Thursday, January 15, 2015

The Fashion Challenges of the Emperor of Hepatitis C Treatment - Now in the BMJ, but Who Will Notice?

As we wrote, most recently last week, the hepatitis C screening and treatment bandwagon keeps rolling along.  There is constant public argument about the prices of treatment regimens, which approach $100,000 per patient in the US.  However, nearly all the public chatter, which seems mostly to come from corporate public relations people and marketers, investors and investment advisers, physicians with financial conflicts of interest, and pundits with little background in clinical epidemiology, seems never to question the assumption that the new drugs for hepatitis C are miraculous cures, which, of course, makes it hard to argue that they should not cost royal amounts.

The Lack of Good Evidence for the New Hepatitis C Treatments

However, starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts herehere, and here.)

The British Medical Journal Publishes a Skeptical Review of Hepatitis C Screening  

Now an article in the British Medical Journal again raises questions about whether the emperor of hepatitis C treatment has some missing garments.(3)  To date, this article has received minimal attention from large media outlets.  I could only find stories in Bloomberg, and by the San Francisco Chronicle to date.

The article by Koretz et al focused on the evidence, or lack thereof in favor of screening for hepatitis C, but affirmed the following points

Most Patients with Hepatitis C Will Not Go On to Have Severe Complications of the Disease

To wit,

At least 2.7 million people are infected with hepatitis C virus in the US, and around 16 000 people each year die or have liver transplantations because of the disease. This suggests that less than 0.6% of infected patients will die of liver disease or be transplanted each year.


Retrospective studies of the natural course of hepatitis suggest that end stage liver disease is common and that it takes about 20 years to develop cirrhosis and 30 years to develop liver cancer. However, such series are usually composed of people who have a medical problem and are thus a sicker subpopulation of the people with chronic hepatitis C infection (referral bias). Furthermore, the total number of infected patients from which they are drawn is unknown.


The risk of developing end stage liver disease is low for the first three decades of infection. Unfortunately, data on the risk beyond that point are limited. Only three studies provide data beyond 30 years, and the data are for children and women (both groups perhaps being at lower risk of progression) and for men in whom it was not clearly proved that the infections were chronic when diagnosed. Nonetheless, these data are consistent with previously cited epidemiological data from the general population, and it is likely that 80-85% of patients with chronic hepatitis C will die from non-hepatic causes

There is No Evidence from Randomized Controlled Trials that Treatment Prevents Most of these Complications

The most convincing way to establish efficacy of treatment is through well designed and conducted randomised, placebo controlled trials using clinical outcomes (morbidity and mortality). However, such trials are available only for interferon monotherapy. Ten randomised trials of interferon alfa have been conducted in patients with severe fibrosis or cirrhosis. The results were disappointing, even though at the time, expert opinion advocated interferon treatment for these patients.

There is No Clear Evidence that SVR Means Cure

Sustained virological response is not a cure. Viral RNA is sometimes found in body tissues even when the serum is clear; in some studies this has been found frequently. The virus also reappears in some patients with sustained response, and though this might be thought to be due to reinfection, at least sometimes these events represent the reappearance of the same virus. Moreover, a few patients with a sustained response develop end stage liver disease. In the largest observational study to assess this risk, 1001 patients with severe fibrosis (84% with cirrhosis) with sustained virological response were followed for up to eight years. During that time, 50 developed hepatocellular carcinomas, a 1% annual risk. Observational studies have suggested that the annual incidence of hepatocellular carcinoma in people with compensated cirrhosis secondary to hepatitis C infection is 1.4-3.3%.

There is No Evidence that the Benefits of Treatment Outweigh Its Harms

Claims of increased safety or tolerability of the newer treatment have been based on fewer and less severe side effects. However, the new drugs can still cause serious adverse events (resulting in persistent disability, hospital admission, or death).


Safety data are limited for the newest drugs. However, in a trial of sofosbuvir versus peginterferon plus ribavirin, 3% of participants taking sofosbuvir experienced serious adverse events compared with 1% in the peginterferon plus ribavirin arm (difference not significant). Combination therapy with sofosbuvir plus ledipasvir with or without ribavirin, was associated with a 0.5-2% rate of serious adverse events. According to a recent analysis of US Food and Drug Administration data, over one year telaprevir accounted for the single greatest number of reported severe and fatal skin reactions of any drug monitored. Unfortunately, we cannot weigh the risk versus the benefit at this time because we have no data on the precise benefit (if any).


Koretz et al supplied these conclusions:

If the treatment of hepatitis C is to be scaled up to cover a large portion of the 125-150 million infected people worldwide, regulatory agencies should ensure that drugs have been evaluated by long term follow-up of clinical outcomes (not just surrogate markers) in several thousands of patients. The financial cost of treatments have been discussed elsewhere, but given the uncertainty about the validity of the surrogate markers, the lack of evidence regarding clinical outcomes of treatment or of screening strategies, and the adverse events caused by the newer regimens, screening may be premature. 

By the same logic, it is not clear that treatment of asymptomatic patients found to have hepatitis C provides benefits that outweigh its harms.

Thus, more authoritative voices are saying that the hepatitis C treatment emperor is seriously fashion challenged.

If there is no good evidence that these drugs do more good than harm for asymptomatic patients, why should physicians prescribe them for these patients?  If use of these drugs in general has not been shown to do more good than harm, why should they be prescribed for any but the most desperate patients?  Finally, if these drugs have not been shown to do more good than harm, and the lack of evidence is clearly the responsibility of  the drugs' manufacturers who chose not to do very large and/or long-term randomized controlled trials and not to assess clinical outcomes, what justification is there for the gargantuan prices of these drugs?

A larger societal question is why the public discussion has been so dominated by enthusiasts for these drugs, and so little informed by the existing evidence, or lack thereof, from clinical research?  

To repeat,.. the Sovaldi (and now Harvoni, Viekira Pak, etc) case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will likely not buy us the promised miracles and triumphs.

It is disappointing that so many physicians and other health professionals have been caught up in this hype and spin, probably abetted by their wishful thinking about cures of hepatitis C, and perhaps also abetted by financial conflicts of interest.  Yet to protect the best interests of their patients, they should be rigorously skeptical of illogical or evidence-free arguments made to further vested financial interests.

As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.

ADDENDUM (19 January, 2015) - See also comments in the blog.

ADDENDUM (22 January, 2015) - See an analysis of logical fallacies found in comments arguing with this post, and employed by authors of rapid responses to the Kortetz et al article in the BMJ, in this post.

ADDENDUM (28 January, 2015) - This post was republished in OpenHealth News here

1.   Ollendorf DA, Tice JA et al.  The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection.  JAMA Inte Med 2014.  Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.
3. Koretz RL, Lin KW, Ioannidis JPA, Lenzer J.  Is widespread screening for hepatitis C justified? Br Med J 2015; 350: g7809. Link here.


Steve Lucas said...

I look at this as a purely financial situation. Today drug companies are looking for a blockbuster to satisfy their stockholders and financial analysis. They have learned that everything from statins to SSRI’s can produce long term income and sales with the trick being to be first in the market, establishing this as the standard of care.

My understanding is that the largest population of hep C positive people is in our jails and prisons. Testing these folks and then administering this drug will become a “right” as there will be legal action, there is always legal action, and governments will be forced to provide this treatment. There is a cognitive disconnect between government spending and personal responsibility leaving the public to foot this bill.

Our local paper has an ask the doctor column and a woman wrote very upset that her sister was hep C positive, seeing a doctor for testing once a year, but was not taking advantage of this new wonder drug. The doctor answered that her reluctance could be to cost, co-pay, insurance coverage for a new drug, or her doctor’s reluctance. The article ended with she should take advantage of this wonder drug and end her sister’s concerns, too clever by half.

Drug companies are no longer the utilities of old. They have become win at any cost sales organizations with profit as their only goal. They know it will take years before enough data is compiled to make a judgment on this product and they will have banked billions of dollars, hopefully expanding its use to those who “we just want to be sure.”

We spend twice what other countries do in terms of medical care with worse outcomes. There is no magic bullet to stop this process since it is the incremental addition of cost that is producing a medical system that is unsupportable. This is a shining example of that problem.

Steve Lucas

Anonymous said...

The article suggests that the INF+RBV therapy is just as good as Harvoni, and at much lower cost. It's not. INF/RBV eradicates the virus in less than 50% of treated people, even less in the most difficult to cure with HCV genotype 1.
Also the claim that INF+RBV causes adverse effects in less than 1% of treated is just false, that's rather the number of suicides commited because of severe depressions caused by Interferon (just read the medicine's package informations).
The statement that most patients will not go on to severe liver damage/liver cancer is unproven. HepC is known since 1989, that's 26 years. Are there any studies that prove, in statistical relevant numbers, the final outcome of HepC after, say 40 or 50 years? There aren't. HCV destroys liver cells, which causes liver scarring and cancer because of the sustained fast reproduction of liver cells, that is what is proven fact.

Concerning SVR after 12 weeks: the author suppresses the fact SVR12 is a commonly accepted evidence for complete eradication of the virus, supported by several studies, as in very few people the virus reappears after that landmark.

To Steve Lucas: the statement that most HCV patients sit in jail goes in the same direction as the statement that all HIV infected are drug addicts, gay, or both. So why care about this disease at all? Nothing to top the cussedness in that statement.
No need to think about the people who drew the infection by blood transfusions, inappropriately sterilized medical instruments etc. In Egypt it is assumed that 20% of the male population are HCV infected, mainly because of the traditional usage of razor knifes in barber shops.

So in summary, this article suggests to avoid the costs by sticking the head into the sand.

Roy M. Poses MD said...

Anonymous of January 21, 9:01 AM:

Your comments seem to based on at least three different logical fallacies.

Since comments are limited to 4096 characters, I cannot respond to them all with appropriate citations of evidence and use of logic here.

So I plan to do so in a blog post.

Meanwhile, since your use of logical fallacies seemed to defend the very commonly held and strongly promoted viewpoint that the new antiviral drugs are miraculous, it is not clear why you did not reveal who you are. We allow anonymous posting of comments, but meant that to protect people with unpopular views, especially those that might offend the powers that be. You seem to be supporting the views of the powers that be. Would you therefore care to identify yourself? And perhaps disclose any relevant conflicts of interest?

Steve Lucas said...


I have to ask: What drug company do you work for, was this blog assigned to you, or did you choose it yourself? Not identifying yourself in some manner leaves many questions unanswered regarding your motives for this type of response.

The straw man nature of your personal attacks indicates a lack of understanding of the business and economic nature of medicine. The fact is the highest concentration of hep C people resides in our jails and prisons. Treating all of those who show a positive indication, but no liver damage, will be a financial windfall for the drug company at the expense of the tax paying public.

Egypt, razors, HIV, and the other issues you raise were never a part of this post and have no relation to the topic.

This post has been linked to other major blogs. The material presented has been researched and referenced. The facts presented may not match your vision of the truth but:

“Facts are the enemy of truth.”

Steve Lucas

Roy M. Poses MD said...

Note that the comments of anonymous of January 21, 2015 are extremely similar to comments found on a Medscape article on hepatitis C screening attributed to one "Dr Thomas Malik." Look here:

In the comment above by anonymous,
"Also the claim that INF+RBV causes adverse effects in less than 1% of treated is just false, that's rather the number of suicides commited because of severe depressions caused by Interferon (just read the medicine's package informations)."

In the comment by "Dr Malik,"
"The authors write INF+RBV therapy had 'adverse reactions' in 1% - that makes me laugh. That's rather the number of suicides committed because of the depressions caused by INF (just read the medicine's package information)."

However, a quick Google search did not succeed in finding any physician or PhD named Thomas Malik.

So I wonder if these two comments were written by the same person, who really isn't Dr Thomas Malik, but who may be working as a "sock puppet?" Just a thought...

Roy M. Poses MD said...

Note further that I posted a perhaps too lengthy analysis of the logical fallacies in the comment by anonymous of January 21, and of the logical fallacies employed by authors of rapid responses to the original BMJ article, here:

Steve Lucas said...

Scot suffered an attack from a sock puppet a number of years ago. The intention is to draw a person into an endless debate or elicit a response based on frustration. Scot’s solution was to find the IP address of the computer being used for the attack.

The result was a call to the computer owner’s corporate PR department. The attacks stopped but started a short time later with a very different time stamp. The person involved went from a day shift to a night shift. Somehow they though people would not notice.

This type of juvenile attack comes straight from the sleazy sales manual of some company. You would think they would know better and control their sales people better.

Steve Lucas

Anonymous said...

I wrote the Anon comment on Jan. 21st. I don't know the doctor you refer to, as i am a patient, and that's also why i won't disclose my identity. I don't do drugs, and am not in jail, so Steve Lucas' prejudice fails, at least on me. Instead i have a rather healthy lifestyle, which didn't protect me from developing advanced fibrosis, bordering to cirrhosis.
I suspect i drew the infection when ear-piercing inappropriately, with an already infected ear-ring. I live with this infection probably for almost 30 years, with the difficult-to-cure genotype 1a.

I don't have any affiliation with US health care or pharmaceutical industry, as i live in germany. I am in the happy situation to be well-insured (so-called german 'private health insurance'), as i pay more than enough for my insurance.
I work as a computer scientist, so i claim not to fail in logics easily :).

The article i referred to was the one by Koretz, BMJ 2015;350:g7809, where he stated that 1% of patients experienced serious side effects compared to 3% in sofosbuvir + ribavirin.
To support this statement, he referred to another article by Eric Lawitz, in which it was mysteriously said that Sofosbuvir+RBV has actually lots fewer adverse events than PEG+RBV. As a side note, Sofosbuvir+RBV is not an approved HCV therapy without the addition of either a 2nd DAA or PEG+RBV. Comparing the efficacy of Sof.+RBV alone with PEG+RBV is therefore questionable.

While it may be true that there is currently no proof for a better long term outcome for patients who have reached SVR compared to untreated people, what's the conclusion? To stop screening and treatment altogether? This wouldn't produce any evidence for any statement.
In his article, Mr. Koretz also shows a tendency to neglect a causality between HCV infection and liver disease, which i find to be ridiculous.
In summary, dwelling on this article, and taking it as reference to bash the pharma industry as the bad guys selling stuff no-one needs, looks just wrong to me.

The cost of these medicines is a whole different story, and to call their producers greedy may be completely true (*without* having evaluated their development costs, did any of you?).
But *please* separate this issue from any discussion whether HVC treatment with one of the new interferon therapies is useful or necessary, or whether mass HCV screening is useful.

And no, i am no sock puppet nor am i made of straw.

Anonymous said...

Sorry, typo in my last post , last sentence , meant interferon free therapies

Roy M. Poses MD said...

Anonymous of January 21 and January 24,

Thanks for your second and third comments.

If you are a patient, I can see why you might want to remain anonymous. Of course, since you choose to remain anonymous, I have no way to confirm whether in fact you are a patient. (If you want to send an email to info at firmfound dot org to confirm your identity, you are welcome to do so, and I will not publish your identity.)

Please note that apparently on the day before you posted your comment, someone purporting to be "Dr Thomas Malik," a gastroenterologist, posted a comment on the Medscape article using some phrasing which was identical to what you wrote. I suppose this could be coincidence, but the similarity is such that it seemed reasonable to suspect that you and whoever posted as "Dr Malik" were the same person, or that you used "Dr Malik's" words without attribution. Any comments?

By the way, if you live in Germany, you might want to read the full report by the German Institute for Quality and Efficiency in Health Care (IQWiG), which is available only in German. (You can get a link from here: ) It covered many of the problems with the evidence base for the new antiviral drugs.

I extensively reviewed the Lawitz et al article here:

The Lawitz article is the only known published article reporting on a controlled trial that directly compared a new drug (sofosbuvir, trade name Sovaldi) with an old drug (peg-interferon). As I wrote, the trial did in fact show that the rate of all adverse events was somewhat but not hugely lower in the Sovaldi group compared to the peg-interferon group. However, the rate of severe adverse events, and the rate of death were higher in the Sovaldi group.

As the only such comparative trial, this study is the best known source of evidence about adverse effects of Sovaldi versus an older drug. It does NOT inspire confidence that Sovaldi is really safer.

I "dwelled" on this study again because it is the best of a bad bunch of studies. Many of the other published studies are not really controlled trials at all. They are essentially separate case series of highly selected patients who are given regimens containing the new drugs, but without control groups given old drugs or placebos.

The Lawitz trial had many methodologic problems, but not as many as most of the other studies of Sovaldi and other new agents. It is fair to say that the comparison the Lawitz et al trial made was not ideal. However, if you do not like the design of these studies, BLAME THE PHARMA COMPANIES THAT RAN THEM, not me.

(My thoughts continue in the next comment.)

Roy M. Poses MD said...

Anonymous of January 21 and 24,

(My further thoughts, separated into a second comment due to character limit imposed by Google on comment length.)

For further discussion of the deficiencies of the evidence base, in English, look at Center for Evidence Based Policy report (Link here:

My conclusion is not to stop all therapy, but that therapeutic decisions need to be individualized. Because of the known harms and unknown benefits of all antiviral regimens, it is not obvious that asymptomatic patients, particularly those without clear liver damage, should get any treatment. Furthermore, because it is not clear that treatment provides benefits that outweigh harms for asymptomatic patients, it is not obvious that screening broad groups, such as middle-aged people, benefits that population.

Note that I have written little about the price of these drugs. The price does seem high, even if the drugs are truly miraculous. But because the drug companies CHOSE not to do good enough studies to justify any claims that they are miraculous, charging such prices for treatments that provide only unproven benefits is outrageous.

Since you originally wrote that either I or Koretz et al declared INF+RBV is just as good as Harvoni, and neither of us wrote that, you are not made of straw, but you did use a straw man argument. (I hope the English here is not too confusing.)

Steve Lucas said...


There are major differences in US vs. German medical care. The US system is based on profit, even for non-profit entities. Pharma pushes for population testing and protocols, not to treat people, but to generate income through mandates.

The jail reference did not refer to you but to the large population of hep C positive people in our jails that would, through a quickly established mandate, be treated with pubic dollars. This would not assure a cure.

I would be very interested in the German insurance industry’s position on population wide testing and treatment on this issue.

Steve Lucas

Anonymous said...

I see the point of making a 'straw man' argument in the first place, and have to admit i was inaccurate in arguing that Mr. Koretz wrote about Harvoni compared to interferon when he was actually writing about Sofosbuvir (which is one component of Harvoni). At a first glance, your blog article (and the article by Mr. Koretz) appeared to me to put down sofosbuvir in general, when you probably meant that the company's data provided to health insurers is weak (which may be so).
I've read the IQWIG article. Here, only the results concerning genotype 2 are considered because of a weak data basis, up to november 2013, for treatment of genotype 1. I did not see the data provided by Gilead to IQWIG, what i am wondering about is that a quick search at indeed revealed several studies regarding sofosbuvir and genotype 1 (NCT01329978 ATOMIC), and even a study directly comparing Sofosbuvir+PEG+RBV with Placebo+PEG+RBV for genotype 1 patients (NCT01188772). Maybe the study arms weren't large enough to hold as an evidence, can't assess that. Maybe Gilead should spend a considerable amount of their yield into more thorough studies (but that's the point of your blog, isn't it).

Now, to Steve Lucas about his statement regarding hepatitis c and prisoners. The numbers i found are the following:
* 2.3 Mio. are incarcerated in the US (whoops had to read this number twice ... different thing here in germany)
* up to a third of which are estimated to have hepatitis c
* makes up ~759 hepatitis c infected in US jails
(See also or for discussions on that matter).

That's inarguably a minority of the estimated 3 Mio. infected people in the US, though that's still a big portion from the residents. I do not know enough about US jurisdiction to tell whether the government may be forced to provide a HepC treatment to each incarcerated, and at the same cost as any other US resident. This is still a different discussion than whether sofosbuvir (or harvoni ...) is worth considering for hepatitis c in general, and wether general hepatitis c screening may be useful or not.

Roy M. Poses MD said...

Anonymous of January 21 and 24,

Thanks for your continuing interest.

Maybe if you insist on remaining anonymous, you could use a pen name of some sort, so we can address you in a less awkward way?

Yes, there apparently was a single trial, not published, of sofosbuvir versus placebo. We discussed it here:

It is difficult to know what to make of it, since we do not have very complete information about it. It did show a SVR of 78%, quite good, but not the >90% found in case-series. Worse, apparently nothing about adverse effects found in that trial has been published.

Again, it was apparently a decision by someone at Gilead not to publish this trial.

I seems to be the pharma companies that are responsible for the lack of much definitive information about these new drugs, In the absence of much definitive information, skepticism about the drugs seems in order.

Steve Lucas said...


One issue clouding the discussion is perspective. I have been fortunate to travel to France a number of times and often speak to people from the EU. Medicine and medical care are common topics of casual conversation.

One of the greatest evening’s of my life was when my wife and I were in Canada and we had dinner with a German couple, both doctors. They had a very matter of fact concept of medicine and could not understand why the US had such a mash up of a system starting with allowing drug advertisements on television.

The countries of the EU treat medicine as a utility with tight government controls. We in the US treat medicine as an income opportunity and this is reflected in that medicine will soon consume 20% of our GDP vs. 10% for most EU countries.

Our Veterans Administration is the only government agency that negotiates drug prices.

This means that any patient number we use for hep C must be multiplied by 100,000, giving the sales of these drugs blockbuster status. The financial stakes are enormous, adding to my skepticism.

The US medical system is a mess. This has allowed those with less than noble intentions to take control and create empires that enrich a few while creating havoc for many. Our government is both in and out of medicine, allowing people to exploit the gaps at great expense to those who often can least afford it.

We in the US are a very generous people and do not want anyone to suffer. My wife and I have met up with a couple from the UK on holiday the past few years and it has taken a week at a time, over a two year period, to explain we are not monsters, and we do allow people to die in the street. He cannot grasp the concept that we have to pay for our medical care since his is provided as part of his taxes.

Perspective can cloud any discussion, medicine is no different.

Steve Lucas

Roy M. Poses MD said...

Please note that the person posting anonymously on January 21 and 24, 2015, got in touch with me and I have personally verified that this person is a patient. He or she is definitely NOT a sock puppet, and he or she made all comments honestly, not cynically.

Furthermore, there was some misunderstanding of the term "straw man" fallacy. Apparently, in his or her native language, "straw man" has a very different meaning, and this caused confusion on both our parts.

I want to again thank this anonymous patient for his or her interest in the blog, and hope he or she continues to comment.