oral therapies for HCV infection gives us an opportunity to eliminate the harm caused by this virus and to delay a process of clear benefit to satisfy demands for more data would expose thousands of undiagnosed treatable patients to the risks of cancer and cirrhosis. This must not be regarded as acceptable.
Graham R Foster FRCP Professor of Hepatology, Queen Marys University of London
Conflicts of interest – speaker and consultancy fees from AbbVie, Gilead, BMS, Janssen, MSD
Charles Gore Chief Executive The Hepatitis C Trust
(Conflicts of interest The Trust receives support from AbbVie, Janssen, MSD, Roche, Gilead)
Dr Mark Hudson FRCP Consultant Hepatologist, Freeman Hospital, Newcastle President of BASL
Conflicts of interest advisory boards and speaking commitments Janssen and Gilead)
Dr Peter Moss Consultant in Infectious Diseases Hull & East Yorkshire Hospitals NHS Trust
President of the British Infection Association
Conflicts of interest consultancy and paid speaking engagements for MSD, Gilead, Janssen, AbbVie, and BMS
Dr Andrew Ustianowski
Consultant in Infectious Diseases North Manchester General Hospital
President of British Viral Hepatitis Group
Conflicts of interest consultancy and paid speaking engagements for AbbVie and Gilead
Dr Stephen Ryder Consultant Hepatologist, Nottingham University Hospitals NHS Trust
Vice President Hepatology British Society of Gastroenterology
Conflict of interest Advisory boards Gilead, Abbvie, Janssen, MSD
Dr Sanjay Bhagani Consultant Physician, Royal Free Hospital,
Chair Hepatitis Committee BHIVA
Conflicts of interest speaker engagements, advisory boards Abbvie, BMS, Gilead, Jannsen and MSD
1. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ. 2015; 350: g7809.
2. Saraswat V, Norris S, de Knegt RJ, Sanchez Avila JF, Sonderup M, Zuckerman E, et al. Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2. Journal of viral hepatitis. 2015; 22 Suppl 1: 6-25.
3. Razavi H, Waked I, Sarrazin C, Myers RP, Idilman R, Calinas F, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm. Journal of viral hepatitis. 2014; 21 Suppl 1: 34-59.
4. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014.
5. England PH. Hepatitis C in the UK. 2014.
6. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008; 48(2): 418-31.
7. Ryder SD, Irving WL, Jones DA, Neal KR, Underwood JC. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut. 2004; 53(3): 451-5.
8. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. Journal of hepatology. 2001; 34(5): 730-9.
9. Lee MH, Yang HI, Lu SN, Jen CL, You SL, Wang LY, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. The Journal of infectious diseases. 2012; 206(4): 469-77.
10. Molnar MZ, Alhourani HM, Wall BM, Lu JL, Streja E, Kalantar-Zadeh K, et al. Association of hepatitis C virus infection with incidence and progression of chronic kidney disease in a large cohort of US veterans. Hepatology. 2014.
11. Alaei M, Negro F. Hepatitis C virus and glucose and lipid metabolism. Diabetes & metabolism. 2008; 34(6 Pt 2): 692-700.
12. van der Meer AJ. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut. 2015.
13. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. Jama. 2012; 308(24): 2584-93.
14. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. The New England journal of medicine. 364(25): 2405-16.
15. Shoeb D, Rowe IA, Freshwater D, Mutimer D, Brown A, Moreea S, et al. Response to antiviral therapy in patients with genotype 3 chronic hepatitis C: fibrosis but not race encourages relapse. Eur J Gastroenterol Hepatol. 2011; 23(9): 747-53.
16. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002; 122(5): 1303-13.
17. Flamm S, M E, MR C, JM D, Arterburn S, Brandt-Sarif T, et al. Ledipasvir/Sofosbuvir With Ribavirin for the Treatment of HCV in Patients With Decompensated Cirrhosis: Preliminary Results of a Prospective, Multicenter Study. AASLD 2015. 2015.
18. Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther. 2010; 32(3): 344-55.
19. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. The New England journal of medicine. 2014; 370(20): 1889-98.
20. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. The New England journal of medicine. 2014; 370(21): 1983-92.
21. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. The New England journal of medicine. 2014; 370(20): 1879-88.
22. Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, et al. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013; 58(2): 497-504.
Competing interests: Conflicts of interest – speaker and consultancy fees from AbbVie, Gilead, BMS, Janssen, MSD
Re: Is widespread screening for hepatitis C justified? Authors' reply to Cryer, Selvapatt, Badrinath, Ward, Anand, Weatherburn, and Zacharia
One of our objectives in publishing the paper challenging both the efficacy of antiviral treatment and the utility of widespread hepatitis C screening was to initiate a conversation about these issues. We thank the authors of the first seven responses (the number that were available when we prepared this response) for accepting this challenge and sharing their perspectives.
Ms. Cryer asserts that our proposal to “undermine” (her word) birth cohort screening is premature since the direct-acting antivirals have only been available for a limited amount of time. However, this is actually a reason to be cautious. More time, longer follow-up, and randomized data with clinical endpoints are needed before we can conclude whether the effects on sustained virological response (SVR) translate into benefits for end-stage liver disease and mortality.
Ms. Cryer also believes that we have undervalued the harms of hepatitis C. The best available data indicate that only 15-20% of infected patients will develop end-stage liver disease and we have no data proving that antiviral therapy will prevent any of that harm (1). Certainly treating the rest cannot make their lifelong asymptomatic condition any better. In addition, the association between hepatitis C infection and premature mortality has not been shown to be causal (i.e., in her words, an “extrahepatic effect”); patients are infected for particular reasons (e.g., risky behaviors or a need for blood transfusions) that, in and of themselves, can result in premature mortality.
Dr. Selvapatt made several points: 1) there is a large number of infected people; 2) birth-cohort screening has demonstrated cost-efficacy; 3) a meta-analysis demonstrated that treatment reduces mortality; 4) previously treated patients with mild to moderate disease are unlikely to suffer further liver damage; 5) quality of life is improved after SVRs; and 6) the newer agents have fewer side effects. The number of patients is not the issue; rather it is whether or not identifying and treating those infected people will result in clinical benefit. Cost-effectiveness analyses cannot be used to address this issue reliably for the reasons that we have already presented (1); the cited reference (2) does not provide many details of the analysis, but we know that natural history was derived from data from tertiary referral centers (which overestimate risk) and the premature mortality of infected individuals (which limits benefit) was not considered. The claim regarding reduced mortality relied on a meta-analysis (3) that compared treated patients who did or did not develop SVRs, not treated versus untreated patients. We know that some patients with severe fibrosis who have SVRs do develop end-stage liver disease; the fact that people with less severe fibrosis have not yet done so cannot reassure us that this will not happen in the future. Quality of life assessments are problematic in unblinded trials. Finally, if there is no or limited benefit from treatment, then any adverse events, including costs, are unacceptable.
Dr. Badrinath cites statements made by NICE to support the use of antiviral treatment, even though he did note that there have been some problems with its methodology. Unfortunately, Dr. Badrinath did not tell us where he thought we erred in our interpretation of the literature. We believe that many organizational pronouncements need to be rethought after a more critical assessment of the evidence.
The remaining letters related to aspects of screening. Chris Ward provides some interesting information about the problem of hepatitis C transmission among men who engage in risky behaviors. As is noted, guidelines already exist for the screening of such people. In this regard, we note Dr. Anand’s comments regarding the potential consequences of widespread screening that may divert efforts on improving screening in high-risk patient groups. Dr. Weatherburn informs us about a study in which abnormal liver tests will be linked to hepatitis C testing; such a project really represents another type of risk-based screening. Finally, Dr. Zacharia enumerates putative benefits of universal screening (which is even more extensive than birth-cohort screening). Unfortunately, we have no reliable data comparing the costs, benefits, and harms of such a scheme, but we would note that a trial like the one we described could provide insight into this proposal.
Ronald L Koretz, emeritus professor of clinical medicine, David Geffen-UCLA School of Medicine, CA, USA
Kenneth W Lin, associate professor of family medicine, Georgetown University School of Medicine, Washington, DC, USA
John P A Ioannidis, professor of medicine, Stanford University, CA, USA
Jeanne Lenzer, medical investigative journalist, New York, USA
1. Koretz RL, Lin KW, Ioannidis JPA, Lenzer J. Is widespread screening for hepatitis C justified? BMJ 2015;350:g7809 doi: 10.1136/bmj.g7809 (Published 13 January 2015)
2. McEwan P, Ward T, Yuan Y, Kim R, L’italien G. The impact of timing and prioritization on the cost-effectiveness of birth cohort testing and treatment for hepatitis C virus in the United States. Hepatology 2013;58(1):54–64
3. Hill A, Saleem j, Heath KA, Simmons B. Effects of sustained virological response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta-analysis of 129 studies in 23,309 patients with Hepatitis C infection. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-11, 2014. Abstract 44
Competing interests: No competing interests