Intended for healthcare professionals

Practice Uncertainties

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

The benefits to patients of novel hepatitis C therapies are beyond reasonable doubt

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.

17 May 2018
Graham S Cooke
NIHR Research Professor
Dr Stephen Barclay, Consultant Hepatologist, Glasgow Royal Infirmary. Professor Eleanor Barnes, NIHR Senior Investigator, University of Oxford. Dr Sanjay Bhagani, Clinical Lead for co-infection, Royal Free Foundation NHS Trust. Dr William Gelson, Secretary to British Viral Hepatitis Group, Cambridge. Prof Matthew Hickman, Director NIHR Health Protection Research Unit in Evaluation, Bristol. Dr Katie Jeffrey, Thames Valley HCV ODN, Oxford. Sir Michael Jacobs, Consultant and Hon Senior Lecturer, Royal Free London NHS Foundation Trust. Professor Paul Klenerman, University of Oxford. Dr Douglas MacDonald, Chair of HCV ODNs, London. Dr Albert Misfud, President of British Infection Association, London. Professor Mark Nelson, Imperial College London. Dr Geraldine O'Hara, NIHR fellow, LSHTM. Professor Caroline Sabin, Director NIHR HPRU in Blood Borne and Sexually Transmitted Diseases, London. Dr Sumita Verma, Reader in Hepatology, Brighton and Sussex Medical Schoo.l Professor Martin Wiselka, former President British Infection Association, Leicester. Dr Emma Thomson, Clinical Senior Lecturer, MRC University of Glasgow Centre for Virus Research
Imperial College London
Paddington, London W2 1NY