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
Dear Editor,
We read the above article (1) and the authors’ responses to queries and comments with interest. Given the significant number of responses, we limit our comments to a couple of additional key issues that we feel have not been raised so far.
1. We had similar concerns to those raised by others regarding the apparent lack of consideration of the benefits of SVR in relation to transmissibility. It was therefore particularly interesting to note the authors’ response stating that “blood-borne transmission is still possible” when SVR has been achieved (1). However, the reference provided by the authors as evidence for HCV-RNA being found in peripheral blood mononuclear cells of those achieving SVR (2) to support the unequivocal statement made by the authors does not provide the required evidence to clearly and definitively substantiate these comments. Within that paper (2), the authors have provided a number of references that mention the findings of viral RNA in body tissues in some of those who achieve SVR. It is possible that we may have missed the secondary reference that clearly demonstrates viral RNA presence in peripheral blood mononuclear cells of those who achieved SVR, and a consequent risk of transmission. However, given the importance of this statement for clinical practice and public health, it is imperative that the supporting evidence for this statement is clearly presented.
2. We also question the value of members of a Cochrane group providing specific practice recommendations, as has been done here. The Cochrane Group state that “Our global independent network gathers and summarizes the best evidence from research to help you make informed choices about treatment and we have been doing this for 25 years” (3). The Cochrane Strategy to 2020 (4) extends to include a number of roles, within this overarching remit of informing health decision making, but it does not include actively interpreting data to make those decisions on behalf of the healthcare profession. In an open and inclusive decision making process, we expect the findings of such reviews to be interpreted in conjunction with a series of other considerations including patients’ views, health service access and funding, and to be fully appraised by a group or panel representing all important stakeholder groups in order to make a decision on practice implementation in a particular locality, region or country. In this case, members of the Cochrane group have been involved in interpreting the findings of the review in isolation to make and publish generalised recommendations for practice implementation. Particularly considering the wide-reaching impact of Cochrane reviews and the weight given by frontline health professionals to their findings, choosing to make such recommendations may have, in this instance, served to limit access to treatment for patients in some countries or situations leading to a missed opportunity to reduce the overall burden and spread of hepatitis C infection.
Dr Sam Ghebrehewet
Head of Health Protection & Consultant in Communicable Disease Control
PHE North West – Cheshire & Merseyside
Dr Katie Smith
Specialty Registrar in Public Health (ST4)
PHE North West – Cheshire & Merseyside
References
1. Jakobsen JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ 2018; 361: k1382.
2. Koretz RL, Lin KW, Ioannidis JP, Lenzer J. Is widespread screening for hepatitis C justified? BMJ. 2015; 13:350:g7809. doi: 10.1136/bmj.g7809.
3. Cochrane (Trusted Evidence. Informed Decisions. Better Health): About Us https://www.cochrane.org/about-us (Accessed 29th July 2018).
4. Cochrane (Trusted Evidence. Informed Decisions. Better Health): Strategy to 2020 aims to put Cochrane evidence at the heart of health decision-making all over the world. https://www.cochrane.org/about-us/strategy-to-2020 (Accessed 29th July 2018).
Competing interests: No competing interests
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
Competing interests: No competing interests
Cooke et al (1) made a number of comments about both an article that we recently published in the BMJ (2) and our systematic review in The Cochrane Library regarding the use of direct-acting agents (DAAs) in chronic hepatitis C (3). We will start with the systematic review. Cooke et al. say that there were serious methodologic flaws in the analysis, fundamental mistakes in the results section, and unjustified conclusions beyond the work carried out (1). Since Cooke et al. did not provide any further details, we assume that the problems they describe were itemized in two subsequently cited references (4, 5). These commentaries came from the European Association for the Study of the Liver (EASL) (4) and the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA) (5).
The EASL commentary (4) said that five areas in our systematic review were flaws:
a) The first was a typo in the text in which two numbers had been inadvertently transposed; this was corrected. (Contrary to the implication of Cooke et al, this was the only revised mistake; the other revision was an enhanced discussion of surrogate outcomes.)
b) The second was that we had included randomised clinical trials (RCTs) of DAAs that were no longer on the market. These trials were included to present all of the available data; our conclusions were based on RCTs of DAAs that were either currently available or on their way to the market.
c) EASL said that we had a cloudy definition of “serious adverse events”, but that definition was explicitly provided.
d) EASL said that we had missed trials assessing quality of life, but did not provide any such references. Our review only considered RCTs including an untreated (or placebo) group. We are not sure what tria we missed, but if those trials were either not randomized or only contained treated groups, they were not eligible for consideration.
e) EASL believes that only primary outcomes and times of followup of each RCT should be considered. However, this is not how systematic reviews are conducted. Rather, systematic reviewers decide, a priori, what outcomes and followup times are of interest to them and then look for such information regardless of what the original investigators chose. Systematic reviewers often contact investigators to obtain information that was not initially reported. In this regard, maximal followup times (which is what we used) are commonly employed in Cochrane reviews in order to obtain the maximum number of outcomes.
The AASLD/IDSA commentary (5) did not explicitly discuss methodologic aspects of our systematic review. The AASLD/IDSA commentary did note that we failed to include many trials because there was no untreated/placebo group. This is not a methodologic flaw. We wanted to assess the absolute (not the relative) efficacy of DAAs, so we needed untreated comparators.
Both commentaries (4, 5) noted that the RCTs that were considered (3) were not designed to capture long-term clinical outcomes (i.e., mortality and morbidity). We completely agree with this criticism of the existing literature. The AASLD/IDSA have confirmed our conclusion that evidence is lacking. To reiterate those conclusions, to date the RCTs have failed to show that the use of DAAs produced any short-term improved morbidity or mortality, there are no long-term data from RCTs to determine if DAAs produce any long-term benefit in these outcomes, and treatment did produce more sustained virological responses (SVRs), a non-validated surrogate outcome (3).
The details of the rigorous Cochrane systematic review process can be found in the Cochrane Handbook for Systematic Reviews of Interventions (6). Systematic reviews are only published in The Cochrane Library when every pertinent criterion in the Handbook is satisfied.
We have indeed read the responses to our review. More importantly, we have read the medical literature regarding the treatment of hepatitis C in great detail. While we understand that many people support the use of DAA therapy, we do not understand the mismatch between that enthusiasm and the level of available evidence; we fear that at least some of this disconnect may reflect the influence of industry. Foster et al. previously provided a rapid response (7) to our BMJ article (2). In that rapid response, Foster et al. also said that DAA treatment was efficacious, largely using the evidence cited in the EASL and AASLD/IDSA commentaries (4, 5). We discussed all of that evidence in our reply (8), so it is available to any interested reader. We will not repeat that lengthy discussion here, but the evidence is remarkably weak, consisting of observational studies compromised by multiple biases (confounding, performance, and/or selection), reports of improvements in other non-validated surrogate outcomes, computer modeling that employed treatment-favorable assumptions, and unproven speculations.
Cooke et al. distinguish “cure of infection” from “cure of disease”. This perspective is not reflected in the marketing campaigns nor in the minds of most patients, other lay personnel and many healthcare workers. Cooke et al. note that curing the infection still leaves the fibrosis but removes the “trigger”. Without a trigger, one would assume that further progression should not occur. Even if Cooke et al. view the residual fibrosis as still being a breeding ground for hepatocellular carcinoma (HCC), why would patients progress to decompensated cirrhosis after SVRs (9)? An alternative explanation is that, in spite of no detectable hepatitis C virus (HCV) ribonucleic acid (RNA) in the serum, the liver disease still progresses (10). We do know that patients who achieve SVRs can still have HCV-RNA demonstrated elsewhere in their bodies (10), so even the infection is not always cured.
Cooke et al. say that there is “compelling evidence” that all-cause mortality and HCC incidence is significantly reduced in those achieving SVRs, regardless of residual fibrosis, citing a reference by Simmons et al. (11). This reference (11) was a systematic review showing that mortality rates were better in groups of patients achieving SVRs compared to groups of patients who either failed treatment or were never treated. However, we know that patients who achieve SVRs have clinical features that are associated with better long-term outcomes (10). Comparing them to untreated patients introduces both selection (better prognosis) and confounding (reasons for not being treated) biases. Comparing them to patients who failed treatment makes no sense at all; any different outcomes between these two groups cannot be due to treatment because all of them were treated.
Cooke et al. decry our recommendation that we undertake RCTs of DAA treatment versus no treatment with a large-enough sample size and a long-enough followup time to assess the effect on mortality and liver morbidity, stating that such a trial would result in needless deaths. Have people forgotten the HALT-C trial (RCT of pegylated interferon [Peg-IFN] versus no treatment)? This large RCT found that the Peg-IFN recipients had the higher all-cause mortality (12).
Cooke et al. say that there have been reductions in various parameters reflecting liver disease in England and Scotland after DAAs were introduced in 2014, citing two references (13, 14). One of those references, an abstract, was not available on-line, as the text was redacted (13). The other reference (14) was discussed in the reply to Foster et al. (8). In brief, if there had been a tapering of hepatitis C-related deaths in England, it appeared to have begun in 2012, and it was unclear how many of the reductions in transplant listings and transplantations were due to expectations about the effects of DAAs.
Our concern about the cost of the DAAs was not a call to reduce the price. Since we do not know what, if any, effect DAA treatment has, we do not know what a fair price would be. However, the current price is so high that any treatment program will require a counter-action by payers (raising the cost of premiums or, more likely in public programs, diverting resources from other healthcare activities). We fear that any such diversion will negatively impact on the health of the community, especially if we reduce resources to healthcare activities with better evidence of efficacy.
Cooke et al. mention some current guidelines. One of us (RLK) has read in great detail the first few sections of the AASLD/IDSA guideline (15), a document that has been criticized for failure to control conflicts of interest (COIs) (16). In this document, the AASLD/IDSA elevated observational studies with historical controls to the evidentiary level of RCTs (15). Associations were regularly interpreted as being causative. There was no explanation regarding how various references were identified and/or then included or excluded. As a result, pertinent information was omitted or excluded. One reference was used to support a claim when the reference actually reported a contrary finding (17). The difference between surrogate and clinical outcomes was not appreciated. Studies that compared treated patients who achieved, or did not achieve, SVRs were repeatedly cited as evidence that treatment was effective.
In their concluding paragraph, Cooke et al. say that we neglect the large literature on the benefits of treatment. We believe that the material that they cite simply does not support the claims that they make.
References
1. Cooke GS, Barclay S, Barnes E, et al. The benefits to patients of novel hepatitis C therapies are beyond reasonable doubt. (Rapid response) BMJ 2018 (May 17): 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. 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
5. 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
6. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.
7. 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
8. Koretz RL, Jakobsen JC, Nielsen EE,Gluud C. Do direct acting antivirals cure chronic hepatitis C? Authors’ response to Foster et al. (Rapid response) BMJ 2018 (May 16): 361:k1382
9. 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)9.
10. 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
11. 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
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. 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)
14. Public Health England, Hepatitis C in England 2018 report
https://assets.publishing.service.gov.uk/government/uploads/system/uploa... (Accessed May 23, 2018)
15. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Updated September 21, 2017. www.hcvguidelines.org
16. Jefferson AA, Pearson SD. Conflict of Interest in Seminal Hepatitis C Virus
and Cholesterol Management Guidelines. JAMA Intern Med 2017 (Mar 1); 177 (3):352-7. doi: 10:1001/jamaintermed.2016.8439
17. Garcia-Bengoechea M, Basaras M, Barrio J, et al. Late disappearance of hepatitis C virus RNA from peripheral blood mononuclear cells in patients with chronic hepatitis C in sustained response after α-interferon therapy. Am J Gastroenterol 1999 (July); 94(7):1902-1905
Competing interests: No competing interests
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
Competing interests: No competing interests
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.
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? Response to Drs. Ghebrehewet and Smith
We are responding to the comments of Drs. Ghebrehewet and Smith (1) regarding our article in the BMJ (2). They raised two points for discussion. The first deals with the relationship between achieving a sustained virological response (SVR) and subsequent risk of transmission of hepatitis C. The second considers the appropriateness of members of a Cochrane group providing specific practice recommendations outside Cochrane.
We are not aware of any systematic study of patients who have achieved SVRs to determine the subsequent risk of transmission that they pose. For example, the most recent guideline published by the American Association for the Study of Liver Diseases (AASLD)/Infectious Disease Society of America (IDSA) contains a section entitled “Benefit of Treatment to Reduce Transmission” (3). That section contains 35 citations; the references quantitated the incidences of infection in at-risk patients (including patients who had been previously successfully treated), described experiences of treating at-risk patients or predictions from models that assumed that transmission could not occur, assessed the value of universal precautions, or contained recommendations for treatment based on the assumption that transmission could not occur. None of the references provided any data regarding the subsequent transmission, or lack of transmission, of hepatitis C by patients who achieved SVRs.
On the other hand, we do know that HCV-RNA can be found in peripheral blood mononuclear cells (PBMCs) of at least some patients who achieve SVRs (4, 5). Even the afore-mentioned AASLD/IDSA guideline (3), while claiming that HCV-RNA could not be found in the PBMCs of patients with SVRs, cited a study in which 2/10 such patients still had positive PBMCs 4 years later (6). We also know that relapses with genetically identical viruses can occur years after SVRs (7), indicating that the virus can exist in some latent phase in the body after the SVR, so the demonstration of HCV-RNA in PBMCs cannot be dismissed as an unimportant epiphenomenon.
We therefore need studies assessing the risk of transmission by people who achieve SVRs (spontaneously or after treatment). Given the current state of our knowledge, it would be inappropriate to assume that blood from patients who have achieved SVRs is not capable of transmitting hepatitis C.
Drs. Ghebrehewet and Smith seem to be confusing a formal Cochrane policy, one that is relevant to the preparation of Cochrane reviews and/or officially representing the Cochrane Collaboration, with the responsibilities that come to academicians in general. Our original BMJ article (2) was requested by the journal’s editorial staff for inclusion in a section of the journal that is known as “Uncertainties”. That editorial staff did recognise that there were uncertainties about the long-term clinical outcomes and the use of a surrogate marker (SVR) for using the newer hepatitis C therapies. One of the specific questions to which we were asked to respond was “What should we do in the light of the uncertainty?” with a direction to “provide practical guidance to clinicians on what to do”.
Our directions (what we believe Drs. Ghebrehewet and Smith are calling recommendations) related to undertaking randomised clinical trials comparing the direct-acting agents (DAAs) with placebo to assess the effect of treatment on clinically important outcomes (mortality, morbidity, quality of life), providing the currently available evidence regarding the uncertainty about DAA treatment to patients who are considering treatment, discussing unsafe behaviors and practices, and trying to achieve a better pricing framework. Any reduction in the future use of DAAs (what we believe Drs. Ghebrehewet and Smith are labeling limited access) would be attributable to the weakness of the evidence, not any direction from this article.
References
1. Ghebrehewet S, Smith K. Do direct acting antivirals cure chronic hepatitis C? Our question is: does Cochrane aim to inform health decision making, or actively interpret data to make those decisions? (Rapid response) BMJ 2019 (Aug 26 2019): 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. AASLD/IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. May 24, 2018. www.hcvguidelines.org (Accessed 6/15/18)
4. 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
5. Pham TNQ, Mulrooney-Cousins PM, Mercer SE, et al. Antagonistic expression of hepatitis C virus and alpha interferon in lymphoid cells during persistent occult infection. J Viral Hep 2007; 14:537-48
6. Garcia-Bengoechea M, Basaras M, Barrio J, et al. Late disappearance of hepatitis C virus RNA from peripheral blood mononuclear cells in patients with chronic hepatitis C in sustained response after α-interferon therapy. Am J Gastroenterol 1999; 94:1902-5
7. 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
1 September 2019
Ronald Koretz
Physician
Janus C. Jakobsen, Emil E. Nielsen, Christian Gluud
Olive View-UCLA Medical Center
Olive View-UCLA Med Ctr, Dept Medicine
Competing interests: No competing interests