Re: Do direct acting antivirals cure chronic hepatitis C?
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
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: email@example.com. 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
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.