Do direct acting antivirals cure chronic hepatitis C?

We are responding to the comments of Barclay et al. (1) regarding both our recent article in the BMJ (2) and our Cochrane systematic review of the efficacy of direct-acting agents (DAAs) in treating chronic hepatitis C (3).

Barclay et al. begin with the observation that the randomised clinical trials (RCTs) included in our Cochrane review were not designed to demonstrate long-term effects of treatment on mortality and hepatic morbidity. When we searched for all RCTs assessing the effects of DAAs, we only found short-term ones. Our conclusion was that there was insufficient information to know if DAA therapy had any effect on long-term clinical outcomes and Barclay et al. seem to agree with us.

Barclay et al. say that observational (i.e., non-randomised) studies showed that interferon (IFN)-based therapies reduce all-cause mortality, citing two studies (4, 5). Of course, observational studies can never with certainty validate intervention effects. One of the citations (4) reported that the mortality rates in patients who achieved sustained virological responses (SVRs) were better than the rates in patients who were never treated. However, we know that patients who achieve SVRs have prognostic factors (e.g., younger age, female sex, less fibrosis, more favorable ILB28 status, etc.) that would predict that they would have a better long-term outcome in general (6). Thus, comparing them to an untreated group introduces two biases, confounding (because there was some reason why the untreated patients were not treated) and selection (because those who develop SVRs are the subset of all untreated patients who have more favorable prognostic features). Both cited references (4, 5) compared patients who did, or did not, achieve SVRs, but such comparisons cannot address the effects of therapy. Any differences that are found between these two groups cannot be attributed to treatment because all of them were treated.

For these same reasons, the two subsequent references cited by Barclay et al. (7, 8) are inadequate to prove that DAA therapy reduces all-cause mortality.

Cochrane systematic reviews do not usually consider surrogate outcomes. However, we included SVRs in our review (3) because this outcome is used in clinical practice. The short-term RCTs did show that DAA therapy produced more SVRs (3). Unfortunately, to date this surrogate outcome has never been validated (i.e., no RCT has shown that creating SVRs translates into better clinical outcomes). Thus, we agree with Barclay et al. that the SVR is a “flawed” surrogate.

We do not understand why Barclay et al. seem to believe that the flaw is less important in the DAA era. SVRs created by DAAs are still more likely to occur in patients with more favorable baseline characteristics (i.e., the DAAs are not agnostic to baseline factors). The SVR rates were lower in those with advanced liver disease in the two DAA papers cited by Barclay et al. (7, 8). Besides advanced liver disease, reduced SVR rates have been associated with ethnicity (9, 10), gender (11), and age (11). It may be that other factors are also important, but, because there is a smaller percentage of patients failing to achieve SVRs, it is difficult to identify them statistically.

Those of us who are calling for RCTs of treatment versus no treatment believe that we need good evidence. Barclay et al. do not know how DAA treatment affects mortality. We would remind them that, in the largest RCT to ever assess the clinical outcomes of antiviral treatment in chronic hepatitis C, the treated recipients had the higher mortality (12).

Barclay et al. say that there has been a dramatic reduction in liver transplantations and improved outcomes in those with end-stage liver disease across Europe (1). Unfortunately, the two abstracts that they cited are not evaluable because the text was redacted (13, 14). However, a similar claim was made in England, but the report indicated that the reduction in transplantation listings and surgeries may have been due to expectations of DAA effectiveness and the alleged reduction in mortality appeared to have begun two years before DAAs were released (15).

Barclay et al. said that DAA treatment improves patient-reported outcomes. Quality of life (QOL) is a subjective outcome and can only be fairly assessed in placebo-controlled blinded RCTs. The situation for hepatitis C is further confounded by the long-standing marketing programs that overestimate the adverse consequences of the disease and the benefits of treatment. Patients entering DAA treatment programs are overly anxious about their disease at the start and overly optimistic about what treatment will do, so it is no surprise that QOL improves if they know that they will receive DAAs. While the cited trial (15) did include a placebo group, the blind was likely broken because of the dramatic difference in SVR rates between the two groups. In order to make any valid conclusions, trials assessing QOL in hepatitis C must prevent the participants from being aware of any of the ongoing laboratory results. No such trial has ever been done.

Hepatitis C virus ribonucleic acid (HCV-RNA) is still demonstrable in the peripheral blood mononuclear cells of some patients who achieve SVRs (6). Thus, we cannot be sure that treatment prevents transmission.

We are not attempting to sow doubt and confusion, but we are attempting to bring all of the facts to the table. The evidence base is not strong and, while it may be getting larger, is not expanding (as we are just doing the same thing over and over again). If proponents of DAA therapy worry that payers will become more reluctant to support treatment, the appropriate path to take is to prove that treatment is worth the investment.

References
1. Barclay S, Bramley P, Dillon J, et al. Do direct acting antivirals cure chronic hepatitis C? Scotland says yes. (Rapid response) BMJ 2018 (May 18): 361:k1382
2 Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ. 2018 (May 10);361:k1382
3. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD012143. doi: 10.1002/14651858.CD012143.pub3.
4. Simmons B, Saleem J, Heath K, et al. 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): 730-740
5. 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):355-364
6. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ 2015, 350:g7809 doi: https://doi.org/7810.1136/bmj.g7809
7. Backus LI, Belperio PS, Shahoumian TA, Mole LA. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. Hepatology 2017 (Jul 27). doi: 10.1002/hep.29408 (epub ahead of print)
8. Backus L, Belperio PS Shahoumian TA, Mole LA. Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. Hepatology 2018 (Jan 29). doi: 10.1002/hep.29811 (epub ahead of print)
9. Backus L, Belperio PS Shahoumian TA, et al. Real-world effectiveness of Dedipasvir/Sofosbuvir in 4365 treatment-naïve, genotype 1 hepatitis C-infected patients. Hepatology 2016 (Aug); 64(2):405-414
10. Su F, Green PK, Berry K Ioannou GN. The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection. Hepatology 2016 (Feb); 65 (2):426-438
11. Fox DS, McGinnis JJ, Tonnu-Mihara IQ, McCombs JS. Comparative treatment effectiveness of direct acting antiviral regimens for hepatitis C: data from the Veterans Administration. J Gastroenterol Hepatol 2017; 32:1136-1142
12. Di Besceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatol 2011 (Apr); 53 (4):1100-1108
13. Perricone G, Mazzarelli C, Vigano R et al. The percentage of patients with HCV infection in need of a liver transplant is rapidly declining while their survival after transplantation is improving: a study based on European liver transplant registry. J Hepatol 2018 (April); 68 (Suppl 1):S116 (The title provided by Barclay et al. was different [Impact of DAA on liver transplantation: major effects on the evolution of indications and results. As study based on the ELTR registry. ILC 2018. Paris; 2018], but the title used for this reference was the only abstract by Perricone in the author index; the text was redacted because of an embargo.)
14. 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. (This abstract was presented at the annual EASL meeting and was published in J Hepatol 2018 (April); 68 (Suppl 1):S67, but the text was redacted in the published abstract because of an embargo)
15. Public Health England, Hepatitis C in England 2018 report
https://assets.publishing.service.gov.uk/government/uploads/system/uploa... (Accessed May 23, 2018)
16. Younossi ZM, Stepanova M, Gordon S, et al. 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

Foster et al. (1) commented both on our recent paper in BMJ (2) and our Cochrane systematic review regarding the use of direct-acting agents (DAAs) in chronic hepatitis C (3). That systematic review concluded that the use of DAAs did not produce any short-term benefit in morbidity or mortality, that there were no long-term data from RCTs to determine if such treatment resulted in any long-term benefit in these outcomes, and that treatment produced more sustained virological responses (SVRs), a non-validated surrogate outcome (3). These conclusions are all true and the systematic review has never been discredited. While this perspective is not popular with many people, we should not confuse opinion or marketing with fact. We would stress that our conclusions reflect the current evidence; it is possible that the SVR will be validated as a surrogate at some time in the future.

Foster et al. say that treatment prevents end-stage liver disease (ESLD) and death, citing two editorial commentaries written in response to our systematic review by the Infectious Disease Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD) (4) and the European Association for the Study of the Liver (EASL) (5). Since we would expect such documents to provide the best evidence available to support the use of DAAs, it is enlightening to understand the substantial limitations of that evidence. In the nine paragraphs that follow, the term “the societies say” will refer to the evidence presented in those references (4, 5).

Since there are no RCTs showing that treatment reduces morbidity, mortality, or prevalence, the clinical evidence consists of three types of observational studies.
(a) Comparing treated to untreated patients: Since there were reasons why treatment was, or was not, offered, such studies are confounded. One reason is that the untreated patients were sicker (6, 7).
(b) Comparing patients who develop SVRs to untreated patients: Patients who develop SVRs have baseline characteristics indicating that they are at lower risk for progression (8). Comparing them to untreated patients adds selection bias to the confounding bias.
(c) Comparing treated patients who did, or did not, develop SVRs: While such studies are widely cited (4, 9), it is illogical to use such data as an argument for treatment. Both groups were treated, so differences in outcome cannot be attributed to treatment.

The societies said that treatment improves other surrogate outcomes (biochemical or histologic). These other surrogate outcomes have also never been validated. Validation requires a demonstration that changing the surrogate outcome also comparably changes the clinical outcome in the same group of patients. Such demonstrations are accomplished with RCTs that assess both outcomes (10). Of note, in one chronic hepatitis C scenario (retreating patients with interferon [IFN]), these various surrogate outcomes, including the SVR, failed to be validated (11). The treated patients had more SVRs (beneficial) and a higher all-cause mortality (detrimental) (11); producing a better surrogate outcome but a worse clinical outcome is the classical definition of failure to validate.

The societies said that treatment also improved some extrahepatic manifestations of hepatitis C (cryoglobulinemia and some lymphoproliferative diseases). The only available RCTs showed that IFN only had a transient effect on cryoglobulinemia, one that disappeared when treatment was stopped (12, 13). Of course, even if treatment were effective in these disorders, that observation provides no insight into the prevention of ESLD or death.

Citing unblinded and uncontrolled studies, the societies said that DAAs improve quality of life (QOL) in patients with chronic hepatitis C. QOL is a subjective outcome that cannot reliably be assessed in unblinded studies (14). Further complicating the problem for chronic hepatitis C are the long-standing one-sided marketing campaigns that overestimate the threats of the disease and the benefits of the treatment, thereby increasing anxiety in patients when they are diagnosed and exaggerating expectations when they are treated. It is not surprising that treatment, or even the promise of treatment, improves QOL. QOL can only be definitively assessed in patients with chronic hepatitis C with placebo-controlled, double-blind RCTs in which all participants (including care-givers) do not know the biochemical and serologic test results. Such trials have never been done.

EASL (5) cited decision analyses to support a claim that treatment is cost-effective. Such analyses require the use of various assumptions. These assumptions typically favour treatment (8). For example, while these models have suggested that IFN would be cost-effective, RCTs comparing IFN with no treatment in patients with advanced fibrosis have failed to show that this treatment provides any consistent meaningful benefit (11). If a treatment is not effective, it cannot be cost-effective.

Furthermore, cost-effectiveness is not necessarily cost-saving. These studies assume that society is willing to pay $25,000-100,000 for a quality-adjusted life year. It has been stated that a healthcare cost increase > 1% is unaffordable and would result in some action to restrict its use, shift resources from other services, or increase premiums (15). The cost for DAA treatment in California represents a 5% increase (15).

EASL said, seemingly without supporting data, that treatment would reduce transmission (5). We know that hepatitis C virus ribonucleic acid (HCV-RNA) can still be demonstrated elsewhere in the bodies of patients with SVRs. In particular, HCV-RNA can be found in peripheral blood mononuclear cells (8). Thus, blood-borne transmission is still possible.

The societies all proposed that DAAs could produce a world-wide elimination of hepatitis C (4, 5). We are unaware of any other example of an infectious agent being eliminated by pharmaceutical agents that directly destroy the agent (e.g., tuberculosis has not disappeared). Diseases such as smallpox were eliminated with vaccines. Since DAAs will not create SVRs in 100% of all infected patients nor will they remove the persistent latent infections, elimination of the virus will not occur. Unlike potential vaccination, DAA treatment will not prevent reinfection. The resources required to treat 70-150 million people are substantial (and could be better used for other healthcare interventions). This proposal seems unrealistic.

The societies equate the SVR with “cure”. This is a misnomer. HCV-RNA can still be present in such patients and relapses with genetically identical viruses can occur months or years later (confirming the presence of latent infection) (8). We also know that patients who achieve SVRs can still progress to end-stage liver disease (8); in those with advanced fibrosis (stage 3 or 4) at the time of treatment, this rate is about 2% per year (16). It is time to stop calling SVRs “cures”.

Foster et al. cited epidemiologic data from an English survey (17) to say that there has been a fall in hepatitis C morbidity and mortality since 2014 (when the DAAs were introduced), even though such observational data can never validate intervention effects with certainty. This argument is not as convincing as Foster et al. argue. The total number of transplant listings and transplantations did appear to fall from about 135 + 15 and 108 + 15 to 75-80 in 2015-2016 (Figure 3 in the report), but it is not clear how many of those absent listings/transplants were simply being delayed because of expectations of healthcare workers about the abilities of the DAAs to influence the disease. While the report did state that there was a 3% drop in mortality attributed to ESLD or HCC caused by hepatitis C after 2014, it appeared that, if anything, there were slightly more deaths in 2015-2016 than in 2013-2014 (Figure 4 in the report). That Figure 4 even seems to show that, while the numbers of deaths were steadily climbing prior to 2012, the line for those next four years flattened off. Thus, the tapering in the number of deaths began before the DAAs were available. Finally, the numbers of new patients with hepatitis C-related ESLD and HCC rose each year from 2013 to 2016 (figure 2 of the report).

To support their opinion, Foster et al. cited an observational study comparing patients with decompensated cirrhosis who were treated with DAAs to an untreated historical group (18). During the first 6 months of followup, no differences in mortality, HCC, or transplantation were seen between the two groups, although the untreated group developed decompensated cirrhosis more often (28% compared to 18%). However, most of the comparisons reported in this paper (18) were between those who had, or had not, achieved SVRs. As already noted, such data provide no insight into the value of treatment. There was no explanation regarding why the untreated patients had not received treatment with DAAs after 2014. While there was no table comparing the demographics of the treated and untreated groups in this paper, the untreated group had been previously described (19) and it appeared that over 60% had failed prior non-DAA (presumably IFN-based) therapy. This reference (18) does not advance the argument of Foster et al.

Foster et al. say that SVRs achieved with IFN-based therapies reduce mortality. However, the RCTs indicate that, if anything, IFN increases mortality when all treated patients are considered (11).

Foster et al. say that we ignore the anxiety suffered by patients. Much of this anxiety is attributable to the misleading marketing programs that have been going on for many years without any critical comments from AASLD, EASL, or IDSA. Why are these organizations, or Foster and his colleagues, seemingly ignoring this problem?

Foster et al. make an analogy between treating hepatitis C and treating the human immunodeficiency virus (HIV), but do not consider the early RCTs demonstrating that treatment of HIV was effective (20) or that clearing the blood of HIV (the “SVR” of the Acquired Immunodeficiency Syndrome [AIDS]) is a validated surrogate outcome. AIDS and chronic hepatitis C are different diseases. In AIDS, the HIV attacks the lymphocyte, so the serum level may be an important pathophysiologic factor. In chronic hepatitis C, the virus is already in the liver and only needs to invade a neighboring hepatocyte; the serum titer may not be important. Furthermore, an untreated individual infected with HIV is almost certainly destined to die of AIDS whereas only a small percentage of patients infected with hepatitis C will go on to develop ESLD (8). It is not scientifically valid to justify DAA treatment for chronic hepatitis C because antiviral therapy of AIDS is beneficial.

Foster et al. challenge the ethics of undertaking RCTs comparing treatment to no treatment. It is never unethical to perform a study to find out what is not known (21). As the HALT-C trial demonstrated (22), such RCTs do not require decades to perform. Our ethical concern relates to how DAA treatment can be justified with the diversion of resources from other healthcare programs with better evidence of efficacy. Shrinking other programs will have adverse consequences for patients.

We cannot speak for the BMJ editors, but we do not consider BMJ to be a journal that reports “mainstream opinions”. Rather, we believe that BMJ focuses on evidence-based knowledge. As we have seen, there is at this time no credible evidence to support the belief that DAA treatment produces clinical benefits. We still believe that the appropriate course to pursue is to attempt to find that credible evidence by undertaking placebo-controlled RCTs.

References

1. Foster GR, Agarwal K, Cramp M, et al. Viral hepatitis experts are convinced of the benefits of antiviral therapy for hepatitis C. (Rapid response) BMJ 2018 (May 16): 361:k1382

2 Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ. 2018 (May 10);361:k1382

3. Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD012143. doi: 10.1002/14651858.CD012143.pub3.

4 Powderly WG, Naggie S, Kim AY, et al. IDSA/AASLD Response to Cochrane Review on Direct-Acting Antivirals for Hepatitis C. Clin Infect Dis 2017 (Nov 13); 65(11):1773-1775

5 European Association for the Study of the Liver. Response to the Cochrane systematic review on DAA-based treatment of chronic hepatitis C. J Hepatol. 2017 (Oct); 67(4):663-664

6. Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. J Hepatol 1997; 27:201-205

7. Belli LS, Berenguer M, Cortesi PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J Hepatol 2016; 65:524-531

8. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ 2015, 350:g7809 doi: https://doi.org/7810.1136/bmj.g7809

9. Solinis RN, Ugarte PA, Rojo A, Gonzalez YS. Value of treating all stages of chronic hepatitis C: a comprehensive review of clinical and economic evidence. Infect Dis Ther 2016; 5:491-508

10. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med 2012; 31:2973-2984

11. Koretz RL, Pleguezuelo M, Arvaniti V, et al. Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. Cochrane Database Syst Rev 2013; Issue 1:CD003617. doi: 003610.001002/14651858.CD14003617.pub14651852

12. Ferri C, Marzo E, Longombardo G, et al. Interferon-α in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 1993 (March 1); 5:1132-1136

13. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2α therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994; 330:751-756

14. Hrobjartsson A,Emanuelsson, Thomsen AS, et al. Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies. Int J Epidemiol 2014 (Aug); 143 (4):1272-1283

15. Tice JA, Chahal HS. Comparative clinical effectiveness of avaue of novel interferon-free conbination therapy for hepatitis C gentorype 1, Summary of California Technology Assessment Forum report. JAMA Intern Med 2015 (September); 175 (9):1559-1560

16. Koretz, RL. How often does hepatic decompensation or hepatocellular carcinoma occur after a sustained virological response? Gastroenterology 2018; in press (To be presented at 2018 Digestive Disease Week, Washington, D.C., June 4, 2018)

17. Public Health England, Hepatitis C in England 2018 report
https://assets.publishing.service.gov.uk/government/uploads/system/uploa... (Accessed May 23, 2018)

18. Cheung MCM, Walker AJ, Hudson BE, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016 (Oct); 65(4):741-747

19. Foster GR, Irving WL, Cheung MCM, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016 (June); 2016 (6):1224-1231

20. Rachlis A. Zidovudine (Retrovir) update. Can Med Assoc J 1990 (December 1); 143 (11):1177-1185

21. Garattini S, Jakobsen JC, Wettersley, et al. Evidence-based clinical practice: overview of threats to the validity of evidence and how to minimize them. Eur J Intern Med 2016 (July); 32:13-21

22. Di Besceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatol 2011 (Apr); 53 (4):1100-1108

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.