Monday, 12 November 2018 21:38

Generic Mavyret (Maviret) Coming Soon!

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The Medicines Patent Pool Signs Licence with AbbVie to Expand Access to Key Hepatitis C Treatment, Glecaprevir/Pibrentasvir

SAN FRANCISCONovember 12, 2018 /PRNewswire/ --

Important collaboration will ensure affordable hepatitis C treatment options in low- and middle-income countries.  

The Medicines Patent Pool (MPP) has today announced a new, royalty-free licence agreement with AbbVie for glecaprevir/pibrentasvir (G/P) - a World Health Organization (WHO)-recommended treatment for people living with chronic hepatitis C (HCV). The licence will enable quality-assured manufacturers to develop and sell generic medicines containing G/P in 99 low- and middle-income countries (LMICs) and territories at affordable prices, enabling access to and treatment scale-up with the most effective pan-genotypic regimens. The agreement was launched at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2018 in San Francisco.

"G/P is a priority therapy for licensing for the MPP, so this agreement with AbbVie is very good news for public health," said Dr Marie-Paule Kieny, Chair of the MPP Governance Board. "It is a really important new option for a significant proportion of HCV patients throughout the world. As with previous MPP licences, we look forward to facilitating access to generic versions of this product as quickly as possible in as many territories as possible."

Globally, 71 million people are currently living with chronic HCV, many of them in LMICs. By the end of 2015, only 20 percent had been diagnosed and a mere seven percent of them had received treatment. In February 2017, the MPP issued its annual report on priority medicines for in-licensing. Given its favourable clinical profile and high potential in LMICs, G/P was listed as a key priority treatment.

G/P is an all-oral, once-daily, pan-genotypic combination regimen and was originally approved in 2017. It has achieved high cure (SVR12) rates of 98 per cent in treatment-naïve non-cirrhotic patients across all six genotypes of the virus. It is recommended by the WHO as a first-line treatment for eight weeks in treatment- naïve non-cirrhotic patients. Treatment-naïve patients with compensated liver cirrhosis require a 12-week treatment course.

Further, the regimen is also indicated for use in HCV patients with any degree of renal impairment, including patients on dialysis. Globally between five and ten percent of all people living with chronic HCV infection are estimated to be living with kidney disease and this treatment will be very helpful for them.

There are 95 countries and four territories included in the MPP/AbbVie licence for G/P at this point.

More details: www.medicinespatentpool.org  

What the MPP's partners are saying:

"Central to our vision at AbbVie is developing therapies, such as our pan-genotypic HCV treatment, for the most serious diseases and providing access to those treatments. We are pleased to have reached today's agreement with the MPP."

Laura Schumacher, Executive Vice President, External Affairs, General Counsel and Corporate Secretary, AbbVie 

"The new agreement is an important step towards achieving elimination of hepatitis C worldwide. We urge national governments to take action now to make such curative treatments available for the millions of people in need."

Dr Gottfried Hirnschall, Director of Department of HIV and Global Hepatitis Programme, World Health Organization 

"Unitaid aims to maximise the public health response by enabling equitable access to better health for all. We welcome this agreement between the MPP - a Unitaid grantee - and AbbVie that will accelerate a more effective HCV response worldwide."

Lelio Marmora, Executive Director, Unitaid 

"Claiming over one million lives each year, viral hepatitis is one of the world's major public health challenges and disproportionately affects people living in LMICs. Therefore access to safe, quality-assured treatments, affordable for all, has to be the fundamental aim of the public health community. This is a big step in that direction. The next step is to see more territories included in the agreement. Each step makes the dream of hepatitis C elimination more real."

Raquel Peck, CEO, World Hepatitis Alliance 

"The Government of Pakistan warmly welcomes the agreement between the Medicines Patent Pool and AbbVie to expand access to glecaprevir/pibrentasvir - a very important therapy for the treatment of HCV - into territories including Pakistan. The HCV burden in Pakistan is endemic, affecting over eight million of our country's population and the prevention and treatment of HCV is a national priority. This agreement will considerably aid our efforts and, ultimately, accelerate the permanent elimination of the HCV virus." 

Mr Aamer Mehmood Kianai, Ministry of National Health Services, Regulations and Coordination, Government of Pakistan 

The MPP has an existing collaboration with AbbVie and has two agreements in place in the field of HIV. These are:

  • Licence on paediatric formulations of lopinavir/ritonavir, signed in November 2014, which is facilitating the development of improved paediatric formulations for at least 102 LMICs
  • Licence on adult formulations of lopinavir/ritonavir for use in Africa, signed in December 2015.

In HCV, the MPP has agreements with Bristol-Myers Squibb on daclatasvir and Pharco on ravidasvir.

About the Medicines Patent Pool 

The Medicines Patent Pool is a United Nations-backed public health organisation working to increase access to, and facilitate the development of, life-saving medicines for low- and middle-income countries. Through its innovative business model, the MPP partners with civil society, governments, international organisations, industry, patient groups and other stakeholders, to prioritise and license needed medicines and pool intellectual property to encourage genetic manufacture and the development of new formulations. To date, the MPP has signed agreements with nine patent holders for thirteen HIV antiretrovirals, one HIV technology platform, three hepatitis C direct-acting antivirals and a tuberculosis treatment. The MPP was founded and is funded by Unitaid.

www.medicinespatentpool.org

Abbvie's MAVIRET (glecaprevir/pibrentasvir) 

EU Indication  

MAVIRET is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Important EU Safety Information  

Contraindications:

MAVIRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers, such as rifampicin, carbamazepine, St. John's wort, phenobarbital, phenytoin, and primidone.

Special warnings and precautions for use:

Hepatitis B virus reactivation  

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment.

Hepatic impairment  

MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B).

Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor  

MAVIRET is not recommended for the re-treatment of patients with prior exposure to NS3A/4A and/or NS5A-inhibitors.

Adverse Reactions  

Most common (≥10%) adverse reactions for MAVIRET were headache and fatigue.

Globally, prescribing information varies; refer to the individual country product label for complete information.

SOURCE Medicines Patent Pool via www.natap.org

Thursday, 08 November 2018 06:09

Liver Cancer (HCC) Treatment Options

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One of the feared complications of Hepatitis C is HepatoCellular Carcinoma (HCC) aka Liver Cancer. While anyone can get this type of cancer it is most common in patients who have liver cirrhosis from any cause. We look for it using a blood test for AlphaFeto Protein (AFP) and/or Ultrasound, CT or MRI.

Ok, so the news has come back that you have an HCC. What are the treatment options?

  1. Do Nothing
  2. Chemotherapy with Sorafenib or Cabozantinib
  3. RFA
  4. TACE
  5. Resection
  6. Transplantation
  7. Experimental/Unproven/Deprecated Procedures

For a detailed rundown of current best practice please see https://bestpractice.bmj.com/topics/en-us/369

For a brief executive summary, please read on.

Do Nothing

While this sounds (and is) very nihilist the reality for some unfortunate patients is that nothing we do is likely to help.

Chemotherapy

Sorafenib, and more recently Cabozantinib are tyrosine kinase inhibitors. They are both tablets and can both slow down the progression of HCC in some patients. The key words are "slow down" and "in some patient" because neither drug can cure the HCC and they don't work in all patients. 

Details on Sorafanib can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702892/

Details on Cabozantinib (the new kid on the block) can be found here: https://www.nejm.org/doi/full/10.1056/NEJMoa1717002

While Cabozantinib is probably better than Sorafanib, it is yet to be widely available. I have had a single patient who was already failing Sorafenib get 2 good extra years on Cabozantinib, but eventually, that too failed.

RFA

RFA stands for Radio Frequency Ablation. The simplest way to look at it as like this. We have a needle we stick into the tumour and the tip of it is like a miniature microwave oven. We then switch this on an cook the surrounding tissue. The idea is to kill all the cancer tissue and the minimal amount of surrounding healthy tissue. All things going well it can cure an HCC. For more details on the procedure: https://en.wikipedia.org/wiki/Radiofrequency_ablation

And for an analysis of the success rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011083/

TACE

TACE stands for Trans Arterial Chemo Embolisation. It is a little like RFA but in this case the "needle" is flexible, and rather than stick it straight through the skin we thread it up through an artery. This bit is similar to an angioplasty for the heart. We continue threading it up the arteries until we find the artery that is supplying the tumour.  We then inject some stuff to block off this artery and release some very toxic routine chemotherapy medications (doxorubicin or cisplatin). The idea is that everything downstream is killed. All things going well it can cure HCC. For more details on the procedure: https://en.wikipedia.org/wiki/Transcatheter_arterial_chemoembolization

And for an analysis of the success rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915316/

Resection

If the HCC is in a favourable position in the liver it may be possible to cut it out. You don't need all your liver so throwing a segment, or a 1/2 of it out is possible.

Transplantation

Where resection is not possible, complete replacement of the liver may be possible. This becomes impossible if the tumour invades vital structures like the blood supply pipes or the bile ducts. Transplantation is complicated, expensive, requires long term immune supression, and there are not enough donor livers or transplant centers available.

Experimental/Unproven/Deprecated Procedures

TARE

TARE stands for Trans Arterial Radio Embolisation and in principle is like TACE except instead of chemotherapy laden spheres being use, radioactive spheres are used. For more information https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497664/

Ethanol Ablation

The technique of Ethanol Ablation is similar to that of RFA in that a needle is inserted into the tumour through the skin, thus the other name PAE (Percutaneous Alcohol Ablation). It has largely fallen out of favour as it is not as effective as RFA and has more side effects. For more information https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296972/

Naturopathy

It remains possible that there are natural medicines, largely unknown to science that may impact on HCC. I am personally aware of one patient who appears to have been cured using this modality.

Recurrence

The sad reality is that the cirrhosis that predisposes to getting one HCC predisposes to getting another, so curing one fixes the immediate problem, but more tumours may appear in the future. Long term follow up and monitoring is vital.

Hepatitis C and HCC

In the context of having Hepatitis C it's important to treat the HCC first, then treat the Hep C. For more details please see https://fixhepc.com/blog/item/108-daas-and-hcc-when-to-do-what-in-plain-english.html

The Good News Front

Without SVR one study showed liver cancer rates of 2.63% per year falling to 0.55% per year so Hep C treatment drops the risk of HCC development to about 1/5 of what it is untreated.

Wednesday, 07 November 2018 22:44

Hep C Guidelines - An Executive Summary

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Detailed expert guidelines are great but often run to hundreds of pages meaning it can be hard to find the specific information you want.

Giten Khwairakpam from TREAT Asia / amfAR just shared this awesome executive summary with me, so I'm sharing it here with you.

As a part of TREAT Asia/ amfAR’s efforts to increase access to hepatitis C and HIV co-infection diagnosis and treatment, we are pleased to share a new fact sheet that summarizes and simplifies key updates from the July 2018 version of the WHO Guidelines for the Screening, Care, and Treatment of Persons with Hepatitis C Infection. It can be accessed at https://www.amfar.org/guidelines/.

A full list of our hepatitis-related resource materials is available at https://www.amfar.org/facts/

We hope that this fact sheet will be useful for treatment advocates, primary care physicians and public health experts in understanding the recommendations better and help in shaping implementation strategies.

Saturday, 27 October 2018 00:48

So you're cured of Hepatitis C - What next?

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So you've made it! SVR12 and you are cured of Hep C. Maybe you battled your insurance company for access to the medications. Maybe you sourced generic medications yourself.

For most patients at this point that's it. It's over. You're cured and Hepatitis C can drift quietly into the past, but there is one group of patients who do need ongoing follow up. That group is the group of patients who have cirrhosis. If this is you please follow the advice below:

Every 6 months arrange for an ultrasound of your liver and an AlphaFetoProtein (AFP) blood test. This is suggested by both AASLD and EASL because cirrhosis carries an increased risk for the development of HepatoCellularCancer (HCC). Prior to treatment that risk was about 3% per year, and with SVR12 it falls to less than 1% but it does not fall to zero. With any form of cancer early detection allows for early treatment and cure, so keeping an eye out for this issue is a great way to protect your health.

 If you look at the impact of SVR you can see quite clearly why treatment is probably the single best thing a patient with Hepatitis C can do for their health.

Hepatitis C SVR12 all cause mortality

Here is an article from the South Centre in Geneva.

Abstract: In late 2013, a new Hepatitis C treatment called direct-acting antivirals (DAAs) was introduced in the market at unaffordable prices. The eradication of the disease is possible if medicines can be purchased at AFFORDABLE prices within health budgets. IF THIS IS NOT THE CASE, governments should consider the use of the TRIPS flexibilities to facilitate access to the treatment.

This article starts like this:

General Context and Background on the Debate over Access to Medicines

The problem of access to medicines until 2014 was concentrated in developing countries where one third of the world’s population had no access to medicines, while industrial countries, thanks to public (Europe) and private (the United States of America) insurances managed to pay the cost of medicines. Currently the situation in developing countries remains the same but the great novelty, unprecedented, is that the industrialized countries are beginning to have difficulties in ensuring the supply of certain medicines to their citizens. The debate and international negotiations on access to medicines began in 1995 with the creation of the World Trade Organization (WTO), at the end of the Uruguay Round, and the generalization of the mandatory use of patents for pharmacological products for all WTO member countries (currently totalling 164).

And in the middle find this:

Pharmaceutical innovation has significantly diminished in recent years

According to the data published by the French review Prescrire in recent years, we find that the number of medicines that constant “an important therapeutic advance” introduced into the French market in the last 10 years are not more than 14 per year; furthermore, innovation appears to be diminishing, as the maximum number of 14 is significantly higher than the average number of yearly therapeutic advances over the past decade:

  • 2007: 14 products
  • 2008: 6 products
  • 2009: 3 products
  • 2010: 3 products
  • 2011: 3 products
  • 2012: 3 products
  • 2013: 6 products
  • 2014: 5 products
  • 2015: 3 products
  • 2016: 1 products

You can read the full article here: https://www.southcentre.int/wp-content/uploads/2018/10/PB54_The-Use-of-TRIPS-Flexibilities-for-the-Access-to-Hepatitis-C-Treatment_EN.pdf but, in short, we are in a "Houston we have a problem" kind of a situation. Despite very high prices, we are seeing very little innovation.

Thursday, 11 October 2018 13:10

Understanding AFP (Alpha Feto Protein)

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AFP is short for Alpha FetoProtein.

As the "feto" in the name suggests this is a protein we see in a fetus. In adults we switch off the genes that produce it so we don't see much (usually <12 units)

Hepatocellular Carcinoma (HCC) represents a loss of control over liver cell growth. These liver cells tend to become more primitive, like the liver cells in a fetus. What often happens is that the genes that produce AFP get switched on again, so instead of seeing <12 units of AFP we see more.

In pragmatic terms:

Most patients will have an AFP <12 and will not have HCC

Some cirrhotic patients will have a slightly elevated AFP in the range 12-24, despite not having HCC. We invariably see this fall during and after treatment. Sitting on my desk I have these results from a cirrhotic patient who is now at SVR

Most, but not all, patients who develop HCC will have a detectable rise of AFP, usually to a level of over 100

Here is a patient who had HCC in whom we treated the HCV and the HCC (with Sorafanib). Notice both the fall in AFP and the fact this lab uses <6 rather than <12 as the cutoff

Please note this: while most HCC expresses AFP and therefore can be detected by an AFP blood test it is possible to have HCC with a normal AFP. Rare but possible. High risk patients with cirrhosis should have 6 monthly screening with U/S (or CT or MRI)

Also note that if you have had HCV but have not developed cirrhosis then your risk of HCC is almost exactly the same as the general population. It happens, but it is rare. AFP screening is more than adequate. If you want to have a look use U/S or MRI as a CT carries about a 1:1000 risk of giving you a cancer (it might be a little lower than this but is does carry a real risk).

Thursday, 11 October 2018 01:34

Are The New Hepatitis C Treatments Poisonous?

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So today, on the chat a patient mentioned "My doctor here is scaring me from getting treated. He is tell that the treatment can be poisonous."

5 years ago this doctor would have been correct, in fact, I used to think the same, going so far as to say "The treatment is worse than the disease".

So what has changed?

5 years ago the mainstay of treatment was PEG Interferon injections and Ribavirin tablets. Both of these drugs have a lot of side effects and with a 1 year treatment required to deliver a 50% chance of cure it's easy to understand why the treatment was not popular. The side effect list looked like this:

  • Flu-like (headache, fatigue, fever, chills, muscle ache)
  • Arthritis-like pain in back, joints
  • Gastrointestinal (low appetite, nausea, vomiting, diarrhea)
  • Low blood cell counts
  • Depression
  • Insomnia
  • Hair loss
  • And lots more...

All that changed in 2013 when a drug called Sovaldi® (Sofosbuvir) reached the market. This was rapidly followed by other drugs like Harvoni®, Viekira®, Zepatier®, Epclusa®, Vosevii® and Mavyret® (Maviret® in some countries). With these new drugs what we got was this:

  1. A typical 3 month treatment period
  2. Taking 1 (or a few) tablets a day
  3. Where there were minimal side effects (and the average patient actually felt better on treatment rather than worse)
  4. And where the treatment delivers a 95%+ chance of cure at the end

To tell you the truth it all sounded a bit too good to be true, but, having treated 3000 patients myself, and seen the results repeated by doctors around the world there is no doubt we have some really good solutions to curing Hepatitis C.

Getting access to these new medications can be a bit of a problem in some countries due to the cost, but affordable generics are available and they deliver the same results at a small fraction of the originator pricing. So, if you have Hep C, and would like to get back to better, do yourself a favour and look into getting treated. If you local doctor can't help, we can help with both your prescription and getting access to the medication.

Tuesday, 09 October 2018 03:35

Why Does Hepatitis C Treatment Fail Sometimes?

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Here is a question I was asked: I am a biochemist myself and studied virology many years ago. Unlike HIV, HEP C doesn’t seem to reside in reservoirs. So looking at your SVR rates they are impressive but could you maybe give me a high level reason why treatment fails? Apart from reinfection where could the virus hide? I have bought 20 weeks worth of meds and now I am on week 18. Was undetectable at week 3 so by the end of treatment I will have kept it at bay for a further 17 weeks. They should surely be enough to eradicate it?

Here's the answer.

There are multiple reasons treatment fails. They can broadly be divided into

  1. Viral Vector Factors
  2. Host Factors
  3. Drug Factors
  4. Resistance and Selective Pressure

Viral Vector Factors

The genetic code of the Hepatitis C virus is single-stranded RNA. Unlike DNA, which has two mirror image strands that deliver error checking, HCV RNA is duplicated like this:

  1. First, the RNA polymerase makes a mirror image (non-sense) strand of RNA from the viral RNA.
  2. Then it uses this to make another mirror image (sense) strand.

There is no error checking and 50% of the RNA produced is non-sense. This process is inefficient and error-prone. Every time the RNA duplicates there is about a 1:1000-1:10,000 chance the new RNA copy is inaccurate. Mostly this means it does not work properly, but sometimes it confers resistance. The so-called “wild type” is the most common form of the virus simply because it duplicates itself better than any other variants, however, some of the resistant variants are known as “fit mutants” because these RAVs (Resistance Associated Variants) reproduce almost as well as the wild type. These are the problem children.

Within one person there are a whole range of similar, but slightly different, variants of HCV RNA – this is why it is called a quasi-species.

The RNA itself is used to code a number of proteins of which the NS3/4A, NS5A and NS5B proteins form the 3 different targets for our drugs. The drugs work in a key/lock fashion where the drug is the key and the protein is the lock. The drug keys occupy a vital space in the protein which needs to be vacant for the protein to do its job. Small changes to these proteins change the lock so the key does not fit as well. Small changes to the RNA genetic sequence underlie these changes to the proteins.

Most of our drugs are what is known as competitive inhibitors, so they compete with usual substrate (the thing that normally fits the lock) and therefore need to be above a certain concentration to do their job. This concentration is known as the EC50 (Effective Concentration for 50% of the maximal inhibition). Sofosbuvir works on the NS5B RNA Polymerase protein. The reason it is so good is that this protein is the engine room making new viral RNA and Sofosbuvir is a suicide inhibitor – it binds permanently to the active site so can’t then be displaced when the concentration falls.

The different genotypes of HCV represent similar (but different) RNA sequences. Some genotypes of the virus are naturally resistant to some of the drugs. For example, Ledipasvir does not work well on Genotypes 2 and 3 because the NS5A protein target is a poor fit.

Logically you’d expect the longer you’ve had the virus, and the higher the viral load the more duplication cycles have happened and the greater the chance of resistance. There are hints that this is the case, but no solid proof.

What we do know to be true is that to be resistant to 1 drug is not that hard, but to be resistant to 2 (or more) is much harder. This relates to the 1:1000 probability of a mutation. To get one (on a single strand of viral RNA is 1:1000) but to get 2 is 1:1000 x 1:1000 = 1:1,000,000 and to get 3 it is 1: 1,000,000,000.

HIV is another RNA virus where we have seen this. When we only had one drug resistance happened quite quickly, with 2 drugs it took years, and with current 3+ drug combinations, resistance and virological breakthrough is rare.

Finally, HCV is very infectious. We know from monkey experiments that just 10 virus particles (virions) injected gives a 50% infection probability, and 100 virions deliver a near 100% infection probability. To get rid of this beast we need to kill it down to very nearly the last virion. It’s truly remarkable we can do this.

Host Factors

There is a disease called pernicious anaemia. Patients get this because they cannot absorb the small drug-like molecule vitamin B12. Similarly, some patients do not absorb some drugs very well. For the Hepatitis C DAAs, if we look at the blood levels of a group of patients, the patient with the highest levels may be absorbing 2-10x as much as the patient with the lowest levels. Ledipasvir and Velpatasvir are more problematic in this realm than Sofosbuvir and Daclatasvir.

While the drugs do much of the work, our immune systems still play a role in mopping up the stragglers. We know that 25% of people can clear the virus themselves, and obviously they have strong anti-HCV immune systems. We also know some people run low viral loads – they have moderately strong anti-HCV immune systems. People with high viral loads have weak anti-HCV systems but this is not as bad as you might think. Firstly the virus does not “eat” much so just letting it do its thing causes very little harm (less than fighting it all the time but not quite winning) and with our current drugs people with high viral loads enjoy similar cure rates, albeit sometimes requiring slightly longer treatment.

Unlike HIV there are no known “reservoirs” where HCV can hide, although that said there kind of are. By "kind of are" I’m referring to damaged cirrhotic liver and probably HCC. With cirrhosis parts of the liver are replaced by scar tissue. This tissue has very little blood supply meaning that a drug circulating in the blood does not reach very high levels in this tissue due to the distance it has to diffuse. This makes cirrhotic patients harder to cure, unless we transplant them when, despite the immunosuppression, they are easy to cure. We also see patients with HCC as being harder to cure. This probably relates to the background cirrhosis, but could also relate to the fact that cancer cells refuse to obey apoptosis (die now) signals they get from the immune system.

Drug Factors

As mentioned earlier some drug keys are a poor fit for the protein locks of certain genotypes. This can be a real problem when a patient is co-infected with 2 types of HCV – say genotype 1 and genotype 2. The genotype 1 will be dominant so that patient may get their genotype reported as simply genotype 1, but with ledipasvir not working well on genotype 2, if this patient is treated with Harvoni they will clear the GT1, but relapse with GT2.

Different drugs have different potencies. A drug with a high potency has a low EC50, and a drug with a low potency has a high EC50. For the drug to work it needs to remain above the EC50 throughout the day, otherwise there are times when it is below the level required to contain viral replication. Here is a table for GT3.

GT3 EC50

ABT-493 and ABT-530 are the Glecaprevir and Pibrentasvir in Mavyret (Maviret). GS-9857 is the Voxilaprevir in Vosevii and MK-8408 was Ruzasvir (now discontinued).

As mentioned before, some patients do not absorb some drugs as well as other patients so, even if properly dosed they may wander below the critical drug levels.

Some patients do not take their medication every day, and this results in blood levels potentially falling below what is required.

Some medications, supplements and foods interfere with the absorption of the DAAs. Sometimes this increases the blood levels, which, although it leads to more side effects, does not compromise treatment. However, sometimes medications (such as antacids with Harvoni and Epclusa) decrease the blood levels of the drugs and this can lead to treatment failure.

The duration of treatment is vital. The disappearance of the virus follows a pattern of exponential decay meaning (for example) on day 1 we have ½ the virus, day 2 we have ½ of that ½ ie ¼ and on day 3 we have ⅛. Now when we remember we need to go from zillions to < 10 actual viruses we can see that this takes time. Although it saves money we see a lot more GT1 Harvoni failures who took 8 weeks than those who took 12 weeks. The extra weeks are a form of insurance. For almost anyone who achieves SVR at some point we are pouring medication into a body that no longer harbours HCV – we have to overtreat to make sure, and we need to pick a “one size fits all” duration.

Another reason duration is vital relates to the half-life of a viral replicon. This is several weeks. If we don’t treat for long enough a replicon can be suppressed from working, but remove the drugs and it can recover. We need to display no mercy and keep kicking it while it is down until there is no chance it can recover.

Just a quick note on Ribavirin. The log kill on Sofosbuvir is 4.5 meaning it will kill 31,999/32,000. For the NS3/4A and NS5A agents is more like log 3 meaning they will kill 999/1000. Ribavirin is weak in comparison with a log kill of 0.5 meaning it will kill only 2/3 but that may just come in handy mopping up the stragglers. Of note is that Ribavirin is not a DAA – it is a fake letter U in the genetic alphabet so not prone to the same resistance mechanisms as the DAAs.

Resistance and Selective Pressure

We know from HIV that a patient who has a detectable viral load is at risk of a virological breakthrough. Why is that?

When we start treatment, pretty much all the easy to kill virus in the quasi-species is rapidly killed off, however not all of it is. Some of the variants will be partially resistant and the drugs are exerting a selective pressure. Now, despite the fact these RAVs may not be as fit as the wild-type, we have removed the competition. If one of these RAVs “lucks out” and mutates in a way that makes it either more resistant to the current drugs, or more resistant to (the usually missing) 3rd drug on a 3rd target we have a “Houston, we have a problem” kind of a moment.

Wrapping Up

Considering the ask – kill down to the last 10 virions - it’s truly remarkable that Sofosbuvir alone can deliver a ~66% cure rate. We know that adding in an NS5A agent improves that to ~95%. We also see that highly potent NS3/4A+NS5A combinations like Glecaprevir/Pibrentasvir can also kick ass, but here is a lesson from HIV. 3 drugs work better than 2. This is particularly relevant for patients being offered G/P for retreatment. The expected SVR is “only” 90% but if it was me… I’d add in the best NS5B ever invented (Sofosbuvir) to the best NS3/4A and the best NS5B.

 

Sunday, 07 October 2018 23:57

Buying Generic Harvoni® Online

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When the drug Harvoni® was announced back in 2014, it was very welcome news for Hepatitis C sufferers around the world. Finally, a single pill treatment for this notorious disease was available. Taken once daily for just 12 weeks, it cured 95% of patients with minimal side effects. Unfortunately, the excitement lasted only until the new drug's price was announced, $94,000 USD. This meant that patients had to be either super rich or eligible for insurance coverage and unfortunately, 90% of patients were neither. Because of Harvoni's astronomical price tag, many insurance companies refused to cover patients unless they were in a very late disease stage, defined as severe liver fibrosis (i.e. F3 or F4). This left 90% of patients unable to access originator (brand name) Harvoni® and having to look for overseas online sellers who supplied generic Harvoni®. But how can a patient safely access generic Harvoni® on the internet that is of the same quality as originator Harvoni®? If you take the following 5 factors into consideration, you will be able to find a trustworthy and affordable online supplier.

1. Watching out for Scammers

We hear a lot about scam websites on the Internet, especially foreign sites in developing countries. So how can you make sure you don't get taken? To avoid scam artists, patients need to do a bit of research to separate honest medicine suppliers from scammers. Google is your friend here - it's a great tool for discovering information. You should search Google for the website's name, the name of its founder (if available), and find out about their track record. If you find none or multiple bad reviews, definitely avoid that supplier as it will be quite risky. Here's a guide: https://fixhepc.com/fixhepc-scam-check.html

Additionally, if media outlets (such as TV networks, newspapers, or well-known websites) publish good or bad information about the website you're researching, that will give you excellent insight about it. It's worth noting that FixHepC Buyers Club was mentioned positively in about a dozen prestigious media outlets, such as The Lancet medical journal, WebMD, BBC Newsnight, The Sydney Morning Herald, and many others. Here is a BBC Newsnight video investigation of one of the early FixHepC patients.

2. Verifying the Quality of the Harvoni® Generic

Just like with all other products, there are good and bad quality generic medications. So how to ensure the quality of the Harvoni® generic you buy? There are two factors that decide the quality of all generic medications: Bioequivalence and GMP (Good Manufacturing Practice).

Bioequivalence:

A generic drug is considered bioequivalent to its originator (brand name) counterpart if their pharmacological effects are exactly the same. The easiest way to ensure this is when the generic manufacturer is granted a license by the originator company to produce the drug. This license notionally guarantees that both the generic and originator drugs are exactly the same however the Gold Standard is a thing called bioequivalence. This is explained in detail in this post: https://fixhepc.com/blog/item/107-bioequivalent-pharmacokinetics-for-generic-and-originator-hepatitis-c-direct-acting-antivirals.html

At FixHepC we only use medication from manufacturers that have proven bioequivalence.

GMP:

Good Manufacturing Practice certificates, as the name implies, are issued by the US FDA and EMA (European Medicines Agency) when a drug manufacturer meets all the requirements for highest quality mass production of pharmaceuticals. Needless to say, you should choose manufacturers that were awarded this certificate. GMP is the only thing that guarantees the latest batch of medication meets the same high quality standards as the batch that passed bioequivalence testing.

3. Avoiding Fake Drugs

Unfortunately, fake drugs are a real problem in many developing countries, such as India and Bangladesh, and almost all generic Hepatitis C drugs are sourced from there. So how can you make sure that you’re buying authentic generic Harvoni® (or other Hep C generics like Epclusa®, Sofosbuvir®, and Daclatasvir®) and not fall victim to dishonest or incompetent online suppliers? The answer is that you have to check the Supply Chain Integrity of the online seller, but that is easier said than done. Here is a primer on how to do that: https://fixhepc.com/supply-chain-integrity.html

4. Getting Guaranteed Delivery

Patients in most countries are not sure if they can legally import generic medications from abroad, and are worried that the medications they will pay for may be stopped by border customs and confiscated. In some countries, importing 3 months worth of personal medications is perfectly legal, as long as a doctor’s prescription is attached with the medications. However in some other countries, this is a gray area, and delivery is not guaranteed. It requires expertise by the shipper and learning how to abide by these countries laws and preparing the required paperwork. To make sure that you will not lose your medicines package due to an overzealous customs officer, only buy from suppliers who offer guaranteed delivery or 100% of your money back. It’s rare to find an overseas medicines supplier who would take that risk and provide that guarantee. To give patients peace of mind, FixHepC does just that, and they are able to do it because they have learned over 4 years now how to deliver drugs successfully all over the world. https://fixhepc.com/delivery-guarantee

5. Getting a Prescription and Medical Support

For one reason or another, many patients are not able to get a prescription for generic Harvoni from their doctor, so how can they get one? Also, many doctors will not monitor patients if they didn’t write their prescription, so what if you need medical support during treatment? It’s inconceivable, you may say, that online drug suppliers would provide such services, after all they are not doctors. Well, you would be right, except in the case of FixHepC. FixHepC was founded and is managed by a licensed Australian doctor, Dr. James Freeman, who is is arguably a leading expert in the field of Hepatitis C treatment. If patients have any questions during or after treatment, they can pose them for free on the site’s live chat platform and get them answered by one of FixHepC’s excellent doctors, or they can post them to the FixHepC Forum and get them answered directly by people who have been there and done that. If patients need a prescription for medications, they can easily get one by booking an online video appointment on GP2U (the Australian online doctor service). The cost for this service is 70 USD. Follow up can be via email or further video appointments.

Conclusion

You don’t have to be super rich or wait many years and get very sick before somebody agrees to treat you. You owe to yourself and to your family to take matters into your own hands and to get treated and cured now. Visit FixHepC to learn how to access high-quality generic Harvoni® for only $1300 USD all inclusive, and rediscover what it feels like to be well again.

 

Monday, 24 September 2018 21:45

Hep C generics set to be released in the USA in 2019!

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The good news is that Gilead plans to launch generic versions of Harvoni and Epclusa in the USA. The bad news is the $24,000 USD price tag. Although this price is substantially lower than list price, the reality is that the VA negotiated a $25,000 price nearly a year ago, so the payers have been seeing this pricing for a while. The biggest bit of upside is that patients could save up to $2500 in out of pocket costs and that's got to be a good thing. Here is the full press release...

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 24, 2018-- Gilead Sciences, Inc.(NASDAQ: GILD) announced today plans to launch authorized generic versions of Epclusa® (sofosbuvir 400mg/velpatasvir 100mg) and Harvoni® (ledipasvir 90mg/sofosbuvir 400mg), Gilead’s leading treatments for chronic hepatitis C virus (HCV), in the United States, through a newly created subsidiary, Asegua Therapeutics LLC. The authorized generics will launch at a list price of $24,000 for the most common course of therapy and will be available in January 2019.

Since the launch of Gilead’s first HCV medication in 2013, the average price paid for each bottle of medicine in the United States has decreased by more than 60 percent off of the public list prices, across health insurers and government payers. Due to the complexity and structure of the U.S. healthcare system, however, these discounts provided by Gilead may not always translate into lower costs for patients. Further, existing contracts, together with laws associated with government pricing policies, make it challenging to quickly lower a product’s list price once it is on the market.

The authorized generics are priced to more closely reflect the discounts that health insurers and government payers receive today. Insurers will have the choice of offering either the authorized generics or the branded medications for both Epclusa and Harvoni. In the Medicare Part D setting, the authorized generics could save patients up to $2,500 in out-of-pocket costs per course of therapy. The authorized generics will also offer substantial savings to state managed Medicaid plans that do not currently benefit from negotiated rebates and that represent a significant number of people in need, potentially opening up access to our medications to beneficiaries who were previously denied coverage.

“Launching these authorized generics is the best solution available to us today to quickly introduce a lower-priced alternative to our HCV medications without significant disruption to the healthcare system and our business,” said John F. Milligan, PhD, President and Chief Executive Officer, Gilead Sciences. “This launch also will hopefully help increase transparency by more closely aligning our medications’ list prices with their cost. Our ultimate goal is to lower the list price of Epclusa – a medication we believe is of great importance given its clinical profile across genotypes – and Harvoni. We are committed to working with all of our partners in the healthcare system to help enable list price reductions of our HCV medications and find better solutions to reduce patients’ out-of-pocket costs.”

Beyond the company’s efforts to reduce patient costs, Gilead is continuing to pursue innovative collaborations and long-term financing models, such as a potential subscription model, that could not only expand access, but aim to eliminate HCV in the United States and around the world.

 

Sunday, 23 September 2018 04:25

Why me? Why do I have Hepatitis C?

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The stigma and stereotype associated with Hepatitis C says "you only get that from IV drug use". While you certainly can get it from IV drug use, the majority of my Baby Boomer patients didn't. How do I know? Well, of course, I can't know for sure how anybody caught any communicable disease, but when talking to the 3000+ patients I've helped access affordable generic medication there is a recurrent theme. That theme is "Hey doc, I never did drugs, I don't have any tattoos, and I've never had a blood transfusion, so how did I get HCV?" That led me to look for the answer. The real answer, not the stereotype.

The short answer is the medical or dental profession probably gave it to you, but how do I know that?

Well, for a start, we know the disease requires blood-blood contact for transmission and, outside of IVDU, tattoos and blood transfusions most of us don't share our blood with friends. So for people who have the disease, but don't have these risk factors, what other blood-blood exposures did they have? The answer to that is clear, they had two distinct exposure risks:

  • Doctors giving vaccinations using reusable glass syringes, reusable needles, and multi-dose vials and jet guns for vaccinations.
  • Dentists drilling and scraping away at damaged teeth using reusable tools.

Nowadays with disposable everything, it's easy to forget what medicine looked like in the 50s, 60s, 70s, 80s and (believe it or not) the early 90s.

As a young child in the 60s I followed my father around. He worked in Intensive care and I got to play with all sorts of cool stuff. Glass syringes, reusable needles, liquid mercury from the blood pressure machines (shudder). My father and the other staff routinely got blood all over their neatly pressed white lab coats with barely a glove or facemask to be seen. Surgeons used that stuff, but not the doctors and nurses in the rest of the medical world.

I was immunized several times in a gymnasium line up with all my school friends. It was a wham bam thank you ma'am type thing. I thought the jet gun was nifty as there was no needle but discovered it hurt more.  As a medical student in the 80s I was aware of HIV but the notion of universal precautions was still a decade in the future. If we got blood on our hands we just washed it off. The world was very different and the acronym OH&S barely existed. 

Here are some timelines:

400 B.C. Campaign Jaundice: Hippocrates (yes, the Hippocratic oath guy) described a condition he called “epidemic jaundice.”

8th century A.D.: Pope Zacharias quarantined men and horses with jaundice. This was meant to control the spread of the disease.

1861-1865: More than 40,000 cases of jaundice were recorded in the Union Army during the Civil War.

1942-1945 Hepatitis and World War II: Approximately 182,383 US service members were hospitalized for hepatitis during World War II. The disease was contracted in two different ways. An epidemic of hepatitis broke out among many service members who were vaccinated against yellow fever. The source of the infection was traced to the serum that was used in the vaccine. A different form of hepatitis, acute hepatitis, was found among soldiers who had received blood transfusions.

1951: Rothauser produced the first injection-molded syringes made of polypropylene, a plastic that can be heat-sterilized. 

1956: New Zealand inventor Colin Murdoch was granted New Zealand and Australian patents for a disposable plastic syringe, it will catch on but will take time.

1964: Ansell manufactures the first disposable latex medical glove based on the production technique for making condoms, but universal use (as part of universal precautions) will take close to 3 decades to catch on.

1965: The hepatitis B virus was discovered by Dr. Baruch Blumberg.

1973: The hepatitis A virus was discovered at the National Institutes of Health by a team led by Steven Feinstone.

1973: Cases of hepatitis not caused by either hepatitis A or hepatitis B come to be called "non A, non B hepatitis".

1989: Hepatitis C virus (previously known as non A, non B) is discovered by scientists at a California biotechnology company called Chiron.

1991: A test for Hepatitis C in the blood supply becomes available.

1992: The Occupational Health and Safety Administration (OHSA) published its Bloodborne Pathogens Standard. Around this time, there was increased awareness regarding HIV, and OHSA implemented the rule to protect workers who would come in contact with bodily fluids. OSHA’s standard required employers to provide personal protective equipment, including disposable gloves, to these workers.

So, we know that Baby Boomers are more at risk of Hepatitis C than any other group? Why? It's actually pretty simple.

Some of the soldiers that returned to the USA from WWII came back with Hepatitis C. Poor medical hygiene spread it, and this spread was almost certainly by vaccination in the 1950s, NOT by IVDU in the 1960s and 1970s. Nice theory, but how can we be sure? One word - genomics. Here is the study, published in the most prestigious journal in the world "The Lancet".

Abstract here: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2816%2900124-9/fulltext

Full text here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245154/

Here it is in plain English, thanks to Sheryl Ubelacker from The Canadian Press.

Canadian researchers have determined the peak of the hepatitis C epidemic in North America occurred about 15 years earlier than previously believed, suggesting it wasn’t youthful indiscretions that put baby boomers at a high risk for the disease.

It was long thought that boomers who were infected with the blood-borne virus likely contracted the disease in their late teens or early 20s, due to such risky behaviours as IV drug use or sexual experimentation.

But a study by B.C. researchers found the peak of the hepatitis C epidemic occurred about 1950, when many baby boomers were young children and had plateaued by 1960 — well before the zenith of injection drug use at the end of that decade.

The oldest of the baby boomers were just 5 years old at the peak of the epidemic, the researchers say.

“The spread of hepatitis C in North America occurred at least 15 years earlier than it was suspected before, and if that is the case, the baby boomer epidemic ... cannot be explained by behavioral indiscretions on the part of the baby boomers,” said co-investigator Dr. Julio Montaner, director of the BC Centre of Excellence in HIV/AIDS.

“We suspect that this is more likely attributable to medical practices at the time,” said Montaner, explaining that hepatitis C hadn’t yet been identified and injections and blood transfusions were given employing reusable glass-tube syringes and metal needles, which were subject to contamination despite boiling.

“The baby boomers in North America ought to be offered hepatitis C screening,” he said, “not because they did anything wrong but because they are baby boomers, and so they were alive at a time in which the standard of care was such that we are all potentially at risk of having contracted hepatitis C.”

If you or a loved one have Hepatitis C, but can't get access to insurance-funded treatment, then maybe getting cured with generic HCV medication is worth a thought. Visit our home page to learn more about generic hepatitis C treatment.

For patients with Hepatocellular Carcinoma (HCC) the options are limited. Caught early enough RadioFrequency Ablation (RFC), TransArterial ChemoEmbolisation (TACE) or surgical resection can potentially be curative. For some patients with advanced disease a liver transplant may be an option, but what about everyone else?

Up until recently, Sorafanib was the mainstay of treatment and the only real option to slow down the progression of the HCC and give patients some extra months or years of time. Nivolumab (Opdivo) appeared in 2017 but remains prohibitively expensive for most patients.

A couple of months ago the New England Journal of Medicine published the Phase 3 results for Cabozantinib which has been shown to work where patients are failing Sorafenib.

https://www.nejm.org/doi/full/10.1056/NEJMoa1717002

Although it's not a cure it can add some precious time. While it is anecdotal, back in 2015, I had a patient who was failing Sorafenib and was rejected from this very trial having been fully worked up. He was shattered and asked for help. Given this drug was, at the time, very experimental we went through an extensive informed consent process, including enlisting the assistance of his oncologist who said "We really don't have much to lose..." As it turned out he did very well on the Cabozantinib and got  2 extra years of good quality life.

It's not a cure, but it does provide cause for hope, as we inch ever closer to more effective treatments for HCC.

Friday, 03 August 2018 01:36

U=U - Undetectable = Untransmissable

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Strictly speaking, this relates to HIV but it also applies the Hepatitis C.

Undetectable = Untransmissable

Get tested, get treated, get cured!

https://ashm.org.au/HIV/UequalsU/

News Flash

MAVIRET® (glecaprevir/pibrentasvir) was listed on the PBS in Australia today.

  • AbbVie is pleased to announce that MAVIRET is to be listed on the PBS on 1 August 2018 for the treatment of chronic hepatitis C virus (HCV) infection in adults.
  • MAVIRET is a new 8 week pangenotypic treatment for treatment-naïve non-cirrhotic HCV adult patients.
  • In clinical trials, MAVIRET demonstrated 98% cure* rate in the ITT population (n/N=943/965) and 99% in the mITT population‡ (n/N=943/952) in treatment-naïve, non-cirrhotic patients pooled across GT1-6 with 8 weeks of treatment3, and a 0.1% discontinuation rate due to adverse events

*Cure defined as HCV RNA below the lower limit of detection at 12 weeks post end-of-treatment (SVR12)

An estimated 9 out of 10 of the remaining people living with chronic HCV are treatment-naïve and non-cirrhotic and may be eligible for 8 weeks of therapy with MAVIRET

Tuesday, 24 July 2018 14:43

Hep C Awareness - Images and Poster

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Most of the messaging to people about Hepatitis C is boring with as much cut through as a blunt knife through a block of titanium. If you were born between A and B, if this, if that, etc. It's time to change the paradigm and speak to the simple reason for getting tested which is get treated and feel better.

Feeling Old & Tired?
Get Tested,
Get Treated,
Get Cured

We owe a debt of gratitude to Marty2Bulls who designed the butter(fly)man logo for us. You can check out Marty's work here: https://www.facebook.com/martytwobulls/

 

The other day, on Facebook, I witnessed a patient, looking for advice, be given some very poor advice. Where poor = wrong and potentially lethal. I provided some accurate commentary which was deleted, leaving a whole lot of no doubt well-meaning, but nevertheless incorrect information.

So the question to hand was "My father has sourced DAAs privately and has started taking them (< 2 weeks ago) - he has just been diagnosed with HCC and his doctor has recommended stopping the medication while TACE or RFA is done".

The short story is that the patient's doctor's advice was correct, and the Facebook advice to continue DAAs was wrong.

Here is an explanation in plain English.

Patients who do not have cirrhosis have a low risk of HCC and can just be treated. They also have a low risk of any problems on treatment and a high probability of cure meaning that in a number of countries no real medical oversight is required during or after treatment.

Patients who do have cirrhosis have an approximately 1/30 chance of developing HCC every year and as a result, need monitoring tests that typically only a doctor can order.

For patients with cirrhosis and who have already had an HCC their risk of getting another one is higher than the 1/30 for a patient with cirrhosis but no history of HCC.

Hep C causes the immune system to attack the liver - that's all the liver - normal liver and cancer liver. So when we treat with DAAs and get rid of the Hep C we make it easier for HCC to flourish.

Here are the rules:

  1. If you do not have cirrhosis you can just treat with DAAs and not worry too much about HCC or indeed on/post-treatment monitoring
  2. If you do have cirrhosis, but have never had HCC, you can treat with DAAs but you have a persistent risk of developing HCC and need regular (6 monthly) Ultrasound/CT/MRI
  3. If you do have cirrhosis, and have had an HCC treated with resection/TACE/RFA, you can treat with DAAs but need very close follow up (say 3 monthly US/CT/MRI) as your risk of a recurrence is significant
  4. If you have had a liver transplant DAA treatment itself is similar to 1 but the liver transplant needs monitoring and there are some drug-drug interactions to be aware of.
  5. If you have an active HCC you should defer DAA treatment until after transplant/resection/TACE/RFA because
    1. DAA success rates are around 74% in patients with HCC so there is a pretty high chance of treatment failure
    2. DAA treatment is likely to accelerate the progression of the HCC and being HepC free but dead of HCC is not a good outcome.

While rules are meant to be broken these rules have a good basis in fact. The full details of the current expert advice can be found here:

http://www.easl.eu/medias/cpg/2018/EASL%20Recommendations%20on%20Treatment%20of%20Hepatitis%20C%202018/English-report.pdf

Facebook is great for peer group support, but if you have a serious medical condition - like Hep C and cirrhosis +/- HCC you really need expert local doctor care.

 

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.

BE

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.

http://www.aidsmap.com/Treatment-intensification-with-sofosbuvir-permits-cure-after-failure-of-previous-HCV-treatment/page/3014995/

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.

Highlights

  • 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.

 Methods

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).

 Results

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.

Conclusions

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.

Lay summary

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.

http://www.journal-of-hepatology.eu/article/S0168-8278(17)32286-9/fulltext 

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.

Tuesday, 19 December 2017 09:56

HCV retreatment 101 in plain English - Part 1

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Any SVR rate <100% means a small number of people will not attain SVR. A 95% SVR means for every 20 people on generic treatment 1 patient will relapse.

Back in early 2016 I came across an excellent article from Dr Jordan Feldwas kind enough to allow it to be reprinted here. It is a great overview from an eminent expert so I'm publishing it here again.

Since this article was written nearly 2 years ago there have been some developments and over the following few days we are going to look at:

  1. Understanding HCV and how the DAAs, Ribavirin, and Interferon work
  2. Viral kinetics and why treatment duration matters
  3. Resistance mechanisms, lessons from HIV and why 3 targets are better than 2
  4. Why we are now at the end of the road for the HCV pipeline, understanding your options and the importance of getting it right 2nd time around

How I Manage Patients With HCV After DAA Treatment Failure

Jordan J. Feld, MD, MPH - 19/1/2016 

The remarkable success of the new direct-acting antiviral (DAA) therapies for chronic HCV infection has led many patients and physicians to expect a cure whenever these agents are used. Although this is indeed the outcome for most, what can we offer the few patients in whom these treatments fail?

The data on retreatment are just starting to emerge. Whereas these studies cannot address every situation, a few general approaches are supported both by good logic and at least some empirical evidence: 1) switching to a different DAA class or classes, 2) treating for longer, and 3) adding ribavirin.

Treating With a Different DAA Class 

The simple approach of switching DAA classes is an obvious option for retreatment. It is certainly effective as there is no cross-resistance across DAA classes. This was established by the outstanding results of clinical trials in which patients who experienced protease inhibitor (telaprevir or boceprevir) failure were retreated with combinations of a nucleotide polymerase inhibitor (sofosbuvir) and an NS5A inhibitor (daclatasvir or ledipasvir).

However, switching to a different DAA class is not always possible, owing to contraindications, comorbidities, or potential drug–drug interactions, and may not be absolutely necessary if the other approaches are followed.

The biggest challenge in treating with a different class is NS5A resistance. NS5A resistance associated variants (RAVs) are very fit; they often emerge even before treatment and almost always persist in patients for whom an NS5A-containing regimen fails. Since NS5A inhibitors are part of most approved and investigational regimens, it can be difficult to avoid NS5A inhibitors when retreating.

Extending Treatment Duration 

Retreating patients with a longer duration of the same treatment that failed can help many patients, but it may not be enough to overcome RAVs. This was demonstrated in the initial retreatment trial presented at EASL 2015 by Lawitz and colleagues. Patients for whom 8 or 12 weeks of ledipasvir/sofosbuvir failed were retreated with ledipasvir/sofosbuvir again—this time for 24 weeks. Among patients without NS5A RAVs, this approach worked very well, resulting in an SVR12 rate of 100%. However, among those with NS5A RAVs, this strategy was suboptimal, with an SVR12 rate of only 60%. Even more concerning, 4 of the patients who failed the second course of therapy also developed RAVs to sofosbuvir. Fortunately, lessons were learned and the retreatment trials presented at AASLD this year proved much more successful.

Adding Ribavirin 

Data from the 2015 AASLD annual meeting highlight that retreatment with a previously unsuccessful regimen is possible with the help of ribavirin. In the C-SWIFT trial, patients who had relapsed after 4-8 weeks of treatment with grazoprevir (a protease inhibitor), elbasvir (an NS5A inhibitor), and sofosbuvir (an NS5B inhibitor) were retreated with the same combination of DAAs but for longer (12 weeks) and with the addition of ribavirin. With this approach, all 23 patients achieved SVR12.

The benefit of adding ribavirin to retreatment is not exclusive to NS5A inhibitors. In a small study of patients for whom a protease inhibitor regimen had failed, most patients were retreated with a protease inhibitor–containing regimen (ombitasvir/paritaprevir/ritonavir plus dasabuvir) plus sofosbuvir and ribavirin. Fourteen of these 15 patients achieved SVR12.

Although the mechanism(s) of action of ribavirin remain elusive, almost all studies using ribavirin with DAAs have shown that it delays or prevents the emergence of resistance, particularly in difficult-to-cure populations. Because ribavirin seems to raise the barrier to resistance, particularly for low-barrier DAAs including NS5A and protease inhibitors, it makes sense to add ribavirin to DAAs when retreating patients with presumed or known resistance.

Combining Strategies

All of the small retreatment studies I’ve mentioned successfully combined at least 2 of 3 approaches: switching to a different DAA class, treating for longer, or adding ribavirin. However, most of these retreatment studies were in patients without cirrhosis, a relatively easy-to-cure population. In clinical practice, many of the patients whose first treatment fails are those with advanced cirrhosis. For these tougher-to-treat patients, a combination of all 3 approaches would likely be worthwhile.

Consider Waiting to Retreat 

Although retreatment strategies are becoming more clearly defined, it is also important to consider that, for most patients, retreatment is not an emergency. For all patients except those with life-threatening cryoglobulinemic vasculitis, retreatment can almost certainly wait. Even for patients with advanced cirrhosis, waiting is not always a bad decision; SVR does not reverse liver failure in many patients, so those who cannot wait may actually be better served by being listed for a transplant.

There are at least 2 advantages to exercising a bit of patience. First, unfit RAVs, such as those to sofosbuvir, often disappear with time. Of more importance, research in HCV management continues to move at breakneck speed. The next meeting in this field may well offer the data we need to guide our decisions so we avoid failing a second time.

 
 
Friday, 01 December 2017 04:12

We can all make a difference...

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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.

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