They say (who are they anyway?) "If it seems to good to be true it probably is". When it comes to generic Hepatitis C medication some people struggle with the idea that something like Harvoni® with a list price of $94,000 USD could be manufactured for under $1000 USD. Surely if the original costs $94,000 there must be something wrong with the more affordable generic. It's cheaper, they must have cut corners or something...
Well, the reality is that it does not cost very much to make a tablet of Harvoni® (about $1 to $2). Let's face it $1000 and is a lot of money for a single tablet, after all it will buy you a new iPhone and that's a lot more complicated than a pill. The $31,000 for a bottle of Harvoni® is the same as the price of a new car. And while $94,000 won't buy you a whole house in most places it is actually 1/2 the median price for a house in the USA. 3 Bottles of pills cost the same as 1/2 a house? Really?
Ok, I hear you say "So now I can understand that the price of Harvoni® represents outrageous price gouging, but that still does not prove the less expensive generics meet the required quality standard now does it?"
Fair point, and one that is answered by a set of tests called "bioequivalence" (BE). Bioequivalence testing starts with baseline things like high-quality factories, using high-quality active ingredients and putting them together into tablets under what is called GMP (Good Manufacturing Practice). GMP is a series of processes that provision QC (Quality Control) / QA (Quality Assurance). Ok, so now we have some tablets. They are in a nice bottle and have been made by experts. These experts have put their brand name on them but... that still does not prove those tablets are going to work the same. Why?
The why is because for a generic tablet to work the same as the originator it needs to have more than the same APIs (Active Pharmaceutical Ingredients) in the correct weights. These tablets also need to be formulated correctly to ensure that when a patient takes them (be it generic or originator) the product delivers the same blood levels to the patients. So how do we do that?
It's actually really simple. We recruit 24-60 volunteers. We give 1/2 of them the originator medication and the other 1/2 the generic. We then make 20 measurements of the blood levels over the next 12 hours. Then we wait a week for the drugs to wash out. Then we repeat the testing but the patients who had the generic first time around now get the originator, and the patients who got the originator now get the generic. This may then be repeated again (fully replicated).
A product is deemed to be bioequivalent if the blood levels at all time points demonstrate the statistical confidence interval (CI) fall within the range 80% - 125%.
Oh, I hear you say, "Does that mean a bioequivalent generic can have up to 20% less or 25% more drug in it?"
Not at all, because I said "confidence interval".
Ok, I hear you say, "WTF is a confidence interval?"
Glad you asked, although your eyes may glaze over!
Consider a coin toss. We toss it once and get a head. So our results are 100% heads. The actual result should be 50% heads (unless the coin is loaded). The confidence interval (technically a binomial confidence interval) is a measure of how confident we are in that 100% result. The confidence interval, in this case, is 2.5% - 100% so you can see we are not very confident. You may note that this range is wide but it does contain the actual value. Now if we toss the coin 3 times we might get 1 head and 2 tails. So we now have 33% heads and the confidence interval is 8.4% to 90%. The result is more realistic, the confidence interval is a little narrower but... Say we toss it 10 times and get 4 heads and 6 tails. Now we have 40% heads and the confidence interval is 12% to 73%. And finally, we toss the coin 100 times and get 49 heads and 51 tails. Now we have 49% heads and the confidence interval is 39%-59%. You can play with other numbers here: http://statpages.info/confint.html
What I want you to notice are 2 things. The more tests we do the more accurate the actual results become and the narrower the confidence interval becomes. With the 100 toss trial the 39% lower confidence interval is 22% lower than the expected 50% and the 59% upper confidence interval is 18% higher so it spans the confidence interval range on the actual value of 50% from 78% - 118% - you may note that this is similar to the bioequivalence threshold of 80% (-20%) to 125% (+25%).
What this means in practical terms is that when we test for bioequivalence the actual values at any point need to be very close together to meet the statistical confidence interval criteria and we need to do a lot of tests to narrow the CI range down. Here's what it actually looks like and as you can see these generic products are very very similar to the originator product. The key values of Cmax (Concentration maximum) and AUC (Area Under the Curve and a measure of total absorption) vary only by a low single digit % amount. Some are a little higher, some are a little lower. All are very similar in absolute and statistical terms.
The full details of our collation of BE testing results are available in the attached article from the Journal of Virus Eradication or online here: http://viruseradication.com/journal-details/Bioequivalent_pharmacokinetics_for_generic_and_originator_hepatitis_C_direct-acting_antivirals/
So you've made it! SVR at last. What now?
Here is a slideset from Clinical Care Options where Ira M. Jacobson, MD, and Paul Y. Kwo, MD, review optimal management of patients with HCV who have achieved SVR, including recommendations for HCV RNA and HCC monitoring.
These doctors are world leading experts so you're drinking from the source...
With HIV we observered that if we use 1 drug resistance develops rapidly, with 2 drugs it is slower, and with 3 drugs it virtually never happens, so it does not come as any great surprise that combining an NS3/4A drug with an NS5A drug and and NS5B drug works well.
We have previously seen Merck retreat Zepatier failures with Zepatier+Sofosbuvir and Abbvie retreat Viekira failures with Viekira+Sofosbuvir and in both cases very good 95% SVR12 results were achieved.
We have also seen Gilead follow the same strategy by adding the NS3/4A agent Voxilaprevir to the NS5A/NS5B Velpatasvir/Sofosbuvir in Epclusa to form Vosevii.
So what happens if you take the strongest NS3/4A inhibitor ever invented - Glecaprevir, and the strongest NS5A inhibitor ever invented - Pibrentasvir, and add in the strongest NS5B inhibitor ever invented - Sofosbuvir. Could it be we have the mythical "Perfectovir".
Abbvie have investigated this by dropping a lifeline to patients who failed G/P in their trials. Sadly they missed perfection with a 95% SVR12 (22/23) but the single patient who failed had previously failed both Harvoni and Maviret.
Anyway, for patients that have failed DAAs this is encouraging news. If we can cure 95% first time around, and then 95% of the 5% who relapsed that makes 99.75% overall and is awesome news.
The full presentation from CROI is available in the attachments to this blog post.
- Ravidasvir is a new NS5A inhibitor for HCV.
- Sofosbuvir + Ravidasvir with or without RBV has achieved very high SVR rates.
- Results are comparable for both patients with and without cirrhosis.
- Serious adverse events were noticed in very few treated patients.
Background & Aims
Although treatment of hepatitis C virus (HCV) and HCV-genotype-4 (GT4) has become very effective, it remains very expensive, and affordable options are needed, especially in limited resource countries. The aim of this study was to assess the efficacy and safety of the combination of ravidasvir (an NS5A inhibitor) and sofosbuvir to treat patients with chronic HCV-GT4 infection.
A total of 300 patients with HCV-GT4 infection were recruited in three groups: treatment-naïve patients with or without compensated Child-A cirrhosis (Group 1); interferon-experienced patients without cirrhosis (Group 2); and interferon-experienced patients with cirrhosis (Group 3). Groups 1 and 2 received ravidasvir 200 mg QD plus sofosbuvir 400 mg QD for 12 weeks and were randomized 1:1 to treatment with or without weight-based ribavirin. Group 3 patients received ravidasvir plus sofosbuvir with ribavirin and were randomized 1:1 to a treatment duration of 12 weeks or 16 weeks. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12).
A total of 298 patients were enrolled: 149 in Group 1, 79 in Group 2 and 70 in Group 3. SVR12 was achieved in 95.3% of all patients who started the study, including 98% of patients without cirrhosis and 91% of patients with cirrhosis, whether treatment-naïve or interferon-experienced. Ribavirin intake and history of previous interferon therapy did not affect SVR12 rates. No virologic breakthroughs were observed and the study treatment was well tolerated.
Treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high sustained virologic response rate for HCV-GT4 infected patients with and without cirrhosis, regardless of previous interferon-based treatments.
This study evaluated efficacy and safety of the new oral hepatitis C drug ravidasvir in combination with the approved oral drug sofosbuvir in 298 patients infected with hepatitis C type 4. Our results showed that treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high response rate in patients with and without cirrhosis.
Trial Registration number: ClinicalTrials.gov Identifier: NCT02371408.
A quick note on how to take your DAA medication. Read the package insert and follow the instructions with respect to with (or without) food.
For example, for Vosevii
Administration with food enhances the oral bioavailability of sofosbuvir, velpatasvir, and voxilaprevir. Relative to fasting conditions, mean sofosbuvir systemic exposure (AUC) increased by 64% to 144%, mean velpatasvir AUC increased by 40% to 166%, and mean voxilaprevir AUC increased by 112% to 435% when the combined sofosbuvir/velpatasvir/voxilaprevir formulation is administered with food.
Food enhances the absorption of all the ingredients. You get roughly 2 x as much Sofosbuvir, 2 x as much Velpatasvir and 3 x Voxilaprevir. To put this another way, if you take Vosevii WITHOUT food you will only get something like 1/2 the dose.
Note that this advice is equally applicable to Epclusa which is the same (just missing the Vox) and the ignoring this advice may cause your treatment to FAIL.
This advice also applies to Viekira and Mavyret which should be taken with food.
Sovaldi, Harvoni, Daklinza, and Zepatier can be taken with or without food.
In terms of food, think a real meal with some protein, fat and carbohydrate.
Once upon a time, there was an old man who used to go to the ocean to do his writing. He had a habit of walking on the beach every morning before he began his work. Early one morning, he was walking along the shore after a big storm had passed and found the vast beach littered with starfish as far as the eye could see, stretching in both directions.
Off in the distance, the old man noticed a small boy approaching. As the boy walked, he paused every so often and as he grew closer, the man could see that he was occasionally bending down to pick up an object and throw it into the sea. The boy came closer still and the man called out, “Good morning! May I ask what it is that you are doing?”
The young boy paused, looked up, and replied “Throwing starfish into the ocean. The tide has washed them up onto the beach and they can’t return to the sea by themselves,” the youth replied. “When the sun gets high, they will die, unless I throw them back into the water.”
The old man replied, “But there must be tens of thousands of starfish on this beach. I’m afraid you won’t really be able to make much of a difference.”
The boy bent down, picked up yet another starfish and threw it as far as he could into the ocean. Then he turned, smiled and said, “It made a difference to that one!”
If you'd like to make a difference to Hepatitis C please visit https://fixhepc.com/fixers
The combination of Sovaldi (Sofosbuvir) and Daklinza (Daclatasvir) was the world's first pan-genotypic Hepatitis C treatment. In the USA and Europe the $140,000 price tag of this combination means it has seen relatively little use, but in the world of generics it has seen extensive use because Daclatasvir is much cheaper to produce than either Ledipasvir (in Harvoni) or Velpatasvir (in Epclusa) so it provides the least expensive treatment option.
Ok, so it's more affordable, but is it as good as either Epclusa or Maviret? These are the new kids on the block, they are more expensive, so surely they are newer and must be better? Not really...
Abbvie conducted a trial called ENDURANCE-3 which demonstrated that Maviret - Glecaprevir + Pibrentasvir - (G/P) is "non-inferior" to the combination of Sofosbuvir + Daclatasvir (SOF/DCV). What is "non-inferior"? Well SOF/DCV achieved 97% SVR and G/P achieved 95% SVR12 in the difficult to treat GT3 population. Maviret is "non-inferior" is one way of phrasing it. SOF/DCV is "slightly superior" would be another way although this is not statistically significant.
Our REDEMPTION trials put the results for generic SOF/DCV in the range 93% (for GT3) to 100% (for GT2, GT5 and GT6) with 97% in GT1 and 95% in GT4 and are based on the results of over 1000 patients.
Published two days ago we have Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt - where the overall results were 95.1%
So there you have it. We have 3 pan-genotypic options. They are all good, and all hit ~95%+ cure. Two are newer, more expensive, and have far less real-world proof. Strip off the marketing hype and if you were looking towards mass scale treatment SOF/DCV looks like the go-to medication because you can get the same cure rates for less cost, at least when using generics.
Recently I have been getting a number of enquires from patients who have just finished their tablets, all asking the same questions, so here is a quick primer. If you are looking for this sort of information you will find a lot more detail in our Frequently Asked Questions and on the Forum.
On treatment 99.5% of patients will drop to <15 on their HCV RNA. This is nice but does not prove cure. We need virtually zero viruses (less than 100 in total) to remain in your system to achieve cure.
When the tablets finish your body starts to remove the medication from your system. Within 24 hours there is less than 1/2, 48 hours 1/4, 3 days 1/8, 4 days 1/16, 5 days 1/32, 6 days 1/64, 7 days 1/128 and by this stage there is definitely not enough of the drugs left in your system to kill the virus.
So with the medicines now below effective levels one of two things happens.
- The virus starts to grow back because there is still some left, or...
- Nothing - ie the virus does not grow back because there is no virus left to grow back
If the virus has not grown back 4 weeks after the last tablet was taken and the HCV RNA PCR remains <15 then there is a 97% chance this will be permanent. We call this Sustained Virological Response (SVR) and because this one happened at 4 weeks we call it SVR4
If the virus has not grown back 12 weeks after the last tablet was taken and the HCV RNA PCR remains <15 then there is a 99.7% chance this will be permanent. We call this Sustained Virological Response (SVR) and because this one happened at 12 weeks we call it SVR12
If the virus has not grown back 24 weeks after the last tablet was taken and the HCV RNA PCR remains <15 then there is a 100% chance this will be permanent. We call this SVR24 but a better word is cure.
Please note this. Your Hepatitis C Antibody (HCV Ab) test will remain positive. Your body produces antibodies in response to infection and these persist for years. For example, if you have Hepatitis B vaccination you will have antibodies that persist for years, and often for life. Similarly to Hepatitis B without an exposure event (booster dose for Hep B, ongoing infection for Hep C) the levels of antibody will slowly fall over time, and may (after 5-10 years) fall below the level we use as a cut off, however, you should expect to remain antibody positive for many years. Cure is a negative HCV PCR RNA and the antibody remains as a marker of past infection.
This period of waiting can be stressful. Forums like https://fixhepc.com/forum can provide useful support.
With the SVR tests liver functions are normally conducted at the same time. These liver function results come back the next day, rather than a week later. If your liver functions remain similar to what they were on treatment (+/- 20%) you can be confident you have not relapsed. I have treated about 3000 patients and, as the statistics predict, seen over 100 relapses. In every case, the patient has been aware of the relapse before the results came back.
If you feel well you almost certainly are, but if you feel unwell it is worth noting that as well as over 100 relapses I have seen about 100 patients assigning every little twinge in their body to relapse (and they did not) so don't panic if you feel anxious - it's pretty normal. The result will be what it will be and worrying is about as effective as chewing bubble gum while trying to solve an algebra equation. If you do relapse it's possible to have another try and the results of take 2 are good although the costs of treatment do double.
It is normal to have some twinges from your liver. It's been suffering for years and now has the chance to recover. Some patients notice this.
In terms of getting pregnant, you should wait until 6 months after the tablets have finished. Ribavirin, in particular, is known to cause birth defects so you need to leave enough time for it to exit your system.
Finally, if you liver functions are not back to normal after treatment this should be looked into. A small percentage of patients with Hepatitis C also have another liver disease and we (as in doctors) have been assuming it is all due to the Hep C... Here is a list of things to look for if your LFTs do not normalise https://www.mayoclinic.org/symptoms/elevated-liver-enzymes/basics/definition/sym-20050830
Some time ago we saw some very bad science published. This suggested that treating Hepatitis C confers no benefits. While experts around the world expressed their firm view this was complete and utter rubbish here is something simple to understand. Get treated, get SVR and... you are far less likely to die of liver cancer.
This slide came from a presentation on Clinical Care Options entitled "Current HCV Therapy". The full slides are attached here:
This is just one of the reason treating your Hepatitis C sooner rather than later is a good idea. Push for coverage and appeal, but if you can't get access we know with 100% certainty that generic HCV medications deliver the same results - only the price is different (they are affordable).
KUALA LUMPUR/GENEVA – 13th November 2017 – Malaysian pharmaceutical company Pharmaniaga Logistics Sdn Bhd (Pharmaniaga), Egyptian pharmaceutical company Pharco Pharmaceuticals (Pharco) and non-profit research and development organization Drugs for Neglected Diseases initiative (DNDi) have signed a collaboration agreement to supply a new hepatitis C treatment regimen to be sold for US$300 in the public sector in Malaysia.
“It is estimated that there are around 450,000 people living with hepatitis C in Malaysia but most of them have been unable to access effective new hepatitis C treatment because of its very high price,” said Dato’ Farshila Emran, Managing Director of Pharmaniaga. “This agreement enables access to cheaper alternatives for patients in Malaysia, and we are proud to be embarking on this collaboration with DNDi and Pharco that would not have been possible without the Ministry of Health’s support.”
In partnership with the Malaysian Ministry of Health, DNDi is currently running clinical trials testing a potentially pan-genotypic treatment, combining the drug candidate ravidasvir, produced by Egyptian drug manufacturer Pharco Pharmaceuticals, with the existing hepatitis C medicine sofosbuvir. The clinical trial is ongoing in six hospitals and is co-sponsored by the Malaysian Ministry of Health, with initial results expected in early 2018.
“We applaud the Malaysian government in its efforts and commitment to make available affordable access to safe and effective treatments for hepatitis C,” said Jean-Michel Piedagnel, Head of DNDi South-East Asia. “The strategic investment from the Ministry of Health in helping develop a public health approach to the epidemic is remarkable.”
The agreement covers the supply of ravidasvir, once approved in Malaysia, and supply of sofosbuvir. A Government Use licence issued by the Malaysian Ministry of Domestic Trade, Co-operatives and Consumerism in September 2017 enables the importation of generic sofosbuvir in order to make this drug available in the public health system throughout the country at affordable prices.
“We hope that our collaboration with Pharmaniaga and DNDi to develop a treatment regimen that costs less than US$1 per day will lead to widespread access to safe, effective, and affordable treatment for hepatitis C patients in Malaysia and around the region,” said Dr. Sherine Helmy, CEO of Pharco Pharmaceuticals.
Currently a full 12-week course of treatment is available in Malaysia for around US$70,000. With the combination of generic sofosbuvir and ravidasvir, the cost for the same treatment will be made affordable with an almost 100% decrease in price.
We have the power to FixHepC, but the real question is... Do we have the willpower?
This was how Dr James Freeman ended his presentation at the World Hepatitis Summit in Brazil.
You can watch the full presentation on YouTube.
In essence, if we applied the same effort to HCV as we do to HIV this epidemic could be over within a single year. Currently, we treat 18 million patients with one year's supply of multiple antiviral drugs. That would translate to 72 million 3 month treatment courses - enough to treat every man woman and child with HCV.
We still have the enormous challenge of finding those patients in time, but we clearly have the funding capacity and the industrial capacity to get it done.
One year, that's all it would take.
The slides are attached below:
Hepatitis C is a disease that can make you feel old before your time. While there is no doubt that treatment with the new generation of direct acting antivirals like Harvoni is by far the best option this is not available to everyone, either because they don't qualify under their insurance, don't have insurance, or can not afford the $1250 cost to get generic hepatitis c treatment.
This guest blog was written by the Outreach Team at Disability Benefits Help and outlines how you can get help if you have become too sick to work. This includes both financial support and the potential to access to subsidised treatment.
Qualifying for Social Security Disability Benefits With Hepatitis C
If you have been diagnosed with Hepatitis C and will be unable to work for at least one year, you might be eligible for Social Security disability benefits. The Social Security Administration (SSA) offers financial resources for people who are unable to work for an extended period of time due to a serious illness. Hepatitis C will not automatically qualify, and unfortunately, most people with the condition will not be approved. Severe cases will qualify though, meaning you could be eligible for payments to help with your daily living expenses, as well as access to health insurance to pay for your hepatitis treatments.
12 Months and Social Security Disability
Social Security disability benefits are never temporary. They’re only available for people who expect to have a disability that lasts at least a year. This means that if you’ve recently been diagnosed with hepatitis C and have a good prognosis with minimal liver damage and a strong treatment plan, you likely won’t qualify. You also will not qualify if you’ve had hepatitis C for years but your symptoms are managed well. The SSA will not consider you to be “disabled” unless you are completely unable to earn at least $1,170 per month (in 2017). If you expect to be finished with treatments within a few months, or your condition is well managed, it’s not advisable to apply for disability benefits.
Qualifying Via the Blue Book
For those with severe liver damage, medical qualification is possible and potentially guaranteed, depending on your liver function. The SSA evaluates all hepatitis C applicants under its own medical guide, known as the Blue Book. The Blue Book is a manual listing all potential disabling conditions, plus the symptoms you’d need to qualify. Hepatitis c would fall under Section 5.05: Chronic liver disease. Chronic liver disease is arguably the most complicated listing in the Blue Book. There are actually seven ways to qualify under this listing, and all require medical tests evaluating your serum levels, blood quality, and more. The Blue Book was written for medical professionals and is available entirely online, so please review the listing with your hepatologist! He or she can help you navigate the guide and determine if your hepatitis c meets any liver disease listings. If you require a liver transplant, rest assured that your liver disease will qualify. You will also automatically qualify for disability benefits for at least 12 months after a liver transplant surgery.
Starting Your Application
Most people can apply for Social Security disability benefits online. If you’d prefer, you can also apply in person at your closest office by scheduling an appointment at 1-800-772-1213. There are over 1,000 offices across the US.
You’ll usually hear back from the SSA within three to five months. If your application is denied, do not give up! The SSA has a thorough appeals process, which allows you to fight your claim. While just 30% of applicants are initially applied, nearly 70% are eventually approved after pursuing their claims further.
About 1 in 100 people, from all walks of life, have Hepatitis C so it is pretty common. Because it is a highly stigmatised disease, linked in the public mind to IV drug use, most patients choose to keep their diagnosis confidential. Despite the fact that the evidence shows most patients were infected too young to have been involved in IVDU, and many patients got it from blood transfusions, tattoos, and unsafe medical procedures, changing the stigma is probably an impossible task.
What this means is that having Hepatitis C is a very lonely experience for many people. Having to deal with the symptoms is one thing, but having to do it alone just adds to the burden. The good news is that help is out there!
One of the great things about the Internet is it allows people from across the globe to connect with other people with a common interest and with complete anonymity.
To find people like you, who have walked in your shoes and know how it feels, please visit the FixHepC forum - https://fixhepc.com/forum
You can browse the forum without logging in but to post you do need to create a login. Most people just use an anonymous email address to do that so there is no problem about maintaining your annonymity.
There are now highly effective treatments available with minimal side effects. For some patients, insurance and Medicaid can come to the rescue. For others, it might be a patient assistance program or the parallel importation of generics (these are the same medications but with a $1000 price tag for the whole treatment rather than a single pill). It is a cruel and unusual punishment to know that cure exists, but not for you.
Drop in to the FixHepC forum and find out how people just like you have navigated the varying processes that can see you get supported, treated and cured.
Just out of embargo for AASLD 2017 is the rather innocuous sounding Abstract 1078 which says, in brief, that these generic DAAs are inarguably proven the same as the originator DAAs.
Bioequivalent pharmacokinetics for generic and originator Hepatitis C Direct Acting Antivirals
Andrew M. Hill1, Loai Tahat2, Mohammed Khalil Mohammed3, Sanjay Nath4, Rabab Fayez Tayyem3, James A. Freeman5, Ismahane Benbitour7, Sherine Helmy6; 1Department of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; 2Pharmaceutical Research Unit, Amman, Jordan; 3ACDIMA BioCentre, Amman, Jordan; 4Faculty of Medicine, Imperial College London, London, United Kingdom; 5GP2U Telehealth, Hobart, TAS, Australia; 6R&D Project Innovations, Pharco, Cairo, Egypt; 7BEKER Laboratories, Algiers, Algeria
Background: Mass production of low-cost generic directacting antivirals (DAAs) will be required to achieve targets of eliminating hepatitis C (HCV) by 2030. Gilead and Bristol-Myers Squibb have granted voluntary licenses to generic companies to mass-produce the DAAs sofosbuvir and daclatasvir at low cost. However generic manufacturers need to demonstrate bioequivalent pharmacokinetics for their generic DAAs compared to the originator versions, to fulfil World Health Organization standards for pre-qualification.
Methods: Randomised, single-dose, two-way, two-period pharmacokinetic studies were performed in 35-54 healthy volunteers, to compare generic forms of sofosbuvir and daclatasvir with the originator versions. Generics evaluated were from Pharco (Egypt), Beker (Algeria) and Hetero (India), versus originator sofosbuvir (Gilead) and daclatasvir (Bristol-Myers Squibb). All studies were conducted under Good Clinical Practice (GCP). Plasma concentrations of each DAA were assessed over 24 hours. Maximum concentration (Cmax) and Area Under the Curve (AUC) were calculated for each subject. Geometric mean ratios and associated 90% confidence intervals were used to compare each generic DAA with the originator version. Pre-specified limits for the 90% confidence intervals were 80% to 125% of the originator pharmacokinetic concentrations for AUC, and 69-145% for Cmax.
Results: Table 1 shows summary Geometric mean ratios for generic versus originator versions of sofosbuvir and daclatasvir. NB Results from Natco and Virchow came in after the deadline for AASLD submission, but are included here.
Table 1: Geometric mean ratio (90% confidence intervals) for generic versus originator HCV DAAs
|Sofosbuvir||Pharco||36||101.0 (88.1-115.7)||103.5 (97.6-109.7)|
|Sofosbuvir||Beker||35||95.4 (84.7-107.5)||98.5 (91.6-106.0)|
|Daclatasvir||Beker||35||35 104.1 (93.1-116.3)||103.0 (94.4-112.4)|
|Sofosbuvir||Hetero||54||95.7 (97.2- 105.2)||100.8 (96.2-
|Sofosbuvir||Natco||N/A||96.1 (81.0-114.0)||100.7 (94.2-107.8)|
|Daclatasvir||Natco||N/A||94.5 (83.1-107.4)||96.5 (87.1-106.8)|
|Sofosbuvir||Virchow||24||94.8 (83.3-107.9)||95.8 (86.9-105.7)|
All three (now expanded to 5) generic forms of sofosbuvir met pre-specified bioequivalence criteria. The Cmax and AUC of daclatasvir were bioequivalent in both cases. There were no serious adverse events observed.
Conclusions: The pharmacokinetics of generic sofosbuvir and daclatasvir were bioequivalent to the originator versions, in three independent single-dose PK studies. WHO pre-qualification of bioequivalent generic DAAs could then permit their export to high-burden countries for mass treatment programmes.
Disclosures: James A. Freeman - Advisory Committees or Review Panels: Pharco Pharmaceuticals, Beker Pharmaceuticals, Beacon Pharmaceuticals; Stock Shareholder: FixHepC, GP2U Telehealth
Ismahane Benbitour - Management Position: BEKER Laboratories
Sherine Helmy - Board Membership: Presidio Pharmaceuticals; Stock Shareholder: Pharco Pharmaceuticals
The following people have nothing to disclose: Andrew M. Hill, Sanjay Nath
Bye bye limitatio (and generics) - Open access to the new Hepatitis C medications for all Swiss patientsWritten by Super User
Switzerland has just announced that all limitations on access to the new DAAs will be abolished allowing treatment for all. Great news for Swiss patients. Here is an article from the Swiss Hepatitis C Association about it. If you are not lucky enough to live in Switzerland generic versions of the new medications are available for 1% of the originator prices. It's interesting to see that all the countries that have parallel imported generics at scale have managed to strike great pricing deals that allow things like this to happen. Australia, Canada, New Zealand, Italy, Switzerland... The list is growing.
Bye bye limitatio – People with hepatitis C are relieved
The rationing of hepatitis C drugs laid down by the Federal Office of Public Health (FOPH) about three years ago will be abolished as of 1 October 2017. For the first time, all patients can be treated regardless of the type of virus and disease progression.
The rationing of Gilead’s hepatitis C medicines will also be discontinued on October 1,2017. Harvoni and Epclusa can thus be prescribed to all hepatitis C patients for the first time, regardless of liver damage. This was after the rationing had already been abolished for Zepatier on July 1 and for Viekirax/Exviera on August 1 for all those affected with genotypes 1 or 4.
The abolition of rationing was accompanied by substantial price reductions, which are now also expected for Gilead products. Since Gilead’s Epclusa can be used for all 6 genotypes, all hepatitis C patients, regardless of their stage of development, can be treated and cured with a very high probability from October 1. This is excellent news for affected patients and represents an important step towards the elimination of hepatitis C in Switzerland.
This concludes a sad chapter in the history of the Swiss healthcare system. For years, leading representatives of the FOPH have claimed that it makes no sense to treat “healthy people”. As a result, thousands of people with hepatitis C were left untreated and continued to suffer from the symptoms of their disease for years. We welcome the latest developments and are extremely pleased with the change of heart in the FOPH. With the abolition of rationing, the core requirement of the SHCA patient organisation and the Positive Council, the “treatment of all HCV patients”, has finally been fulfilled.
This is the demand we have made since our petition to Federal Councillor Berset in July 2015.
The FOPH will boast of having achieved price reductions. This confirms our accusation that the Federal Office fought a price war on the back of the patients for years. This is ethically untenable and we warn against pursuing the same strategy for other life-threatening diseases. Under no circumstances should those affected be the victims of such price wars. We demand that our Parliament develops the necessary instruments to enable the Federal Office to conduct future price negotiations more constructively and transparently.
We would like to thank the experts of the Swiss Hepatitis Strategy, who have worked tirelessly with us to promote the well-being of those affected, and we regard the case of the limitation as a joint success for civil society.
We would also like to thank the industry, whose medicines have cured us and hopefully will now enable many other hepatitis C patients to lead a new life. Their willingness to compromise in the negotiations with the FOPH made it possible to abolish rationing.
What exactly is chronic HCV? In a nutshell, it refers to ongoing inflammation of your liver. But it can lead to symptoms throughout your body. Over time, living with this condition can cause your body to be especially vulnerable to serious health complications. Here is a great infographic from Healthline about the effects of Hepatitis C on your body.
Last week there was some celebrations after Under pressure, Gilead expands Sovaldi licensing deal to four middle-income countries.
So great news, right? Not exactly, because in order for a country to have PRACTICAL ACCESS the product needs to be registered for sale there.
Now Sovaldi hit the market in late 2013 and back in February 2015 Gilead announced Gilead is committed to increasing access to its medicines for all people who can benefit from them, regardless of where they live or their ability to pay and providing a list of 91 countries where generics would be available. That list has since been expanded to include 101 countries.
That was 2 and a half years ago, so surely Sovaldi must be available in all the original 91 by now, afterall, Sovaldi was fast tracked by the FDA with one of the most rapid approvals ever seen...
Nope. To date Sovaldi is only registered in 26 of those 101 countries, with applications filed in another 6. That's 32/101 countries filed in 2 1/2 years.
- Without filing, there can be no registration.
- Without registration, there can be no availability.
- Without availability, there can be no patients treated.
This is the reality behind Gilead's PR-access. It is PR, it is not access.
By Priti Krishtel
Last week, the FDA approved AbbVie’s Mavyret—a new hepatitis C virus (HCV) drug that treats all genotypes of the disease and cures more than 90% of patients within just 8 weeks of treatment. This has been reported as a threat to Gilead Sciences’ dominant position in the market, sparking rumors of a potential price war that could lower prices on the infamously expensive treatments.
There is reason to be tentatively optimistic. The initial published price on Mavryet was lower than expected at $13,200 per month—or $26,400 for a full course of treatment—appearing on the surface to be a significant discount from the $94,500 per-treatment course costs of Harvoni, Gilead’s market-leading treatment.
And while the published price is a step in the right direction to getting more people the treatment they need, it isn’t the whole story. The set Mavryet price is reflective of the current market conditions. With behind-the-scenes payer negotiations, the announced price on Mavyret is only an approximately 15% discount to the current net price paid for Gilead’s products.
While AbbVie’s pricing is now the lowest for a curative HCV drug, it is not a radical undercutting of Gilead prices. Millions of Americans with HCV—and tens of millions globally—are already blocked from getting treatment at the current exorbitant prices set by the pharmaceutical industry and the subsequent rationing of treatment approval by payers.
The United States is currently facing an HCV epidemic. There are an estimated 3.6 million Americans with HCV—and that number is expected to rise in the coming years. There is a cure, but every day 48 people in the United States die from HCV, the deadliest infectious disease in America. That’s because 2 out of every 3 Americans who have been diagnosed with HCV do not receive treatment, largely due to the high costs. States such as Louisiana and Pennsylvania are forced to ration treatment to the sickest of patients, and many insurers refuse to cover it because of the high price.
A week out from the FDA’s approval, it is not clear what the introduction of Mavyret will do to change this situation. What is clear, however, is that people should not die of an entirely treatable illness. One of the root causes of the unaffordability crisis is the fact that pharmaceutical companies such as Gilead over-patent drugs, including extending its market monopoly on Sovaldi for at least the next 2 decades.
Gilead’s initial price on Sovaldi has skewed what the market considered a fair price for HCV treatment. I doubt we would see this level of praise for AbbVie now if Gilead hadn’t launched this lifesaving medicine at $84,000 for a single course of treatment.
Until we address the core of the drug pricing problem—unjustified patents—pharmaceutical companies will be able to abuse the system to obtain monopolies on the market and charge astronomical prices that prevent people from getting access to disease-curing medicines.
About the Author
Priti Krishtel is co-founder and co-director of the Initiative for Medicines, Access & Knowledge (I-MAK), a US-based nonprofit group of scientists and lawyers working globally to get people lifesaving medicine. Prior to founding I-MAK, Krishtel obtained her law degree from New York University School of Law worked as a health attorney in the United States, Switzerland and India.
"To our knowledge, this is the first large-scale study to demonstrate the effect of newer DAA regimens upon survival. Treatment with 2 commonly used DAA regimens, PrOD and LDV/SOF, was associated with significant improvements in survival within the first 18 months of treatment, compared with demographically and clinically similar untreated HCV-infected controls. Treatment with either PrOD or LDV/SOF was associated with a 57% reduction in mortality, and attainment of SVR was associated with a 43% reduction in mortality….Benefits of treatment at a population level are expected to be substantial…..similar benefit can be expected with other DAA-based regimens"
Effect of Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir and Ledipasvir/Sofosbuvir Regimens on Survival Compared With Untreated Hepatitis C Virus–Infected Persons
Adeel Ajwad Butt Peng Yan Tracey G. Simon Abdul-Badi Abou-Samra
Clinical Infectious Diseases, cix364, https://doi.org/10.1093/cid/cix364
Published: 20 July 2017
Interferon-based regimens are associated with a substantial survival benefit for persons infected with hepatitis C virus (HCV). Survival data with direct-acting antiviral agents are not available. We conducted this study to quantify the effect of paritaprevir/ritonavir, ombitasvir, dasabuvir (PrOD) and ledipasvir/sofosbuvir (LDV/SOF) regimens upon mortality.
In the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans, we identified HCV-infected persons initiated on PrOD or LDV/SOF, excluding those with human immunodeficiency virus, hepatitis B surface antigen positivity, hepatocellular carcinoma, or missing HCV RNA or FIB-4 scores. For each case, we identified a propensity score–matched control never initiated on treatment. Primary outcome was survival. Outcomes were assessed using frequency of events, Kaplan-Meier curves, and Cox proportional hazards regression analyses.
We identified 1473 persons on PrOD, 5497 on LDV/SOF, and 6970 propensity score–matched untreated persons. Treated persons were more likely to be obese and have cirrhosis, but less likely to have stage 3–5 chronic kidney disease (CKD), alcohol or drug abuse or dependence diagnosis, and anemia. The proportion of persons who died was higher in the untreated group compared with either treatment group (PrOD, 0.3%; LDV/SOF, 1.4%; untreated controls, 2.5%; P < .001). A significantly larger percentage of treated patients survived to 18 months of follow-up, compared with untreated controls (P < .001). In multivariable Cox regression analysis, treatment with either regimen (hazard ratio [HR], 0.43; 95% confidence interval [CI], .33–.57) and attainment of sustained virologic response (SVR) were associated with significantly lower mortality (HR, 0.57; 95% CI, .33–.99).
Treatment with PrOD or LDV/SOF and SVR are associated with a significant mortality benefit, apparent within the first 18 months of treatment.
Here is a copy of the presentation, called "Practivism, it's the new black", given by Dr James Freeman at the International AIDS society meeting in Paris today.
Here is the text that went with the images.
Crisis, What Crisis?
This crisis. Look at this price comparison. I mean seriously?
We only have to look at Egypt to know these medications can be made affordably
Pricing negotiations are one sided and conducted by bandits
Our funders simply can not afford to cover the costs so…
We have rationing that sees only the sickest patients treated
And virtually nothing is being done for high burden populations like prisoners
And People Who Inject Drugs
Politicians pay lip service to the issue
Many advocacy groups are directly funded by Big Pharma*.
And in the Ukraine earlier this year generics were shot down by data exclusivity
Treatment rates are similar to infection rates
In short we are currently going nowhere fast.
Patients are stigmatized and don’t speak out so in the zeitgeist there is no crisis
But we desperately need a new balance between patent rights and patient lives
And now seven seconds of silence to remember those of us for whom treatment will come too late
One second for each patient who died during the time it's taken to give this presentation
Was it really only 50 years ago our Statesmen talked like this and the crowds came to listen?
What we call the “big picture” is really just the product of what each and every one of us chooses to do.
What we do as individuals, thinking globally but acting locally, exhibits a butterfly effect so I would like to suggest adopting this butterfly symbol and a simple slogan like "Wear if you care"
Over the past year there has been quite a lot of discussion about the risk of liver cancer following treatment with Direct Acting Antivirals like Harvoni® and Sovaldi®.
Here is a quick explanation and the latest thinking from the academic gurus.
First, the risk of Hepatocellular Carcinoma (HCC aka liver cancer) only starts to rise when patients develop cirrhosis, so for patients without cirrhosis there is little to worry about.
In patients with cirrhosis, and untreated Hepatitis C the annual risk of developing liver cancer is 3%. With SVR (cure) following treatment this risk falls to around 1%, so is much less.
In patients who have already had one HCC, treatment increases their short term risk of getting another one (this is probably one they already have but is simply too small to see) and demands very close monitoring both during and immediately after treatment.
So the bottom line is pretty simple. Treat before you get cirrhosis, but if you already have cirrhosis, you are still better off treating. If you have previously had an HCC you can still treat but need very close follow up.
Below you will find the text of a press release from EASL 2017. EASL is the European Association for Study of Liver Diseases and represents the best experts in the world telling it how they see it.
ILC 2017: Is direct-acting antiviral therapy for Hepatitis C associated with an increased risk of liver cancer? The debate continues
Eight studies being presented at The International Liver Congress™ 2017 demonstrate contrasting evidence on the potential link between direct-acting antiviral treatment for Hepatitis C and liver cancer
April 20, 2017, Amsterdam, The Netherlands: According to data from eight studies being presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, there remains continued debate on whether patients are at risk of developing liver cancer after achieving sustained virologic response (SVR) with a direct-acting antiviral (DAA) regimen for Hepatitis C virus (HCV). Investigators will present the results of their studies that show both sides of the argument – DAA therapy is associated with a higher risk of liver cancer compared with interferon-based therapy, versus there is no difference in liver cancer risk following cure with either therapy.
Whilst remarkable progress has been made in the development of successful antiviral therapies for HCV infection, some recent studies suggest that curing patients does not eliminate the risk of developing liver cancer. There also appears to be an unexpectedly high rate of liver cancer (also known as hepatocellular carcinoma [HCC]) recurrence in patients who previously had their tumour treated successfully and had received DAAs.
This claim was further supported by a Spanish study led by Dr Maria Reig and Dr Mariño, Hospital Clinic Barcelona, Spain in which patients with HCV and HCC who had previously been cured of HCC received DAA therapy. After a median 12.4 month follow-up, following treatment with DAAs, the rate of HCC coming back (recurrence) was 31.2% (24/77) and of those who received HCC treatment at recurrence, 30% (6/20) of patients presented progression in the immediate 6-month follow-up. This is an update of the study that will be published in the May 2017 issue of Seminars in Liver Disease, and is available here: https://www.thieme-connect.de/products/ejournals/html/10.1055/s-0037-1601349.
“Our study offers further support to previous findings that there is an unexpected high recurrence rate of hepatocellular carcinoma associated with DAAs, and that this association may result in a more aggressive pattern of recurrence and faster tumour progression,” said Dr Maria Reig, Barcelona Clinic Liver Cancer Group, Hospital Clinic Barcelona, Spain, and lead author of the study. “These data indicate that there needs to be further research conducted in this area, clarifying the mechanism for the association between liver cancer recurrence and DAA therapy.”
Identifying those patients at risk of liver cancer is essential, a task that Dr Etienne Audureau, Public Health, Henri Mondor University Hospital, Créteil, France, and colleagues attempted to achieve by developing a prognostic tool for HCC. They found that in patients with severe scarring of the liver due to HCV (compensated cirrhosis), failure to achieve SVR was the most influential factor in predicting liver cancer. In addition, risk factors for liver cancer differ according to SVR status. The investigators recommend that in patients with compensated cirrhosis, eradication of HCV should be achieved before liver function is impaired and people who have achieved SVR should be monitored for liver cancer after 50 years of age.
The mechanisms behind the development of liver cancer following HCV cure are not yet understood. One group of investigators led by Prof Thomas Baumert, Inserm Institute for Viral and Liver Diseases, University of Strasbourg, France, aimed to investigate if HCV infections produce epigenetic and transcriptional changes that persist after the infection is cured, and whether these epigenetic changes drive liver disease and HCC following cure. They found that the epigenetic and transcriptional changes are only partially reversed by DAAs and persist after HCV cure, suggesting that these changes are a driver for liver cancer that develops after HCV infection has been cured. The investigators concluded that these findings open a new perspective to develop novel biomarkers to identify patients at high risk of HCC and provide an opportunity to develop urgently needed strategies for HCC prevention.
On the other side of the debate, a systematic review, meta-analyses, and meta-regression study, by Prof Gregory Dore and Dr Reem Waziry from The Kirby Institute, UNSW Sydney, and colleagues, found no evidence for higher risk of HCC occurrence or recurrence following DAA treatment, compared with interferon-based HCV therapy. A total of 41 studies, including 26 on HCC occurrence and 15 on HCC recurrence (in total, n=13,875 patients) were included. In studies assessing HCC occurrence, average follow up was shorter and average age was higher in DAA studies compared to interferon studies; incidence was lower with longer follow-up and younger age. In studies assessing HCC recurrence, average follow up was also shorter. Ultimately, in the meta-regression analysis, no evidence in favour of a differential HCC occurrence or recurrence was found between DAA and interferon regimens, after adjusting for study follow-up and age.
“Recent studies have reported contradicting evidence on risk of hepatocellular carcinoma following direct-acting antiviral therapy; our aim was to bring some clarity to this,” said Prof Gregory Dore, Kirby Institute and lead author of the study. “These data show the higher incidence of HCC observed following DAA therapy can be explained by the shorter duration of follow-up and older age of participants, rather than the DAA treatment regimen.”
A Scottish study, led by Dr Hamish Innes, School of Health and Life Sciences, Glasgow Caledonian University, Scotland, found that the risk of liver cancer following SVR was not associated with the use of DAAs, but baseline risk factors. Furthermore, risk of HCC development was similar in patients taking interferon-free regimens versus interferoncontaining regimens, following a multivariate adjustment (IRR: 0.96, p=0.929) and no significant differences in HCC risk were found when treatment regimen was defined in terms of DAA containing regimens versus DAA free regimens. These data indicate that rather than the treatment regimens themselves, it is the baseline risk factors that determine risk of hepatocellular carcinoma.
Another interesting study in Japanese patients with HCV genotype 1 infection, found a reduced incidence of liver cancer following achievement of SVR after 12 weeks of therapy with an interferon-free regimen (ledipasvir plus sofosbuvir) to a similar degree as that obtained with an interferon-containing regimen (simeprevir with peginterferon plus ribavirin). This study, which was conducted by Dr Masaaki Korenaga, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan, and colleagues, also found that unexpected development of liver cancer following SVR in patients without previous liver cancer could potentially be predicted by imaging procedures (computer tomography or enhanced magnetic resonance imaging).
Similarly, a Chinese study led by Dr George Lau, from the Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, in Beijing, China, found no increase in the incidence of liver cancer in patients who achieved SVR12 with DAA compared to peginterferon plus ribavirin.
A Sicilian study conducted by Dr Vincenza Calvaruso, University of Palermo, Palermo, Italy, and colleagues, demonstrated that patients who achieved SVR with DAAs had a similar risk of developing liver cancer when compared to historical controls of patients with compensated cirrhosis who achieved SVR after interferon-based therapy. In addition, those who achieved SVR with DAAs had a lower risk of developing liver cancer than those patients whose HCV infection was not cured.
“The original observations made by researchers from the Barcelona Clinic Liver Cancer Group have sparked a huge number of studies aimed at verifying the potential association between DAA treatment and increased HCC recurrence after cure,” said Prof Francesco Negro, Divisions of Gastroenterology and Hepatology of Clinical Pathology, University Hospital of Geneva, and EASL Governing Board Member. “At this stage, there is no reason to alter treatment guidelines until the issue is definitively clarified. We cannot exclude, however, that we may have to revise post-SVR surveillance in some specific patient subgroups.”
- Ends -
About The International Liver Congress™
This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 – 23, at the RAI Amsterdam, Amsterdam, The Netherlands.
Here is the response from EASL to the recent Cochrane review. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf
EASL, the European Association for the Study of the Liver, one of the world leading associations of liver specialists, feels compelled to express its serious concerns after the recent publication of a Cochrane Group systematic review entitled “Direct acting antivirals for chronic hepatitis C” by Jakobsen et al. After reviewing 138 clinical trials, including 25,232 participants, the authors conclude that: “Overall, direct acting antivirals (DAAs) on the market or under development do not seem to have any effects on risk of serious adverse events. […] 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.”
The inability of the authors of the Cochrane review to determine a clinical benefit of DAA-based treatment of hepatitis C unfortunately reflects their flawed methodological approach and their ignorance of the natural history of hepatitis C virus (HCV) infection and associated systemic diseases. The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain an SVR is a pivotal outcome of treatment, and does not accept the likelihood that an SVR will reduce the risks of long-term outcomes of hepatitis C.
With this deduction comes responsibility. The uncertainty created by the illconceived Cochrane group’s conclusions and the attendant press publicity could grievously affect policy making, and constrain the gathering momentum for diagnosis, testing and linkage to care of individuals with hepatitis C. It will create dangerous confusion in the mind of patients treated or about to be treated and their families. The World Health Organization (WHO) has published an authoritative Global Hepatitis Report, expressing its alarm at the burden of disease, and has promulgated critical targets for global elimination of hepatitis C by 2030. In the absence of a prophylactic vaccine, the Cochrane review jeopardises treatment as a necessary intervention to reduce the global morbidity, mortality and prevalence of chronic hepatitis C.
The primary endpoint in DAA investigational drug development trials has been the sustained virological response (SVR), i.e. undetectable HCV RNA 12 or 24 weeks after completion of treatment, which corroborates permanent elimination of the viral infection. The Cochrane review evaluated the effect of DAA treatments on several outcome measures, including hepatitis C-related mortality, all-cause mortality, serious adverse events, no SVR and health-related quality of life (HRQOL). Most of their conclusions are flawed.
- The report from 32 trials including 7115 participants indicates that a total of 1180/1692 (69.7%) patients in the DAA groups and 915/5194 (17.6%) patients in the control group had “no SVR” during the observation period. This can only be an error as the authors deduce that meta-analysis showed that DAAs “seemed to reduce the risk of no SVR (risk ratio=0.44, p <0.00001) […]“.
- It is inappropriate to have pooled the data to include 57 trials that included drugs that have been withdrawn or discontinued. These are experimental drugs that have been discarded for lack of safety or inferior efficacy and that have been superseded by more effective and safer drugs, making the review dated and ignorant of current clinical decisions and guidelines in the context of a rapidly progressing field. Including treatments that are not or no longer used, and/or overly heterogeneous introduces a bias in the meta-analysis.
- From 43 trials involving 15,817 patients, the authors report serious adverse events (SAEs) in 2.7% of DAA-treated patients versus 5.5% in the control group during the observation period. They conclude that there is no firm evidence that DAAs reduce risk of SAEs. However, the terminology is clouded as the authors fail to clearly indicate whether they consider drug-related SAEs or clinical SAEs, i.e. clinical events resulting from the natural history of HCV infection which would happen months to years after the period of observation of the clinical trials.
- The HRQOL analysis has missed many recent studies. Several systematic reviews have been performed which have shown significant improvement in quality of life parameters with DAA therapy. The results show improvement over interferon and ribavirin-based treatments and are an encouraging aspect of an SVR with chronic hepatitis C, that further support the use of the SVR as surrogate. Very detailed and comprehensive analyses have been compiled before, during and after treatment objectively demonstrating improved patient-reported outcomes.
- The major weakness of the Cochrane review is that results are only assessed at “maximum follow-up”. These are of course short-term results for a disease with a long clinically latent period. A meta-analysis should only evaluate the primary endpoint selected by the clinical studies. The trials were not designed or powered to capture long-term outcomes such as hepatitis C-related morbidity or all-cause mortality, but to establish whether infection, reflected by persistent viremia, could be safely and effectively terminated.
The risk of clinical liver outcomes increases with aging and duration of disease. It is the result of chronic production of viral antigens during ongoing infection which incite host immune responses. The resulting hepatic inflammation in turn triggers fibrogenesis, the basis of liver disease progression towards aggravating fibrosis, cirrhosis and, ultimately, decompensated cirrhosis and hepatocellular carcinoma. The harmful effects of chronic hepatitis C take years to develop in patients that generally remain asymptomatic for long periods of time. Thus, although there is variation in rates of progression of fibrosis, early disease does not indemnify an individual from subsequent progressive disease, that can be accelerated by various cofactors and comorbidities. The authors of the Cochrane review have unfortunately not considered the possibility, the necessity and feasibility of arresting progression of early stage disease to more advanced fibrosis, cirrhosis, decompensated cirrhosis, or the ultimate development of HCC.
Achieving SVR, i.e. eliminating the infection, removes the trigger, thereby halting or considerably slowing the progression of liver disease. Terminating active infection also alters the natural history of a number of HCV-induced extrahepatic morbidities, such as diabetes and renal insufficiency. This has been clearly demonstrated by long-term follow-up studies in patients with chronic hepatitis C cured of their persistent infection during the interferon era. An SVR is associated with normalization of serum aminotransferases and improvement or disappearance of liver necroinflammation and fibrosis in patients without cirrhosis. Hepatic fibrosis generally regresses and the risk of complications such as hepatic failure and portal hypertension is reduced in patients with severe liver disease. Recent data showed that the risk of HCC and all-cause mortality is significantly reduced (although not eliminated to zero) in patients with cirrhosis who clear HCV compared to untreated patients and non-sustained virological responders. For the first time, DAAs have allowed patients with decompensated cirrhosis access to anti-HCV therapy, improving their liver function and reducing the indications for liver transplantation in a large proportion of cases, with a major impact on transplant programs already evident. Moreover, the possibility to treat patients after solid organ transplantation with high infection cure rates has opened the door to the use of HCVpositive grafts, increasing transplantation rates, reducing on-list mortality and containing healthcare costs for management of patients on the transplant waiting list.
National and international regulatory authorities have accepted the primary endpoint of an SVR and demonstrable safety as evidence for DAA licencing. Because the complications of chronic hepatitis C take years to occur, depending on the stage of liver disease, and clinical trials with new DAAs with SVR as main endpoint last only a few months, the benefits in terms of clinical outcomes of achieving an SVR cannot be measured in these trials. The Cochrane group’s conclusion is therefore illogical and inappropriate, as it fails to respect the methodology this organization has developed. The Cochrane review also ignores the opportunity of reducing the risk of transmission from viremic individuals, particularly in highrisk groups. Overall, the Cochrane review displays a lack of understanding of hepatitis C and drug development in the context of a transmissible infectious disease with a long natural history.
The Cochrane review authors’ conclusion that “randomised clinical trials assessing direct effects of DAA are needed” suggests an ethical anathema of leaving patients untreated to accrue increasing hepatic fibrosis, in the face of treatments that are likely to arrest viral replication in the overwhelming majority. This conclusion evokes memories of the infamous Tuskegee study conducted by the United States Public Health Service, in which patients with syphilis were left untreated to observe the natural history even after advent of and proven efficacy of penicillin. This unethical approach is unacceptable in a context where: (i) the HCV treatment landscape has markedly altered with the introduction of DAA-based regimens which in both clinical trials and real-world data have shown remarkable SVR (i.e. infection cure) rates in treatment-naïve and -experienced patients with or without cirrhosis across all genotypes; (ii) modelling has clearly demonstrated the benefits of DAA-based therapies in reducing long-term hepatitis C-related morbidity and mortality as compared to no treatment (individual benefit) and reducing HCV transmission (collective benefit). In summary, to arrive at such a flawed conclusion reflects the squandering of a vast amount of considerable time-consuming endeavour and significant public funding. The premise of the Cochrane review will be viewed as so egregiously mistaken that the conclusions will rightly be disregarded. As the findings do not assist or advance the field, they will not be pertinent to clinical decision making or guidelines.
EASL will continue to emphasize and reinforce the fight against HCV and to lend its support to the international efforts aimed at eliminating HCV, a major aetiology of severe liver and extra-hepatic diseases, complications and related mortality, by 2030. There is no precedent for a disease to be eliminated only 40 years after the discovery of its causal agent thus far. This chance cannot, and will not be missed.
This article was just published in the Lancet
The introduction of direct-acting antiviral (DAA) medicines in 2013 revolutionised the treatment of chronic hepatitis C virus (HCV) infection. The efficacy of DAA therapy is impressive—in many clinical trials HCV cannot be detected by sensitive laboratory assays in more than 90% of people who complete DAA therapy, and observational studies have documented similar results.1, 2 High efficacy combined with low rates of adverse events have led WHO to include DAAs in the WHO Model List of Essential Medicines.3 Several countries, including Australia, Georgia, Iceland, and Morocco, have started national DAA-based treatment programmes to eliminate HCV infection, and WHO has called for the expansion of HCV therapy with DAAs as part of its global hepatitis elimination strategy.4
HCV is an important contributor to global mortality, causing an estimated 399 000 deaths each year worldwide, and as HCV treatment expands, it is anticipated that mortality from HCV infection will decline.5 However, because the annual risk of death from HCV infection is low and the DAAs were introduced only recently, there are limited data on how these drugs affect mortality. Clinical trials that evaluate the efficacy of DAAs do not assess mortality as an outcome but rather a surrogate outcome called the sustained virological response (SVR). An SVR is defined as the absence of detectable HCV by nucleic acid testing of blood samples obtained 12–24 weeks after completion of HCV therapy. An SVR is deemed equivalent to a cure because once an SVR is achieved, it is maintained in more than 99% of patients, even after years of follow-up.6 Also, an SVR is associated with resolution of cirrhosis in about half of patients with cirrhosis followed-up clinical trials.7
However, documenting in a clinical trial that DAAs result in an SVR is not the same thing as showing that they reduce mortality or morbidity. A recent systematic review by Jakobsen and colleagues8 from the Cochrane Hepatobiliary Group sought evidence from clinical trials of HCV therapies to assess this issue. The authors reviewed randomised clinical trials that used SVR as the primary outcome in people receiving DAA therapy compared with those either not treated or treated with other regimens (primarily interferon-based therapy). Jakobsen and colleagues concluded that DAAs were effective in producing an SVR (relative risk 0·44, 95% CI 0·37–0·52); however, the analysis did not find a reduction in morbidity or mortality after DAA therapy. At first sight, this conclusion seems to contradict systematic reviews of observational data that show that people who have an SVR after treatment with interferon and ribavirin had a 50% (95% CI 37–67) reduction in overall mortality and 76% (95% CI 69–82) reduction in the incidence of hepatocellular carcinoma as compared with people who were treated but did not achieve an SVR.9, 10 The reduction in overall mortality was even greater (81% [95% CI 72–87]) when persons with an SVR were compared with those not treated.9 Other studies have shown improvements in extrahepatic manifestations of HCV infection and quality of life among people with an SVR after DAA treatment.11, 12 Data on the effect of DAA therapy are also beginning to be reported from national programmes that are scaling up HCV therapy. In England where HCV therapy increased by 48% in 2015, compared with 2014, there were reductions in the incidence of HCV-related cirrhosis (42%), liver transplantations (32%), and deaths (8%).13
Observational studies are biased towards showing an effect of treatment since treatment decisions are based on the likelihood of a successful outcome, and people achieving an SVR may be predisposed to a better outcome for reasons unrelated to the treatment. However, the magnitude and consistency of health benefits across studies and outcomes support the conclusion that HCV therapy resulting in an SVR substantially reduces mortality and morbidity.
How to explain these apparently contradictory results? An important difference between the studies reviewed by Jakobsen and colleagues is the duration of follow-up, which was short at an average of 34 weeks compared with an average of more than 5 years in the other reviews.9, 10 Simply put, the clinical trials included in the systematic review by Jakobsen and colleagues were not designed to answer the question posed by the authors about the effect of DAA treatment on morbidity or mortality. These studies generally followed up patients for only 24–48 weeks after the completion of DAA therapy, and the risk of HCV-related disease and death during such a short period is extremely low because the harmful effects of chronic HCV infection take years to develop. In fact, no morbidity was reported, and only 16 deaths occurred among the 2996 patients enrolled in all the DAA trials that were assessed by Jakobsen and colleagues. Thus, the statistical power to show a difference between the two groups is very low. In addition, the non-intervention groups in many of the studies included in Jakobsen and colleagues' systematic review did in fact receive HCV therapy, primarily an interferon-based regimen, which would minimise any mortality benefit of DAA therapy. Finally, Jakobsen and colleagues' study included early, less effective DAA regimens that were discontinued or withdrawn before marketing. They propose that, to resolve definitively whether DAA therapy reduces morbidity and mortality, randomised clinical trials with a non-treatment comparator group be done with clinically relevant outcomes such as death. Clearly, with the ready availability of safe and effective DAAs and ample evidence showing the health benefits of achieving SVR, such a study design is unethical and would be unacceptable to institutional review boards and harmful to patients' health. Several organisations, such as patients' groups and international hepatology associations, have expressed their concerns about the methods and conclusions of the Jakobsen review.14, 15, 16
People who are knowledgeable in the field of HCV therapy can readily ascertain the limitations of the approach taken in the systematic review by Jakobsen and colleagues and will be able to place their results in the proper context relative to other data that document the health benefits of DAA therapy. But for some patients, health-care providers, and decision makers who may be less knowledgeable about HCV therapy, this type of analysis, especially as reported in the mainstream media,17 could lead to conclusions that DAA therapy has no benefit, resulting in decisions to decline to prescribe or take DAA therapy or to decline to approve budgets for DAA treatment programmes, particularly in view of their expense. This would be a tragic outcome, as it would lead to preventable deaths. Public-health policy makers who must decide on budget allocations for HCV treatment cannot wait for perfect data on mortality endpoints, since the types of trials that would generate these data will never be done. Rather, they must assess available, albeit imperfect, data from observational studies and trials using surrogate outcomes that are reliably predictive of clinically important outcomes. Based on the fact that DAA therapy is safe and effective in achieving SVRs, that the SVRs are durable in most patients, that HCV-induced liver damage improves after SVR, and that observational data show a large reduction in morbidity and mortality, health-care decision makers and providers can take comfort that the evidence is strong in favour of treatment. A more definitive assessment of impact on morbidity and mortality will take time, but this should not be used as a reason for denying HCV therapy and delaying efforts to eliminate HCV infection.
About 1 in 5 patients taking Direct Acting Antivirals will get insomnia. Here is a post of mine from some years ago about how to manage it.
Insomnia is a common and often frustrating problem. Part of the reason it's frustrating is that, unless an accurate diagnosis of the root cause(s) is made, treatments tend to be temporary band aid solutions and rapidly lose their effectiveness.
Do you have an underlying medical problem?
There are a range of medical condition that can cause insomnia.
Chronic pain, sleep apnoea or a need to urinate frequently caused by an enlarged prostate gland can all cause insomnia.
Diseases like arthritis, cancer, heart failure, lung disease, gastroesophageal reflux disease (GERD), overactive thyroid, Parkinson's disease and Alzheimer's disease have all been implicated.
Mental health problems like stress, anxiety and depression can also cause problems.
Many of these issues are amenable to treatment, and by fixing the root cause, sleep patterns can return to normal.
Are your medications to blame?
- SSRI antidepressants
- ACE inhibitors
- Cholinesterase inhibitors
- H1 antagonists
Note that you should consult with your doctor before stopping any prescribed medications.
Are your daily habits contributing?
There are many habits and work patterns that promote poor sleep
- Not enough light at midday and too much light (device screens) at night
- Shift work - this scrambles your body clock (circadian rhythm)
- Eating late in the evening
- Fluids in the evening (we were all trained as children to wake up and not wet the bed)
- Excess caffeine, nicotine and other stimulant (ie Red Bull) consumption
- Using stimulants in the afternoon and evening
- Not getting enough exercise
- Too much alcohol - although alcohol is a sedative it prevents entry into deep sleep
Could your sleep hygiene be improved?
If you use your bedroom for other activities than sleep and sex you are missing the opportunity to program your thinking along the lines of go to bed, go to sleep.
You will sleep better if:
- You have got a good dose of daylight during the day, and less light at night
- Your bedroom is pitch black
- Your bedroom is quiet
- You bedroom is not too hot, not too cold
- You have a comfortable mattress
- You have a comfortable pillow - not too high or too low, too soft or too firm - get one that's just right (and remember they wear out over time)
- You have enough blankets so you're not too hot when you go to bed, but also don't wake up freezing when it cools off in the early morning
What can my doctor do for me?
For a start, any doctor worth his/her salt can discuss everything with you and look for root causes. It's always best to fix the source(s) of problems.
A simple plan (from Dr Margaret Hardy)
- Work out average amount of actual sleep per night from sleep diary
- Choose a regular wake-up time
- Set a regular bedtime by subtracting average sleeping hours from the planned wake-up time
- Review at weekly intervals and, if tired, increase time in bed by going to bed 30 minutes earlier
Your doctor can also provide medications including:
- Melatonin (which re-sysncs your body clock and is thus really good for shift work and jetlag
- First generation sedating antihistamines (promethazine, doxylamine)
- Benzodiazepines (temazepam, zopiclone, zolpidem and many others) which are good for short term (particularly stress related insomnia). Long term you become first tolerant (needing ever increasing doses) and then addicted (needed the medication or you won't be able to sleep)
- Antidepressants like amitriptyline and mirtazipine which are used (usually in low doses) not to treat depression but for their common sedating side effect. Their advantage over benzodiazepines is that tolerance is far less of an issue, so they can be used longer term.Don't despair. Most people can get
Don't despair. Most people can get a far better nights sleep with a few simple changes.
Talk to your doctor, or see one of our expert GPs online from the convenience of home.
Dr James Freeman
Yesterday the Guardian published an article called '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.
There is some really interesting stuff happening in the "reverse liver fibrosis" realm.
Here is state of the art in 2009 (great review of the mechanism) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702953/ where we had no clear candidates, and
Here is state of the art in 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703795/ where we have literally hundreds of candidates (coffee and milk thistle (silymarin) and resveratrol are in there), and
Here is the state of the art in 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754444/ in an article called Promising Therapy Candidates for Liver Fibrosis
I like this bit from the conclusion:
Since both animal experiments and clinical studies have revealed that liver fibrosis, even early cirrhosis, is reversible, treating patients by combined therapies on underline etiology and fibrosis simultaneously might expedite the regression of liver fibrosis and promote liver regeneration.
Here is a copy of the generic hep c medication presentation given by Dr James Freeman at EASL 2017 today.
Mostly the presentation followed the slides.
The last words, with the last slide were "I want everyone to join the club, not the hep c buyers club, this club, the hep C cure club."