'Miracle' antiviral hepatitis C drugs may have no clinical effect

[Jorah]

I just saw this today, the Cochrane group supposed to be a respected group any of the pros care to comment? I thought that by stopping the virus you stop the damage.

Review concludes drugs hailed as cure for potentially fatal liver disease may clear virus from blood, but there is no evidence they prevent harm or save lives

Drugs that have been hailed as a cure for a debilitating and sometimes fatal liver disease – but have threatened to break the health budgets of most countries because of their cost – have not been proven to have any effect, according to a new review.

The startling conclusion came from the respected and independent Cochrane Collaboration, which has assessed all the drug company trials of the breakthrough hepatitis C treatments.
Hepatitis C is a viral infection that causes chronic liver disease and can lead to death from cirrhosis and cancer. Previous treatments were not very effective and had side effects that many patients could not tolerate.

The new direct-acting antiviral drugs (DAAs) were hailed as little short of a miracle because they cleared the hepatitis C virus from the blood within 12 weeks, but the price, at about £30,000 per patient, has caused huge concern around the world. Experts from the World Health Organisation (WHO) said last June that no country in the world could afford to treat all those who needed the drugs.

The WHO estimated that treating all those infected would eat up a large part of the drugs budget in every country, from 10.5% in the Netherlands to 190% in Poland. The UK would have to spend a third of its drugs budget on the medicines. About 160 million people are infected and there are about 700,000 deaths a year globally as a result of hepatitis C.

But the Cochrane Collaboration, whose expert group on liver disease is based in Denmark, has published a review of all the randomised controlled trials conducted by the manufacturers in order to get the drugs licensed. It finds that the drugs may clear the virus from the blood, but there is no evidence that they prevent harm from disease or save lives.
Janus Christian Jakobsen, chief physician at a clinical trial unit in Copenhagen and deputy co-ordinating editor of the Cochrane Hepato-Biliary Group, said: “It is never possible to show that something does not work, but there is no evidence [that they do]. Our results indicate [the drugs] may have no clinical effect.”

The effect of the drugs has been measured in the trials by the amount of virus remaining in the blood stream after treatment. But, the review says, that does not mean there is no virus lingering in the body. There is evidence, they say, that in the sickest people treated with the drugs (stage 3 or 4), the virus can return and cause end-stage liver disease.

The trials collected very little evidence about the impact of the drugs in countering the symptoms of hepatitis C disease and there were few deaths either among those taking the drugs or those taking a placebo, says the review.

The reviewers included all the drug trials they could find, published and unpublished – in total, 138 trials randomising a total of 25,232 participants. All the trials were funded by the manufacturers of the drugs and therefore “at high risk of bias,” they say.

“The lack of valid evidence and the possibility of potentially harming people with chronic hepatitis ought to be considered before treating people with hepatitis C with DAAs,” they conclude.

AbbVie, one of the companies making the drugs, commented: “We do not recognise the conclusions of this report, as both controlled trials and real world experience contradict its findings. A cure in [hepatitis C] is defined as undetectable virus in the blood 12 weeks after completing treatment and, in the UK, fewer than 1% of people treated with AbbVie’s therapy did not achieve this.”

Gilead, which manufactures the drugs, said that the primary goal of treatment was to “cure the infection by eradicating the hepatitis C virus”. Nice, the National Institute for Health and Care Excellence, had said they were value for money because the patient becomes less infectious and is likely to require fewer NHS visits. A report from Public Health England in 2015 showed there had been an 8% decrease in end-stage liver disease and a decrease in liver transplants following introduction of the drugs.

The Cochrane reviewers say, however, that they have included all controlled trials in their review. “Sustained virological response is a surrogate outcome,” added Jakobsen. “From a patient perspective, it does not matter if virus cannot be detected in the blood if DAAs do not improve survival or lead to fewer hepatitis C complications. Furthermore, the validity of this surrogate outcome has been questioned before our review was published.”

A second company making the drugs, Bristol Myers Squibb, said it had no comment to make about the review.

https://www.theguardian.com/society/2017/jun/08/miracle-hepatitis-c-drugs-costing-30k-per-patient-may-have-no-clinical-effect

[gnatcatcher]

Note that this article in The Guardian says, "A report from Public Health England in 2015 showed there had been an 8% decrease in end-stage liver disease and a decrease in liver transplants following introduction of the drugs." The Cochrane review [ http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012143.pub2/full ] concludes that "DAAs do not seem to have any effects on the risk of hepatitis C-related morbidity or all-cause mortality." Yet, they seem to have evaluated short-term studies. How can they assess the long-term consequences of sustained virological response? According to fibroscans, I and others on these forums have less fibrosis than before we were cured. Are there studies that document such improvements? Has enough time even passed to give an unbiased assessment of DAAs' effect on length and quality of life post-SVR? It's been less than three years since the FDA approved Harvoni. I don't know the date of the phase I trial, but it can't be too many more years. Are there data on how those people are now? If not, the Cochrane review itself may be "at high risk of bias" (to use the review's term for the studies it examined).

The Wikipedia article about the Cochrane Library and the Cochrane Reviews they publish [ https://en.wikipedia.org/wiki/Cochrane_Library ] indicates the following people don't have to pay to see the full article in question: residents of Wyoming, parts of Canada, the United Kingdom, Ireland, the Scandinavian countries, New Zealand, Australia, India, South Africa, and Poland. Would a forum member who has free access please read the entire article and let us know if any study used in the meta-analysis actually covers longer-term results? TIA.

Gnatty

[Jorah]

Its huge Gnatty,   maybe 80 pages or more...here is some of it:

Abstract

Background

Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications.
Objectives

To assess the benefits and harms of DAAs in people with chronic HCV.
Search methods

We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016.
Selection criteria

Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language.
Data collection and analysis

We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE.
Main results

We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn (or discontinued) DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.

Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I2 = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.

Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I2 = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20% and when one trial with an extreme result was excluded then the meta-analysis result showed no evidence of a difference.

Withdrawn DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I2 = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I2 = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.

DAAs seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I2 = 77%, 6886 participants, 32 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.

Only 1/138 trials assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).

The majority of all outcome results were short-term results, so we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma).
Authors' conclusions

Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.
Plain language summary

Review question

To assess the beneficial and harmful effects of direct-acting antivirals (DAAs) for chronic hepatitis C.

Background

Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Numerous previous interventions have been used for hepatitis C, but none of these interventions have proven effective on patient-centred outcomes. DAAs are relatively new but expensive interventions for hepatitis C, and preliminary results have shown that DAAs seem to eradicate hepatitis C virus from the blood (sustained virological response). However, it is questionable if an eradication of hepatitis C virus in the blood leads no hepatitis C in the body and improved survival and fewer complications. In this Cochrane Review, the authors assessed the evidence on the clinical effects of DAAs for hepatitis C.

Study characteristics

The authors included 351 publications of 138 randomised clinical trials. All included trials were at high risk of bias. The 138 trials used 51 different DAAs. Of these, 84 trials assessed DAAs on the market or under development; 57 trials were on DAAs withdrawn from the market. Trials were conducted from 2004-2016. The trials were from all over the world including 34 different countries. We included 17 trials where all the participants had previously been treated for hepatitis C (treatment-experienced) before being included in the trial. There were 95 trials that included only participants who had not been previously treated for hepatitis C (treatment-naive). The intervention periods ranged from one day to 48 weeks with an average of 14 weeks. The combined intervention period and follow-up period ranged from one day to 120 weeks with an average of 34 weeks.

Key results

DAAs do not seem to have any effects on the risk of hepatitis C-related morbidity or all-cause mortality. In fact, there were no data on hepatitis C-related morbidity and very few data on mortality (15 deaths/2377 direct-acting antiviral participants (0.63%) versus 1 death/617 control participants (0.16%) resulting in an odds ratio of 3.72, 95% CI 0.53 to 26.18, P = 0.19, I2 = 0%, 2996 participants, 11 trials, very low-quality evidence). DAAs do not seem to have any effects on the risk of serious adverse events (376/13,574 (2.77%) direct-acting antiviral participants had one or more serious adverse events versus 125/2,243 (5.57%) control participants during the observation period resulting in an odds ratio of 0.93, 95% CI 0.75 to 1.15, P = 0.52, I2 = 0%, 15,817 participants, 66 trials, very low-quality evidence). When analysed separately, simeprevir was the only direct-acting antiviral that showed evidence of a beneficial effect when assessing risk of a serious adverse event. Our analyses, however, showed that the validity of this result is questionable and that 'play of chance' might be the cause for the difference. There was not enough information to confirm or reject if DAAs have clinically relevant effects on other clinically relevant outcomes. Our results confirm that DAAs seem to have an effect on the risk of no sustained virological response, but all of the trial results were at high risk of systematic error ('bias'), and the clinical relevance of results on virological response is questionable. The lack of valid evidence and the possibility of potentially harming people with chronic hepatitis ought to be considered before treating people with hepatitis C with DAAs.

Quality of the evidence

Due to several limitations, we assessed the quality of the evidence in this review as very low quality. First, all trials and outcome results were at high risk of bias, which means that our results presumably overestimate the beneficial effects of DAAs and underestimate any potential harmful effects. Second, there were limited data on most of our clinical outcomes, that is, there were only relevant clinical data for meta-analyses on all-cause mortality and serious adverse events, and for these, data were sparse. Third, most trials primarily focused and assessed the effects of DAAs on sustained virological response; however, it is questionable if sustained virological response has any clinical relevance to the person with chronic hepatitis C (see ‘Background’ in this Plain language summary).

[Jorah]

Authors' conclusions

Implications for practice

Direct-acting antivirals (DAAs), considered as one overall intervention, do not seem to have any effects on risk of serious adverse events in adults with chronic hepatitis C. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. When analysed separately, simeprevir was the only DAA that showed evidence of an effect when assessing the risk of a serious adverse event, but this result was at high risk of bias and high risk of random errors. Withdrawn DAAs seemed to increase the risk of serious adverse events. DAAs may decrease the risk of no sustained virological response but the clinical implication of the results on this non-validated surrogate outcome is unclear. All the trials and all of the outcome results were at high risk of bias, so there is a great risk that out results overestimate benefits and underestimate harms. Further evidence of long-term clinical benefit of DAAs on hepatitis C virus-related morbidity and mortality is needed to determine the efficacy of this treatment with greater certainty.
Implications for research

Randomised clinical trials assessing the clinical effects of DAAs are needed. Such trials should be conducted with low risk of bias, low risk of design errors, and low risk of random errors. Future trials ought to focus their assessments on patient-centred clinical outcomes.
Future randomised clinical trials ought to avoid the negative aspects we noted in the first 138 randomised clinical trials conducted on DAAs versus placebo or no intervention:
many of the trials employed skewed randomisation, so that more participants were randomised to DAA compared with placebo or no intervention. This reduces the power for the trials and makes it more difficult to assess rare outcomes such as clinical outcomes and serious adverse events;
most of the trials used as primary outcome a non-validated surrogate outcome, that is, sustained virological response. This outcome has previously been shown to work as an invalid surrogate for clinical outcomes for the effects of IFNs or IFNs combined with ribavirin, as this may also be the case for DAAs;
most of the trials were at high risk of for-profit bias;
most of the trials were extremely short term, with trial intervention durations below 48 weeks and a follow-up period below 38 weeks;
too many of the trials had problems with randomisation and too short follow-up periods;
many of the trials used co-interventions that were not equally distributed among the participants in the experimental and control groups;
lack of trials assessing the effects of DAAs on quality of life;
many of the trials used multiple intervention arms making it hard or impossible to assess intervention effects properly; and
many of the trials reported adverse events in a way that it was hard or impossible to assess their severity.
Future trials ought to be designed according to the SPIRIT guidelines (Chan 2013) and reported according to the CONSORT guidelines (Schultz 2010). Threats to the validity of the evidence ought to be accounted for (Garattini 2016).
Acknowledgements

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of Cochrane Hepato-Biliary through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.

Peer reviewers for the protocol: Thomas Baumert, France; Domenico Sansonno, Italy.
Contact editor for the protocol: Norberto C Chavez-Tapia, Mexico.

Peer reviewers for the review: Thomas Baumert, France; Lauren A. Beste, US.
Contact and sign-off editor for the review: Norberto C Chavez-Tapia, Mexico.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012143.pub2/full

[gnatcatcher]

Thank you, Jorah. The excerpts you posted give a much clearer picture. If all they had available were 138 trials assessing the effects of 51 different DAAs, there wasn't much information per DAA, so I am glad they conclude that there need to be long follow-up periods so that we'll know if such lab indicators as long-term SVRs and long periods of normal AST and ALT values do or don't give people a better quality of life.

Gnatty

[Jorah]

My pleasure Gnatty...

Must be my brain fog but I don't understand :  "It finds that the drugs may clear the virus from the blood, but there is no evidence that they prevent harm from disease or save lives."

But doesn't stopping the virus prevent further disease? This sames strange to me...

[Lynn K]

or perhaps most were not in danger of negative effects like dying from liver disease with or without having hep c as only 20% of patients will develop cirrhosis after 20 years of infection so for most patients curing hep c does not change the course of their lives.

[gnatcatcher]

My pleasure Gnatty...

Must be my brain fog but I don't understand :  "It finds that the drugs may clear the virus from the blood, but there is no evidence that they prevent harm from disease or save lives."

But doesn't stopping the virus prevent further disease? This sames strange to me...

Since they're scientists, they're saying the only thing proven at this point is the removal of the virus from the blood. The studies they looked at do not offer evidence from which conclusions can be drawn regarding whether reaching SVR actually saves lives. That will take properly constructed long-term studies, which is why their "Implications for Practice" section details how such future studies should be conducted.

[lporterrn]

I have to sit down and really analyze all the flaws, of which there are many. Basically they looked at clinical trial data, but no long-term natural history data. Two points they buried in the paper are:

"We chose pragmatically to only assess outcomes at one assessment time point, that is, the trial's result as provided at maximum follow-up. Most trial results were only short-term results. Hence, our results can neither confirm nor reject that DAAs have clinical long-term effects, which is a further limitation of our present review results, especially because most of the harmful effects of hepatitis C take years to develop."

"The combined intervention period and follow-up period ranged from one day to 120 weeks with an average of 34 weeks."

[Lynn K]

Wow how can one draw long term conclusions based on an average of 34 weeks post treatment

scheesh

:/

[dragonslayer]

So, the virus is removed from the blood, but there's no diminution of the effects of HCV in the body, in health, or in morbidity?

Hmmm....  The virus can live in the body, but not be detected in the blood after treatment?   We all know about rare relapses, and it was alluded to in the link.  But a whole lot more than that is being said.

I hardly know what to say... these findings are more than a little confounding.  From all we know about HCV and how it works, it hardly seems possible.  Are they saying that while the DAAs are successful at removing the virus its basically a pyrrhic victory?  It basically makes no difference to the individual?   The markers for success dont work and are meaningless?   WTF?

More than a little confused......

[Lynn K]

Based on an average of an average post treatment observation time of 8.5 months not really enough time to draw much on a conclusion

[lporterrn]

Here is what Jason Grebley from Australia wrote (I am a fan of his),

I am not sure that the authors conclusions re: “Our analyses showed that most DAAs seem to decrease the risk of no sustained virological response but, as mentioned, this result is based on trials at high risk of bias and the clinical relevance of results on this non-validated surrogate outcome is questionable” and the media article stating that DAAs “have not been proven to have any effect, according to a new review” are NOT supported by the other data in the scientific literature.
 
A couple of key points to make here:
 
1)    The clinical trials of DAA therapies were only designed to evaluate the primary endpoint of SVR12 (e.g. viral cure). These studies were not designed with sufficient follow-up to evaluate the impact of DAA therapy on long term outcomes, such as decompensated liver disease, liver cancer, and liver-related mortality.
 
2)    There are clear data from observational cohort studies and some clinical trials highlighting the individual-level benefits that successful HCV treatment provides, including improvements in health-related quality of life (see attached systematic review by Younossi et al), decreased risk of liver disease progression (see review attached recently published in the Journal of Hepatology reviewing the literature in this regards), and improved survival in people with advanced liver disease (see attached paper from van der Meer et al and also the attached review).
 
I just feel that it is important to clearly state the considerable potential benefit that HCV therapy provides both at an individual and population-level.
 
We need to be careful about over-interpreting studies and media articles such as this in light of the other overwhelming data in the literature which clearly demonstrate the benefits of HCV therapy.
 
Regards,
 
Jason
 
Jason Grebely BSc PhD
Associate Professor
Kirby Institute, UNSW Australia
NHMRC Career Development Fellow

[lporterrn]

Still need convincing? All these studies show the benefits after HCV eradication:

Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis
JAMA. 2012 Adriaan J. van der Meer, MD et al.
"our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis…….The risk of all-cause mortality was almost 4-fold lower in patients with SVR compared with patients without SVR…...Our study with a long follow-up duration demonstrated a lower risk for all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis who achieved SVR. In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure, and liver-related mortality or liver transplantation in patients with SVR…...Thirteen patients (7%) with SVR and 100 patients (30%) without SVR died after prolonged follow-up of our cohort, which was more than 4 times the number of deaths registered during the first data collection (n = 2 among patients with SVR and n = 24 among patients without SVR)…..Seven patients with SVR (4%) were diagnosed with HCC, up to 6.8 years after SVR was achieved. In the without SVR group, HCC occurred in 76 patients (22%). ….After 10 years, the cumulative occurrence of HCC was 5.1% (95% CI, 1.3%-8.9%) in patients with SVR and 21.8% (95% CI, 16.6%-27.0%) in patients without SVR (P < .001) …...In a Spanish cohort of patients with cirrhosis, the 5-year mortality was 2% in patients with SVR vs 14% in patients without SVR….A further new finding of our study was the approximately 2-fold increased risk of all-cause mortality and HCC in patients with HCV genotype 3 infection compared with patients without genotype 3 infection"

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population - (04/13/16) …."We report herein that survival of patients with HCV compensated cirrhosis who achieve SVR is similar to that of the sex and age matched general population, hence achieving the maximal survival benefit and an optimal allocation of resources. In conclusion, eradicative treatment of patients with compensated HCV cirrhosis is strongly justified since the achievement of SVR originates a major survival benefit, with a life expectancy similar to the general population. In patients with compensated HCV cirrhosis, treatment should be administered as early as possible in order to achieve the highest benefit. Availability of IFN-free DAA regimens will allow for an SVR to be achieved even in sicker patients and in those ineligible for IFN or previously excluded for co-morbidities, a major advance given that the mortality rate of these patients is extremely high in comparison to the general population. Since a failure in modifying the disease course in decompensated cirrhosis irrespective to viral eradication was recently reported in almost half of all treated subjects [18], with some patients seemingly beyond a point of no return even after viral eradication, the overall impact of SVR remains to be assessed in further dedicated studies.”

EASL: SVR Reduces Morbidity/Deaths by 5-10 Fold - Abbvie Analysis - Percent of Subjects Experiencing Liver Morbidity Over a Lifetime Horizon with AbbVie 3D (Abt-450/Ritonavir/Ombitasvirand Dasabuvir) Versus No treatment - (04/31/15)

EASL: Healthcare Costs by Stage of Liver Disease in Chronic Hepatitis C Patients in the United States - (04/27/15)

EASL: Reduction in Annual Medical Costs with Early Treatment of HCV Using Abbvie 3D (AbT-450/Ritonavir/Ombitasvir and Dasabuvir) ± Ribavirin in the United States - (04/28/15)

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis; Direct acting antivirals for decompensated cirrhosis. Efficacy and safety are now established - Editorial - (05/18/16)

EASL: Ledipasvir/Sofosbuvir With Ribavirin Is Safe in >600 Decompensated and Post-Liver Transplantation Patients With HCV Infection: An Integrated Safety Analysis of the SOLAR-1 and SOLAR-2 Trials - (04/29/15)

AASLD: Sofosbuvir/Velpatasvir Fixed-Dose Combination for the Treatment of HCV in Patients With Decompensated Liver Disease: the Phase 3 ASTRAL-4 Study / ASTRAL 1, 2 and 3 - (11/30/15)

Daclatasvir Plus Sofosbuvir With or Without Ribavirin for Treatment of Chronic HCV Infection in Patients With Advanced Liver Disease: Results of a European Compassionate Use Programme - (04/20/16)

EASL: Time Course of Hepatic Improvement using the HepQuant® (HQ)-SHUNT Function Test during and after Treatment with Ledipasvir/Sofosbuvir in Liver Transplant Recipients with Allograft Fibrosis or Cirrhosis and Patients with Decompensated Cirrhosis who have not undergone Transplantation - (04/29/15)

EASL: Improvement in Liver Function and Non-Invasive Estimates of Liver Fibrosis 48 Weeks after Treatment With Ombitasvir/Paritaprevir/r, Dasabuvir, and Ribavirin in HCV Genotype 1 Patients With Cirrhosis - (04/24/15) post-SVR markers of HCV disease improved including all- non-ivasive estimates of liver fibrosis - FibroTest, APRI, FIB-4, FORNS Index

AASLD: Long-term Follow-up of Patients With Chronic HCV Infection and Compensated or Decompensated Cirrhosis Following Treatment With Sofosbuvir-Based Regimens - (11/14/16) >99% SVR durability 21 months followup; "incidence rate of de novo HCC among patients with compensated cirrhosis was lower (0.50 rate) than the rates of 1.39 and 1.89 per 100 patient years reported for interferon treated patients with cirrhosis who achieved SVR.

3 Year Followup - Durability of SVR
AASLD: Long-term follow-up of patients with chronic HCV infection & treated with daclatasvir-based regimens in phase 2 and 3 studies - (11/15/16) >99%

AASLD: The impact of sustained virological response to HCV infection on long term risk of hepatocellular carcinoma: The BC Hepatitis Testers Cohort - (11/17/16) 6 fold reduction in HCC when SVR is achieved vs not achieved

EASL: Prognostic value of viral eradication for major adverse cardiovascular events in hepatitis C cirrhotic patients. ANRS CO12 CirVir Cohort - (04/26/17)

EASL: THERAPY WITH DIRECT ANTIVIRAL AGENTS IN PATIENTS WITH HCV-RELATED LYMPHOPROLIFERATIVE DISORDERS AND MIXED CRYOGLOBULINEMIA - (04/26/17)

AASLD: The Impact of Hepatitis C Viral Cure on Progression of Renal Disease - (11/14/16)

SVR Reduces Kidney Disease & CVD, Cancer Risk - 'These findings argue for the prescription of HCV therapy in coinfected/all patients regardless of fibrosis stage.' - (05/15/17)

EASL: The cumulative prevalence and incidence of extra-hepatic manifestations in patients with hepatitis C virus infection: real-world evidence from the United States - (05/03/17)

EASL: Potential effect of hepatitis C treatment on renal, cardiovascular and metabolic extrahepatic manifestations: Results from clinical trials of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin - (04/28/17)

Early Treatment For Women Recommended
EASL: Extra-hepatic manifestations from hepatitis C virus infection related to female infertility and adverse pregnancy outcomes: A real-world observation - (05/03/17)

CROI/2016: Understanding the Relative Contributions of IDU and HCV on Systemic Immune Activation HCV should be aggressively treated in current IDUs even more if HIV and/or HCV positive - (04/4/16) HCV treatment should be aggressive in IDUs because their immune system is activated, immune activation can lead to inflammation which can have poor long-term outcomes, we know that the onset of & early & accelerated & premature onset of comorbidities like heart disease, neurologic impairment, and perhaps kidney disease, bone disease & frailty are all associated with immune activation & to inflammation.

Patient reported outcomes & Work productivity Improves
Improvement of Central Fatigue is Associated with Sustained Virologic Response (SVR) Following Sofosbuvir-Containing Regimens - (04/24/14)

Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries - (02/09/16)…..About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of 435 million and a weighted average per-employed patient (PEP) gain of 900 in the EU5.

The Impact of Sustained Viral Eradication on the Work Productivity of Patients with Chronic Hepatitis C (CHC) from the Five Western European Countries and the United States - (06/16/15)

Ledipasvir and Sofosbuvir Combination Improves Patient-Reported Outcomes During Treatment of Chronic Hepatitis C: The Result from ION-1 Clinical Trial - (04/24/14)

Independent Predictors of Patient-Reported Outcomes (PROs) and Quality of Life (QOL) in Chronic Hepatitis C Patients Receiving Interferon (IFN) -Free versus IFN-Containing Regimens with Sofosbuvir (SOF) - (04/24/14)
--------------------
Reversion of disease manifestations after HCV eradication Jnl of Hepatology Oct 2016 Adriaan J. van der Meer1,⇑, Marina Berenguer2

[dragonslayer]

Thanks, Lucinda, for bringing some sanity back into the fold!

[gnatcatcher]

Lucinda, when I saw this one in your list:
SVR Reduces Kidney Disease & CVD, Cancer Risk - 'These findings argue for the prescription of HCV therapy in coinfected/all patients regardless of fibrosis stage.' - (05/15/17)
I was looking forward to an unimpeachable study unequivocally supporting the title as listed. However, the actual report abstract found at http://www.natap.org/2016/AASLD/AASLD_02.htm lists the following study limitations:
- Results for the time to ESRD analysis may be unstable due to the small number of observed ESDR results
- A larger proportion of Blacks and those with cirrhosis were excluded from analysis due to missing SVR. However, we do not expect that missing Black and cirrhotic patients have worse outcomes than those included in the analysis and thus, do not expect bias from their exclusion
- These results may not be generalizable to cure by INF-free direct-acting antivirals

In essence, this study is not sufficiently large and/or longitudinal; the confidence level may or may not apply to Blacks and cirrhotics because there weren't enough in the pool who'd reached SVR; there hasn't YET been enough time to evaluate DAAs.

The Cochrane review is pushing for extremely high standards in study design. There is nothing wrong with that. Perhaps there are other studies in your list that do meet their standards but which the Cochrane reviewers didn't include; they listed all the sources from which they pulled studies and wrote, "Searches were last run in October 2016." That's very early in the life of DAAs.

Unfortunately, news media (in this case, The Guardian) go with what is most sensational without providing the necessary qualifications.

Eventually, enough proper studies will have been done to verify anecdotal data.

Meanwhile, enjoy your HCV-free lives, everyone.

Gnatty

[Lynn K]

Thanks Lucinda!

Mmmmmmm data yummmmm

[Mugwump]

What all these studies fail miserably to consider is the fact that HCV once cured cannot spread. Was this not the main reason for getting treatment in the first place for many of us?

The long term costs of HCV are mostly in the fact that if it not brought under control it will continue to cost billions not just in terms of health care dollars for the treatment of HCV but also in the secondary costs to society. We cannot know how many have actually died of this disease because before it was isolated in 1989 most cases were written off as either fatty liver, alcoholism or undefined HCC! There is no way of knowing how much damage HCV has done or how much it will do in future if not eradicated the way polio was.

End of story.

[lporterrn]

Hi Gnatty,
I don't think I've ever seen a perfect study, and yes, that one is less than perfect. But the findings don't refute the conclusion. The Cochrane review claims to be something it isn't.

We chose pragmatically to only assess outcomes at one assessment time point, that is, the trial's result as provided at maximum follow-up. Most trial results were only short-term results. Hence, our results can neither confirm nor reject that DAAs have clinical long-term effects, which is a further limitation of our present review results, especially because most of the harmful effects of hepatitis C take years to develop.

I think fundamentally what is disturbing here is that humans see what they want to see (yes, I include me in the human column). But sometimes what you see is true. The world isn't flat and hep C drugs make a difference. 71 million people in the world have hep C, and the hep C death and new infection rates are rising. Cochrane's study can be very damaging, especially in these highly-charges times when healthcare dollars are stingily distributed.

[gnatcatcher]

Lucinda, the excerpt you cite is precisely where the Cochrane report disclaims any attempt to be definitive. Problems arise only if media reports omit the disclaimers. So, we have a situation in which the Cochrane reviewers had to stop somewhere, sometime, or they would never finish. The Cochrane scientists were in an awkward situation: either they had to give up trying to do a review at all, or they had to set parameters for their work and be clear about what they could and couldn't establish based on those parameters. They chose the latter. The excerpts from the report that I have seen aren't the problem, but what Janus Christian Jakobsen said (if quoted accurately by The Guardian) was irresponsible because it lacks the disclaimers that are in the actual report. The Guardian may have printed a partial statement, therefore taking Janus Christian Jakobsen's words out of crucial context. I agree that The Guardian's article will cause harm.

Gnatty

[lporterrn]

I hope you will be patient with me. Just because I don't see it the same way as you, doesn't mean I am right. What am I missing Gnatty? If anyone can show me the limits of my brain, I'd love it to come from someone I trust, such as you.

S here is how I see it: I think that disclaimer is superfluous. It is like measuring life expectancy beginning at birth and stating that we can't stick around for more than 2 years to see what happens. But we'll draw conclusions on data without looking at other data. those babies live to be 2, then concluding that we live forever.

Cochrane had other data sets, but chose not to use them. It just seems like poor data.

[gnatcatcher]

All the work that went into this particular Cochrane review does seem pointless, since all they actually concluded is that the clinical trials of DAAs that the manufacturers ran were flawed and too short-term and thus didn't, with one exception, show anything other than that a huge percentage of participants reached SVR without dying or being greatly maimed during the period of time covered by the clinical trials.

Let's go back to the start of this thread. The first thing posted was the article that ran in The Guardian by Sarah Boseley, Health editor. Whoever wrote the headline and lede certainly wanted a sensational attention-grabber. Ms. Boseley or her editor allowed in one contrary paragraph (. . . Nice, the National Institute for Health and Care Excellence, had said they were value for money because the patient becomes less infectious and is likely to require fewer NHS visits. A report from Public Health England in 2015 showed there had been an 8% decrease in end-stage liver disease and a decrease in liver transplants following introduction of the drugs. . . .), and she gave each leading manufacturer the chance to put in a sound bite. Typical 21st-century journalism, which I would take with a tablespoon of salt if it were safe to consume that much salt

Unfortunately, most readers stop at what they read in the popular press, and they read in a hurry, so they might not even notice the few qualifications that are attributed to Janus Christian Jakobsen: “It is never possible to show that something does not work, but there is no evidence [that they do]. Our results indicate [the drugs] may have no clinical effect.” (Emphasis mine.) Did Jakobsen also mention the limitations of the Cochrane review team's restricting the scope of their review "for pragmatic reasons"? We can't tell.

Boseley's article intrigued me enough to find out more about the Cochrane Collaboration, to find and read the abstract and plain language summary, to ask if anyone could see the full article for free, and to suggest to the moderators that this thread be moved from "Considering Hepatitis C treatment" to its present location, since it was already clear from my further reading that Boseley's piece was "careless." The excerpts Jorah then posted gave me a very different view: the actual report was careful to state the limitations of its work. I have used "pointless" to describe the report, because its listed objective in the abstract was "To assess the benefits and harms of DAAs in people with chronic HCV." The report most definitely does not do that. It places the blame on biased, overly short studies; we might place it on the limits the Cochrane Collaboration adopted on which studies got included.

I like that the report seeks to have future clinical trials conducted better (free of funding bias, for a longer time frame, and gathering more types of data). Of course, the flip side is that such trials would come too late for some people to survive and others to avoid getting infected. Here's where you and I may actually differ: you were willing to endure excruciating, long-odds treatments to get cured, whereas I view it as still unknowable whether my taking Harvoni will have yielded a net benefit. The actual report's reluctance to over-claim suits my personality.

Gnatty

[Mugwump]

The wake up call for me comes from the fact that I personally known 6 people who have died directly from the complications of HCV. However there are no real stats as to how many have actually died. What this means to me is that the real rates of HCV caused morbidity and mortality are not known. Otherwise the numbers would be mind boggling considering the death and morbidity rates I have seen as one individual.

I think that the number that were infected through tainted blood is much greater than is currently believed, thus the numbers that went on to spread the disease in the 1950s through to the 1990's is an unknown factor. The spread through the use of street drugs is certainly a huge part of the same equation and this spread is by no means over. All these studies are not relevant because they fail to consider the numbers who have already died or gone on to develop secondary diseases because of HCV.

Studying only the direct causation of cirrhosis by HCV makes these studies irrelevant and completely misses the fundamental problems that HCV creates. Of the individuals that I know who died of HCV only one died of cirrhosis caused directly by HCV and that was after a liver transplant and 14 years of life after transplant when his immune system was not able  to cope with the infection and his transplanted liver failed quickly. The others either died of GI bleeds, kidney failure or HCC. And one directly from the psychological pressure of having the disease.

What would be more relevant would be studies of the numbers with HCV who develop other problems and what those problems are because the disease itself most likely increases the risks of many other conditions long before it progresses to full blown cirrhosis.

From my perspective and from what I have seen amongst those infected, long term active chronic HCV infection seems to have much worse outcomes and is much more debilitating than we are lead to believe in these very biased and small studies of the victims of HCV.

Eric

[lporterrn]

I love this conversation and everyone's input. I try to live with an open-mind, so discussing this in this format has stretched me. Thank you.

[Lynn K]

There is data available on deaths attributed to HCV

This from the CDC for example

https://www.cdc.gov/media/releases/2016/p0504-hepc-mortality.html

Hepatitis C Kills More Americans than Any Other Infectious Disease

Deaths associated with hepatitis C reached an all-time high of 19,659 in 2014, according to new surveillance data released today by the Centers for Disease Control and Prevention (CDC).

A second CDC study, published online today in Clinical Infectious Diseases, shows that annual hepatitis C-related mortality in 2013 surpassed the total combined number of deaths from 60 other infectious diseases reported to CDC, including HIV, pneumococcal disease, and tuberculosis. Further, both studies use data from death certificates, which often underreport hepatitis C, so there likely were even more hepatitis C-related deaths than these numbers suggest.


There are many other hits in Google on the search for HCV related deaths

https://www.google.com/amp/s/amp.cnn.com/cnn/2016/05/04/health/hepatitis-c-deaths-all-time-high/index.html

https://www.cdc.gov/hepatitis/statistics/2013surveillance/commentary.htm

[gnatcatcher]

I just read the Wikipedia article about Cochrane (which is different than the article about the Cochrane Library the link to which I posted earlier). It includes the following criticisms: "Compared to non-Cochrane reviews, those from Cochrane are less likely to reach a positive conclusion about the utility of medical interventions.^[24] Key criticisms that have been directed at Cochrane's studies include a failure to include a sufficiently large number of unpublished studies, failure to pre-specify or failure to abide by pre-specified rules for endpoint^[25] or trial^[26] inclusion, insufficiently frequent updating of reviews, an excessively high percentage of inconclusive reviews,^[27] and a high incidence of ghostwriting and honorary authorship.^{[28][not in citation given][29]} In some cases Cochrane's internal structure may make it difficult to publish studies that run against the pre-conceived opinions of internal subject matter experts.^[30]" Here's the link: https://en.wikipedia.org/wiki/Cochrane_(organisation)

Thanks, everyone, for a fascinating thread with wide-ranging, thoughtful input!

[lporterrn]

Gnatty, you scored big time with that post.

So here is my lesson. I've been a huge fan of Cochrane for many years. But my belief in them was a bit too one-sided. Truth is a complicated pursuit.

[gnatcatcher]

. . . Truth is a complicated pursuit.

Indeed. Today I read the following in Yuval Noah Harari's Sapiens: A Brief History of Humankind [pages 250-251]:
"Modern science is based on the Latin injunction ignoramus -- 'we do not know'. It assumes that we don't know everything. Even more critically, it accepts that the things that we think we know could be proven wrong as we gain more knowledge. No concept, idea or theory is sacred and beyond challenge."

An interesting side note about Cochrane: their long-term study Re: screening mammography seems to be based on solid data (different regions of Denmark implemented mammography at different times); it reached a similarly negative "conclusion about the utility of medical interventions."
http://annals.org/aim/article/2596394/breast-cancer-screening-denmark-cohort-study-tumor-size-overdiagnosis

[Jorah]

More comments on the Cochran study...and link to:  AASLD Presentation on SVR Outcome.


Yesterday the Guardian published and article called 'Miracle' hepatitis C drugs costing £30k per patient 'may have no clinical effect'

https://www.theguardian.com/society/2017/jun/08/miracle-hepatitis-c-drugs-costing-30k-per-patient-may-have-no-clinical-effect

The problem with this sensationalist headline is that while it is reporting what was said by the Cochrane Collaboration what they looked at was trial specifically designed to test SVR rates, and not specifically designed to look at long-term outcomes.

Here is a commentary from Dr Andrew Hill and the study to which he refers which was presented at AASLD in 2015 and published in Clinical Infectious Diseases.

Total rubbish!  Here is our paper showing a really strong correlation between curing HCV and improved survival.
 
They only had 16 deaths included in the analysis! 
 
Please see the attached paper where we had much longer follow up and showed a strong effect of SVR on improved survival.  Our analysis included 2210 deaths - slightly more than the Cochrane study!


http://fixhepc.com/blog/item/81-bad-science.html

[gnatcatcher]

Given that Dr. Hill's study was presented in 2015, I hope he's continuing to study outcomes, because the current DAAs were far too new or not yet approved by then. The IAS 2015 write-up ( http://hivandhepatitis.com/hiv-hep-coinfection/hiv-hcv-coinfection/5289-ias-2015-access-to-screening-and-treatment-key-issues-for-hepatitis-b-and-c-and-hivviral-hepatitis-coinfection ) included the following in the "Benefits of Treatment" section: "There is little data yet on the long-term benefits of direct-acting antivirals for hepatitis C, though there is considerable evidence that successful treatment with interferon is associated with reduced disease progression and liver-related death."

Also on my wish list: studies comparing quality of life pre- and post-tx with each DAA. True gold-standard studies may not be possible since pain, for example, can't be quantified in the way that ALT or AST can be, but whatever data can be obtained from a large population over a long time frame will be helpful.

[lporterrn]

This is the best response to the Cochrane report I've seen: https://www.aasld.org/about-aasld/press-room/aasld-expresses-concern-cochrane-review-daas

[gnatcatcher]

Highly useful -- thanks!

[CureSeeker]

 Further, both studies use data from death certificates, which often underreport hepatitis C, so there likely were even more hepatitis C-related deaths than these numbers suggest.

This is very true in my state.  Perhaps it is somehow related to HIPPA of 1990 Act, as Death Certificates are used for many things outside of the realm of HIPPA compliant.  My husband's Death Certificate merely indicates he died of 'natural causes' so anyone using Death Certificates as a basis for reliable data in a random sample would not be including him in any research involving a death from complications due to HCV infection.  Likewise, anyone dying of any infection (HIV/AIDS, HBV, various cancers etc) would not be included in any research using Death Certificates.

I can see this being a good thing as it relates to the privacy of the patient and any surviving family members.  I can see it being a good thing for the drug companies - if they do not wish to report deaths for failed treatments in any studies produced. 

I don't see it as being 'good science' in the end, and researchers should not consider Death Certificates as any better source of information than a high school teacher would consider a direct quote from Wikipedia to be.

Is it possible that the Cochrane Group is just looking to lay a foundation to be built upon in the future as more data is gleaned over time? 

I believe any drug needs to be studied for at least 20 years to determine its true value to patient's and society.  If that is true, in the realm of diseases like HCV and HIV/AIDS where most, if not all patient's really don't have that much time to wait, and improvements are available too quickly, while old methodologies are discarded when those improvements become initially validated and available for use - as they should be, all well before a time frame of 20 years for proper analysis.

I conclude that it all has to be left in the hand's of the drug companies, and frontline practitioners to provide accurate and valid data.  The man who treated my husband can tell you what he died of, but his death certificate never will.  There is no impartial source of data, that would be cost effective to a researcher, for a good faith application of the Scientific Method.  But, I know for a fact that hundreds, and possibly thousands of people die annually in the major metropolis that is my 'hometown', and if they all died of complications from HCV - whether treated or not - their Death Certificate would merely report 'natural causes'. 

Ultimately, and overall, I agree with Mugwump.  This is a virus that we know can be disabled and eradicated.  Just like polio, it should be.  And, as time progresses, the cost should be reducing as the drug companies realize more and more profits for their efforts.  The ability to be cured should not be held hostage for profits alone.  It should be available to help bring viruses like HCV to its demise for the benefit of society at large.

I have been treated and cured.  I sought that treatment of my own free will.  If a harmful effect becomes realized 10, 20 or 30 years from now due to that treatment that I practically begged for, it doesn't take away from the fact that the virus is DEAD inside of me.  30 years from now I will be over 80 years old.  Something else could kill me long before any unforeseen harmful effect from treatment ever comes to the surface.

Any latent harmful effect doesn't take away from the fact that I do not need a liver transplant, and cannot infect anyone else with the virus.  Those things are well worth the benefits of early detection and treatment for anyone.

[andrew j]

The research is based on a ridiculously short study period, so it's as good as useless.

Why it was even published is beyond me.
Maybe they get payed for publishing research ... any research?!

Something that isn't often touched upon:

I was really unwell when I had Hep C.
The brain-fog was so bad, I couldn't think straight. For years.
I was mis-perceiving things all the time - making incorrect decisions.
... It culminated in injuring myself ... an injury I'll probably never recover from ...  and that's not even thinking about all the opportunities I've lost ... the relationships I could have had ... the screwed-up relationships!

The losses are incalculable.

... And on that subject - I'm sorry for your loss, CS.

Best wishes,
A.

[CureSeeker]

Thank you Andrew, and I agree its stupid and rubbish.

Our doctors told us that I was only a year or two away from my husband's condition if I remained without treatment.  This would indicate that I should be producing test results that do not reflect a healthy liver right now, IF the treatment did nothing to extend my life.

In fact, this time next year, I should be in process of joining my husband in heaven, IF the findings of this study are to be taken the least bit seriously.

If this is an effort to put pressure on the drug companies to reduce costs, as world-wide budgets breaking is definitely mentioned, then its a piss-poor way to go about getting costs reduced (excuse my language - but really).

It's a STUDY that has the potential to do more harm than good, when it comes to people reading it on Wiki and thinking that treatment won't really help them.  In that light, it's a down right lie and all traces of it should be removed from public view.

Ignorance has no clinical value with such a serious topic.

[andrew j]

Totally, CS.

Even the simple FACT of fibrosis regression following Tx must constitute evidence of better health outcomes?

... Better health outcomes?!!

Everyone knows ...

Oh - never mind?!!!

[BillT]

I did my own trial.It was 100% successful.Take it for what it's worth.

[lporterrn]

When you are the 100%, it sure feels good!

[Lynn K]

Hi CureSeeker

So sorry for your loss

[BillT]

It is a wonderful Feeling Lucinda.One thing to remember is that there are far more positive studies in favor of these treatments and post treatment results.I'm not really concerned about this one simply because anyone doing research will read more than one study and realize that this one doesn't measure up to the majority of findings.