Hello Thurl,

Twinvir was launched on 27th of August. I launched the product. Patients started using this medicine from September earliest. SVR 12 is measured 12 weeks after treatment cessation. So no, there hasn’t been sufficient time to measure to SVR12 is any patients. But there are a number of patients who had been undetectable viral load during treatment. You are taking Twinvir. Have you measured your viral load during this time. What is your viral load status? I haven’t read the comment of the New Zealand doctor. Can you share the link with me?

Twinvir launched on the 27th August 2015, so there are patients past SVR4 but not SVR12. The first SVR12 results will appear in mid March.

My first patients started on it mid November. All were viral load zero within 4 weeks.

Prior to using it we tested Twinvir at the NATA accredited National Measurement Institute. If you search the certification documents for Sofosbuvir and Ledipasvir for the word Twinvir you will see that testing noted. You can find those certification reports here:

http://fixhepc.com/blog/item/16-testing-provisions-patient-safety.html

We did RVR testing on Twinvir during the period 20-28 November and observed excellent clinical effects with the worst 1 week viral load drop being 1,200,000 -> 636 (F3), the best being 2 million to undetected.

If you read the TGA submission here:

https://www.tga.gov.au/file/8444/download

You will find it stated that:

Ledipasvir is practically insoluble (<0.1 mg/mL) across the pH range of 3.0-7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). The partition coefficient (log P) for ledipasvir is 3.8 and the pKa1 is 4.0 and pKa2 is 5.0.

This is why you must have stomach acidity to absorb it – without that it won’t dissolve well. Once it is dissolved it’s not in a crystalline form and will be absorbed. The normal volume of the stomach fluid is 20 to 100 mL and the pH is acidic (1.5 to 3.5) so I’m actually quite surprised it is not without food (to increase the acidity) but as you will read in the auspar document it still gets absorbed in the presence of food.

If you read Gilead’s submission to the European Medicines Agency here:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003850/WC500177996.pdf

On page 8 you will find Gilead stating:

Three crystalline forms are known and ledipasvir acetone solvate is the designated commercial form. The first step for finished product manufacture involves the dissolution of ledipasvir in ethanol followed by spray-drying and thus precise control of morphology and particle size is not considered important.

Ledipasvir acetone is what Twinvir uses.

On the topic of crystalline forms most people don’t know that Gilead tested crystalline Form-I Sofosbuvir but substituted Form-II in the commercial product. See page 12 here, and note that the AUC data in the commercial product is inferior to what was trailed…..

https://www.tga.gov.au/file/6066/download

We will be publishing generic SVR results at EASL if our abstract is accepted. The are no nasty surprises in it.

Vororo, thanks so much for your comment, the chemistry is beyond my education. That scenario of generic Ledipasvir leading to relapses is a very scary one and I would love for it to be a fantasy/scare mongering. My specialist told me reaching UND would be a big test of the generic meds. Well I crossed that bridge at 4 weeks, now we have NZ’s most prominent specialist suggesting it might unravel. What about the theory that taking Sofosbuvir alone might lead to UND, which he seems to suggest?

It sounds like scare tactics to me. They haven’t tested the meds and are commenting on the possibility of them not being up to snuff. If they haven’t tested the meds it doesn’t seem to be very scientific on their part. You’d figure a knowledgable expert would do some clinical research before speaking about possible problems. Twinvir has been tested here and passed. Lesovir-C is made by Beximco and they are a drug company with FDA approval. Hmmmm. I guess we will all have to wait and see.

Hi Chapel,

I don’t remember what prof Gane said about Sofosbuvir alone and rebound after SVR. I don’t have time to listen again to the broadcast. But here is an earlier post from Dr James on log kill and treatment failure mechanisms:

https://fixhepc.com/forum/resistance/164-resistance-and-treatment-failure-mechanisms.html

The key is to zap the virus as quickly as possible with a high log kill in the first weeks. Then even if “UND” might mean a few undetectable stragglers remain, a few more weeks of treatment would guarantee that they also eventually get whacked. I imagine that if someone gets UND on Sof alone, then there would only be a risk of rebound if the UND appeared right at the end of the treatment. So this is why a dual DAA combo is always recommended, and why triple or even quad-combos (3-week treatment) is the way of the future:

https://fixhepc.com/forum/media-news/512-raymond-schinazi-rational-pricing-generics.html#6378

If 3-weeks of quad-DAA really is enough, it seems to me that this must mean reaching UND in just a few days!

So if you or Lynn are at UND after 4 weeks on dual-DAAs, it seems a pretty safe bet that you can now relax and enjoy the show…

Prof Gane’s fields of expertise are hepatology and virology not API molecular chemistry and manufacturing. He will be receiving advice about those aspects as do all experts about related but non core areas. As he is an intelligent man with some knowledge that advice will need to be plausible for him to heed it and issue a warning. But plausible does not equal correct and may be applicable in some instances but not others.

The comment about needing sophisticated facilities to manufacture Ledipasvir sounds about right. However, mentioning that in the same interview as expressing concerns about some Chinese manufactured drugs does not mean that Mesochem is incapable of producing quality Ledipasvir.

As Doctor James said by nature Doctors are conservative for our good do you think Dr James would write a script for something he didn’t have confidence in or the Compounding Pharmacies which are registered Australian Businesses would distribute meds they are unsure about They are all tested look at the massive HCV viral destruction going on here these meds are the real deal Professor Gane and rightly so is just exercising caution but also appears encouraged by FixHep C result. my take anyway.