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Super User

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

Wednesday, 25 July 2018 00:43

Hep C Awareness - Images and Poster

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:


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:

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:

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:

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.

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: 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.

Tuesday, 19 December 2017 20:56

HCV retreatment 101 in plain English - Part 1

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 15:12

We can all make a difference...

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!”

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