Do direct acting antivirals cure chronic hepatitis C?
BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1382 (Published 10 May 2018) Cite this as: BMJ 2018;361:k1382
All rapid responses
We write to express our serious concerns about the decision of the BMJ to publish a piece under its "uncertainties" section reserved for "areas of practice where management lacks convincing supporting evidence"(1). Treatment of hepatitis C (HCV) is not an area lacking convincing evidence and to portray it as such has the potential to undermine current public health efforts and cause unnecessary uncertainty for patients infected by the virus. The development of direct-acting antiviral drugs (DAAs) to treat the HCV is one of the most significant advances in medicine of our time, providing a potential cure for the 70 million people infected around the world who would otherwise face an unacceptably high risk of cirrhosis and hepatocellular carcinoma.
Following publication of the authors' Cochrane systematic review in 2017 (2), the scientific community were quick to point out serious methodological flaws in the analysis, fundamental mistakes in the results section (some of which were subsequently revised) and unjustified conclusions beyond the work carried out. This included strong rebuttal statements from leading liver disease organizations (EASL(3), AASLD and IDSA(4)). We assume the authors have read the extensive international response to their views and thus for these statements to remain unmodified and be given an uncritical platform in a leading journal with wide readership is deeply concerning. Rather than repeat the arguments made before, we would refer interested clinicians to these statements to make it clear that the article's authors are out of step with the field as a whole.
As HCV replicates in the liver over a long period of time, fibrosis in the liver accumulates and may progress to cirrhosis, a condition which is only rarely reversible. The statement that the word "cure is not adequate… because patients who achieve sustained virological response can progress to end stage liver disease" confuses the cure of infection with the cure of disease resulting from fibrotic scarring of the liver resulting from that infection. Curing the virus that acted as the trigger for such damage will not reverse all the long-term consequences of liver fibrosis that have accumulated over many years, but it will prevent further damage. There is compelling evidence that all-cause mortality and occurrence of liver cancer is significantly reduced in those achieving cure, even when fibrosis remains (for example reference 5 ). It is important that patients are treated before such damage occurs in order to prevent progression to cirrhosis and cancer and delay in the belief that there is no benefit from treatment would be hard to justify if challenged.
Under "Recommendation for Further Research" the authors repeat their previous call for placebo-controlled trials with mortality outcomes for patients with advanced liver disease. The proposal the authors put forward might appear rational on paper, but is in reality a dangerous one. Given that a standard of care with potential for cure existed even before the introduction newer DAA drugs, no ethical committee would ever allow such a placebo study, to say nothing of the practicalities of recruitment. Beyond any reasonable doubt, such a trial would lead to unnecessary loss of life.
In the absence of placebo-controlled trials, the authors recommend explaining to patients "that there is no evidence so far that DAA treatment will reduce the risk of liver complications". This is simply inaccurate and misleading. We are already starting to see the benefits of curative DAA therapy for hepatitis. Since their introduction in 2014, there have been significant declines in admission with HCV related cirrhosis in Scotland (6) and declines in HCV related transplantation and mortality in England (7).
The authors conclude that stakeholders should implement a fairer pricing framework. We strongly agree, but this issue has not been addressed in any meaningful way in the article and the suggestion that doctors should discuss the price of the treatment with patients deserves a full article in itself. For many clinicians (e.g. in Scotland and England) the price of the drugs they prescribe is regarded as commercially sensitive by healthcare providers. The public health importance of DAAs is reflected in their inclusion in the WHO Essential Medicines List. Much work needs to be done to improve costs and access, but arguing as to their efficacy is not part of the solution.
The article concludes with a section asking clinicians "based on reading this article, is there anything that you will do differently in your practice?". By neglecting the large literature on the benefits of virological cure as defined by sustained virological response (SVR), the article could lead clinicians to change their practice in ways that they would not with all the evidence available, putting patients at risk as a result. Articles such as these require a balanced perspective, supported by evidence. The message from all current guidance issued by the EASL, AASLD and the World Health Organisation is that all patients infected with hepatitis C should be offered treatment. There is overwhelming evidence that such treatment reduces morbidity and mortality - so much so that WHO aims to achieve elimination of the virus by 2030. We strongly recommend that, where it is available, any patient infected with the virus should be referred immediately for consideration of treatment.
References
1. Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ 2018; 361: k1382.
2. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9: CD012143.
3. European Association for the Study of the Liver. Electronic address eee. Response to the Cochrane systematic review on DAA-based treatment of chronic hepatitis C. Journal of hepatology 2017; 67(4): 663-4.
4. Powderly WG, Naggie S, Kim AY, Vargas HE, Chung RT, Lok AS. IDSA/AASLD Response to Cochrane Review on Direct-Acting Antivirals for Hepatitis C. Clin Infect Dis 2017; 65(11): 1773-5.
5. Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis 2015; 61(5): 730-40.
6. Hutchinson S, Valerio H, Dillon JF, et al. Reduction in the incidence of hepatitis C related decompensated cirrhosis associated with national scale-up of DAA therapies targeting patients with advanced liver fibrosis. ILC 2018. Paris; 2018.
7. PHE. Hepatitis C in England 2018 report, 2018.
Competing interests: SB, SB, GC, WG, MH, MN, CS, SV have given educational talks and/or provided consultancy for one or more of Gilead Inc, MSD and abbvie. EB collaborates with GSK on HCV vaccine development.
Dear Editor
Viral hepatitis experts are convinced of the benefits of antiviral therapy for hepatitis C.
We were dismayed that the Editors of the BMJ presented the widely discredited Cochrane review of Hepatitis C virus (HCV) therapy as mainstream opinion (1,2). It is not. This Cochrane review contained significant methodological flaws and lacked clinical insight or knowledge of the natural history of HCV. The opinion of informed hepatologists, infectious disease, and public health physicians, as well as the World Health Organisation (WHO), the National Institute for Clinical Excellence (NICE), and all international liver associations, is that directly acting antiviral (DAA) oral therapy for hepatitis C represents a breakthrough development that prevents end stage liver disease and death (3,4). This opinion is based on the dramatic benefits following widespread use of these drugs. Independent surveillance data from the Public Health England hepatitis C annual report (5) show that deaths from hepatitis C related end stage liver disease and hepatocellular carcinoma were increasing, more than doubled, between 2005 and 2014, but have fallen since 2014 with the introduction of HCV treatment with these drugs. PHE data indicates that registrations for liver transplant and transplants undertaken, where post hepatitis C cirrhosis is given as the indication for transplant, had remained relatively stable between 2008 and 2014, but have fallen since 2014 (5). Similar changes have been seen in every country where these drugs have been introduced. There is no credible explanation for the fall in hepatitis C liver disease morbidity and mortality associated with the introduction of effective anti-virals other than the use of these drugs.
Independent experts agreed that the most appropriate end-point in therapy trials for hepatitis C was sustained virological response (SVR). This was chosen, by independent regulators as the trial end-point. It was selected because in almost every infectious disease where there is a link between the pathogen and disease, clearance of the infection is beneficial and there is evidence that SVR with interferon-based therapies reduces mortality. The reasonable assumption that viral clearance with DAAs would reduce liver-related complications has been confirmed by long term follow up studies: the English Early Access Programme (EAP) shows a fall in deaths in patients who achieved SVR (6), and emerging data from large patient cohorts confirm this. There remains a risk of hepatocellular carcinoma in patients who developed cirrhosis prior to viral clearance, but evidence from studies of patients with advanced liver disease suggests that this risk is reduced. The legitimate debate about the value of an inflammatory milieu in patients with liver cancer and the role of viral clearance in this scenario does not obviate the clear mortality benefits from therapy and can not be used to imply that physicians are concerned about therapy in patients without cancer.
Hepatitis C is an infectious virus – the obvious extrapolation that effective therapy prevents transmission has now been confirmed. Dr Jakobsen and colleagues ignore the anxiety suffered by patients who are frightened of infecting their loved ones. Quite apart from the personal benefits of DAA therapy to patients who are already infected and their immediate contacts, reducing the overall burden of infection will reduce the risk of transmission to the rest of the population. DAA treatment of hepatitis C represents a rare opportunity to eliminate hepatitis C as a major public health concern and this opportunity is clearly recognised by WHO in its Global Strategy for Viral Hepatitis.
To suggest to patients that they should continue to suffer and not access safe and highly effective curative treatments that have been used in hundreds of thousands of patients without incident is inhumane.
The clinical utility of a drug is not inversely proportional to its price and NICE’s assessment of hepatitis C antivirals is that they are cost effective. We are not aware of any data questioning the NICE review. Since this review NHSE have negotiated a reduction in the price of these lifesaving drugs and the NHS is now in a position to plan an affordable hepatitis C elimination programme. This will focus on those populations most affected – often vulnerable members of society, such as people who inject drugs and the homeless. Many patients with hepatitis C do not attend primary care physicians to discuss the risks and benefits of therapy – they attend needle exchange, drug and alcohol, and homeless health services where they need to be identified (at considerable expense), engaged and offered antiviral therapy that may save their life. This gives them an opportunity to re-engage with society and move on with their lives. The overwhelming majority of clinicians are confident that there is very convincing evidence of benefit from DAA therapy and are planning to move antiviral services to all patients to amplify the remarkable benefits already demonstrated.
Dr Jakobsen is factually correct that only a large, placebo controlled trial over several decades with death as an end-point will prove beyond all doubt that SVR improves mortality. If the BMJ believes this to be an ethical approach it should have the courage to say so, and should then make the case for patients to live with the clinical, psychosocial and public health consequences of being infected and suffer symptoms until death to prove a scientific point. In the opinion of clinical experts the current data prove, beyond reasonable doubt, that achieving an SVR stops people transmitting and dying from hepatitis C. In the early HIV era a handful of idiosyncratic scientists refused to accept the association between HIV and AIDS and recommended that effective antiretroviral therapy be withheld. Sadly some governments, notably South Africa, followed this ill-informed advice and many vulnerable South Africans died as a direct consequence. It would be unfortunate if Dr Jakobsen’s views led to a similar tragedy in HCV. We hope that the BMJ will make clear that his personal opinion is not shared by reputable clinicians and policy makers. Patients should be encouraged to be tested and then treated for hepatitis C safe in the knowledge that they will join the millions of treated patients who will be protected from liver fibrosis and premature death.
Graham R Foster NHSE ODN Clinical Lead
Kosh Agarwal, Transplant hepatologist, HCV CRG member
Matthew Cramp Chair BASL
John Dillon Chair Scottish HCV Clinical Leads
Ahmed Elsharkawy Chair BVHG
Charles Gore CEO The Hepatitis C Trust
William Irving Chair NSGVH
Sema Mendal PHE HCV Lead
Peter Moss Chair HCV CRG
Chloe Orkin Chair BHIVA
Stephen Ryder Chairman HCV Coalition
References
1 Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ. 2018 May 10;361:k1382
2 Jakobsen JC, Nielsen EE, Feinberg J, etal . Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017. 10.1002/14651858.CD012143.pub3.
3 Powderly WG, Naggie S, Kim AY, Vargas HE, Chung RT, Lok AS.IDSA/AASLD Response to Cochrane Review on Direct-Acting Antivirals for Hepatitis C
Clin Infect Dis. 2017 Nov 13;65(11):1773-1775.
4 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. Response to the Cochrane systematic review on DAA-based treatment of chronic hepatitis C. J Hepatol. 2017 Oct;67(4):663-664
5 Public Health England, Hepatitis C in England 2018 report
https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
6 Cheung MCM, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, Brown A, Gelson WTH, MacDonald DC, Agarwal K, Foster GR, Irving WL; HCV Research UK. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016 Oct;65(4):741-747
Competing interests: Professor Foster has previously received funding from companies that market antivirals for hepatitis C but no longer does so. PHE staff have no competing interests. Other authors have received speaker and consultancy fees from companies that market oral antiviral agents for hepatitis C. Peter Moss and Charles Gore, no personal competing interests.
Re: Do direct acting antivirals cure chronic hepatitis C? Scotland says yes.
We read with dismay the article by Jakobsen et al [1], entitled “Do direct acting antivirals cure chronic hepatitis C?”
The authors contributed to a Cochrane review [2] that analysed registration trials of direct acting antivirals (DAAs) for evidence of outcomes they were not designed to demonstrate. Clinicians, international societies, patient groups and (relevant to trial design) regulators have long accepted sustained viral response (SVR) as an appropriate outcome for assessing hepatitis C (HCV) treatments.
Achieving an SVR with older interferon based regimens has been shown in observational studies to lead to a reduction in all cause mortality [3]. In Scotland, where competing risk factors for death related to drug and alcohol use are prevalent, SVR nonetheless reduces all cause mortality after adjustment for baseline factors [4].
In the interferon era it was more credible (though still in our opinion wrong) to suggest that SVR may be a flawed surrogate marker that simply identifies those who will do well irrespective of treatment due to unidentified confounding factors. This argument is difficult to sustain with new treatments that are virtually agnostic to baseline factors, achieving SVR in over 95% of patients, including those with cirrhosis. The minority of treatment failures achieve SVR with second line regimens [5]. In this context, patients achieving SVR with DAAs have been shown to have reduced all cause mortality amongst large cohorts of patients with [6] and without [7] advanced liver disease in comparison to the small minority of patients not achieving SVR or those who remain untreated.
It may be that those who hold randomised controlled trials above all else, still require such a trial to prove that more patients with cirrhosis will die if left untreated. Such a trial would need to take place in a world where the scale up of DAA treatment has, as expected by those familiar with the pre-existing data, coincided with an unprecedented reduction in liver transplantations for hepatitis C across Europe, and markedly improved outcomes for those who do require transplantation [8]. In Scotland we have seen a population level reversal of what was an inexorable rise in first presentations with HCV related decompensated liver disease [9]. To us such randomised trials would be unwarranted and unethical.
Whilst arbiters of cost effectiveness (these drugs are approved by both Scottish Medicines Consortium (SMC) and The National Institute for Health and Care Excellence (NICE)) are most concerned by mortality, these are not the sole concern of patients. For many, successful treatment is a key part of their recovery from addictions, removing stigma and fear of transmission to partners, current and future children. Data published subsequent to the Cochrane review demonstrates improvements in patient reported outcomes compared to placebo arms of registration trials, in keeping with our anecdotal experience that patients feel better following treatment [10].
This misinformed article seeks to sow doubt and confusion where none exists.
The clinical community is rallied behind the World Health Organisations goals of eliminating HCV as a public health concern by diagnosing 90% and curing 80% of those infected by 2030. Those not involved with HCV care should be reassured that by testing those with risk factors, and referring those affected for treatment, they are acting in their patient’s best interests and on an evidence base which is strong, clear and rapidly growing. On behalf of the HCV community in Scotland our answer to the question, “Do Direct Acting Antivirals Cure Hepatitis C?” is yes.
1. Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ 2018; 361: k1382.
2. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9: CD012143.
3. Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis 2015; 61(5): 730-40.
4. Innes HA, McDonald SA, Dillon J et al. Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. Hepatol 2015 Aug;62(2):355-64
5. Bourlière M, Stuart C. Gordon SC, Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med 2017; 376:2134-2146
6. Backus LI, Belperio PS, Shahoumian TA, Impact of Sustained Virologic Response with Direct-Acting Antiviral Treatment on Mortality in Patients with Advanced Liver Disease. Hepatol. 2017 Jul 27. doi: 10.1002/hep.29408 (epub ahead of print)
7. Backus L, Belperio PS Shahoumian TA, Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. Hepatol. 2018 Jan 29. doi: 10.1002/hep.29811 (epub ahead of print)
8 Perricone G, Mazzarelli C, Vigano R et al, Impact of DAA onliver transplantation: major effects on the evolution of indications and results. As study based on the ELTR registry. ILC 2018. Paris; 2018
9 Hutchinson S, Valerio H, Dillon JF, et al. Reduction in the incidence of hepatitis C related decompensated cirrhosis associated with national scale-up of DAA therapies targeting patients with advanced liver fibrosis. ILC 2018. Paris; 2018.
10. Younossi ZM, Stepanova M, Gordon S, Patient-Reported Outcomes Following Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir. Clin Gastroenterol Hepatol. 2018 Apr;16(4):567-574
Competing interests: SB, JD, PH, SH, NK, CL have given educational talks, provided consultancy or received grants from one or more of Abbvie, BMS, Gilead, Roche, Janssen and Merck. Dr Bramley, Dr Fraser, Professor Goldberg, Mr Innes, Mr Wylie have no conflicts of interest.