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Thursday, 13 March 2014

On Participating in a Phase III Trial of Sofosbuvir and GS-5816 for Hepatitis C

Late last year, after my usual visit to the Hepatology Department at Auckland Hospital (actually it has the encouraging name Liver Transplant Unit, but I choose to ignore that) I received a call asking me if I'd be interested in taking part in a drug trial. I've had Hep C, genotype 3, for a long time, and I've never fancied taking antivirals. When I was first diagnosed in 1991, interferon monotherapy was a terrible thing. Most people who did it suffered greatly, very few cleared the virus (only one guy I know, and he was the only one who didn't suffer at all), and most of those who didn't clear the virus have died of liver cancer since or needed liver transplants. Later on they added Ribavirin to the Interferon, people got a bit sicker but more of them cleared. But still, those who didn't clear weren't better off for having tried. At this point I felt so sick that I couldn't have borne feeling any worse for the 6 months or a year or whatever the treatment took, and the odds didn't seem that good. Later, when I started taking antioxidants, fixing my diet, and feeling much better, I thought "hey, I'm getting things done, feeling good - why risk screwing all that up?". I learned I could control my viral load and keep my liver fat-free by restricting carbs, and that I could get rid of most of the symptoms by eating Paleo, without any longer spending a fortune on supplements.
But over the last year or so I met a few people who'd been in trials of some new drugs. They hadn't needed to take Interferon, they'd cleared the virus, and they couldn't tell me anything bad about the treatment. That sounded promising. I've always thought that "fighting the dragon" was a foolish idea. HCV has some immunosuppressive effects that protect the liver, together with the virus, from the host immune response to some extent. You don't necessarily want to lift that protection without good reason. The virus is still cytotoxic anyway, it's not doing you any favours, but it's mainly the host immune response (often triggered by things like LPS from the gut) that causes cirrhosis. As I put it, "I'm not going to fight the dragon till I see two strong guys holding it down". And it seemed that day might have come. I thought, I'll go into this trial, and if I don't like anything about it, I'll just pull out, wait a bit longer. At best I'll clear the virus, at worst, well, knowledge has its own value to me.
The trial I went into was called VULCAN

Live Long and Prosper
VULCAN is a Phase III trial of Sofosbuvir (NS5B RNA polymerase inhibitor) and GS-5816 (pan-genotypic NS5A inhibitor), with or without ribavirin. Ribavirin might have been a deal-breaker for me - the people who got it suffered fatigue and depression - but I was lucky. I was randomised to receive Sofosbuvir (400mg) and the lowest dose of GS-5816 (25mg instead of 100mg), one pill of each once daily, and the trial was only to last 8 weeks. Would this be long enough? Would the low-dose GS-5816 be enough? Would my low-carb, high-fat diet help or hinder the drugs?
The interesting thing about GS-5816 is, that the viral protein it targets, NS5A, isn't just needed for replication, it's also one of the viral products responsible for HCV interfering with metabolism.

For example:
 
The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus RNA genome is shown here to induce the activation of NF-κB and STAT-3 transcription factors from its cytoplasmic residence via oxidative stress. NS5A causes the disturbance of intracellular calcium. Ca2+ signaling triggers the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-κB and STAT-3 into the nucleus. Evidence is presented for the constitutive activation of STAT-3 by NS5A. In the presence of antioxidants [pyrrolidine dithiocarbamate (PDTC), N-acetyl l-cysteine (NAC)] or Ca2+chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-κB and STAT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis associated with the viral infection.
It might be good to have a drug that would intercept those effects, even if it didn't kill the virus. GS-5816 might act as an antioxidant and antiinflammatory in people with active HCV infection. Unlike interferon and ribavirin, this was a drug that might 
potentially make you feel better, independent of its antiviral effect.

Anyway, I nearly pulled out of the trial when I got my information kit by email. GS-5816 had been tested in humans alright - for 1-9 days in healthy volunteers, and for 3 days in volunteers with HCV..
Here is the email I sent back:

after careful consideration I have decided not to take part in this trial. However I still want to be considered for future trials.
My reasons, in the event they may be useful to know, are as follows:
1) Efficacy. I understand from my reading that combinations including sofosbuvir have already proved effective in Gt1. It is reasonable to expect that they will be similarly effective and safe for Gt3. However this study appears to be trialing a novel combination to see if it is effective.
2) Safety. The novel drug GS-5816 has, if I read correctly, not been tested for longer than 9 days. 

I have survived with chronic HCV infection since before 1991 and for the last few years have been able to thrive and recover my health. I would like to clear the virus, am prepared to take some risks to do so, including entering a Sofobuvir trial, but I only want to do this once. It appears to me from the studies your group has already published, and from the people I have met who have taken part in them, that there are Sofosbuvir combinations that, combined with my circumstances, would give me an excellent change of clearing HCV safely. It seems inevitable that these will be tested in a Gt3 patient group in the near future, and I would like to be considered for a trial of this description. If not, then I am confident I can manage my condition until the best product makes it to market.
Thank you for including me and for the very interesting reading material.


Well, they rang me up right away and talked me into coming in to see them. The information was out of date; of course people had since taken GS-5816 for long periods, because the trials were up to phase III now. And if anything had gone horribly wrong, Gilead would have cut their losses and moved onto the next drug. And I was impressed by how much the study doctors knew. They were virologists, not hepatologists, and they had worked out how to target the virus without involving the host. The drugs were specific for viral replication products, not for any part of my metabolism or immunity. That was what I wanted to hear.
I knew I wouldn't be allowed to take herbal medicines, but I wasn't prepared for the reason why. Because they might work. Now, herbal meds don't work that well against HCV. But neither do Sofosbuvir or GS-5816, taken on their own. It's only in combination that they deliver a 1-2 sucker punch. So any herb, with its weak effect, could still skew the result when combined with these guys. One or two, like St Johns Wort, could interfere in other ways. I was taking grape seed extract (OPCs) so I stopped that. I had to list whatever else I was taking:

Zinc 30mg as gluconate
Magnesium 150 mg as chelate
B2 25mg
Taurine 1,000mg

I was meant to keep taking these for the next 5 months (8 weeks treatment plus 12 weeks to SVR12) but stopped things I couldn't afford or didn't need any more, like the taurine. I used things like vitamin C and probiotics for short periods when I had a good reason.
They gave me an ECG, multiple blood tests, and sent me off for a fibroscan. The score was 7.4 which is moderately scarred (normal is under 5, cirrhosis is over 12). The blood tests were so hard, what with me having no normal veins left, that I was left out of the pharmacokinetic arm of the study.
My viral load at the pre-trial screening (22-Oct-13) was 600419 (log 5.78) which is fairly high for me, my ALT was 174. With a month to go before the trial started, I decided to get more serious about LCHF. Having a regular series of blood tests due meant I could check out whether going very low carb again would make any difference.
On the day the trial started (18-Nov-13), before the first dose, I gave blood again. Viral load 27167, log 4.43. That's the drop I associate, from previous experience, with being in, or near, ketosis, that is, under 50g carbohydrate/day (previous test was more like 100-150g/day). And, my ALT was 30. That was a big drop, lowest it had been since Hep C diagnosis in 1991. I didn't put that down to ketosis - more likely it was due to the zinc, which I'd started taking about 2 months earlier, based on this paper. It's also possible that stopping the grape seed extract helped. Phytochemicals that are hepatoprotective can sometimes become hepatotoxic. This happens with green tea extract, and I wouldn't rule it out with OPCs, which are chemically similar. Anyway, I started taking the Sofosbuvir and GS-5816.

I went back a week later (25 Nov 2013) - my viral load was  less than 15 (log less than 1.18) meaning it was too small to measure by PCR. And my ALT and AST were 18. And that's the whole story really. My viral load stayed below 15, until the end of the trial (EOT) when it was undetectable (I missed the week 6 test so had no results between week 3 and the EOT. At week 4, which I read at EOT, VL was still detectable at under 15. So I had to wait till week 10, 2 weeks after EOT, to actually find out that I'd cleared the virus, or it became undetectable, sometime between week 4 and week 8).

At week 8, EOT I had another fibroscan. 5.5, down from 7.4. During the course of treatment my scarring had significantly regressed. That is amazing.

Side effects? I had a few, but then again too few to mention. For the first week my skin felt dirty and gritty, and my girlfriend said I was over-sensitive. Maybe true, but I think there was some confirmation bias involved. She hadn't liked me jumping into this experimental drug trial without really consulting her, and I can't say I blame her. I'm sorry I was pigheaded enough to put her through that anxiety. After that, I had a sore throat, cough, a bit of laryngitis, and a swelling under my tongue. And I could taste the drugs all the time. But after week four, nothing at all. The last 4 weeks was a breeze. And, from the start, I was sleeping better, and my energy level was good. There were not serious side effects and I never considered stopping the trial. And I say that as a total hypochondriac who couldn't stand to take aspirin or antibiotics for 8 weeks.

It's week 8 after treatment, so in another month I'll know about SVR12. I have met one person who relapsed after successful treatment on a similar combo, a very unusual outcome so far, but I've had all the advantages they didn't have. But you know, if this didn't work out, I would have no hesitation about trying a longer course, a higher dose, a different combo. It's been no sweat. Amazing. Pharma made something that worked, cured a disease that, as far as I'm concerned, had no cure before.

It can be done.

38 comments:

Peter said...

Cool!

M said...

I just wanted to say that I'm very happy that you have found a treatment that appears to be working, and that I hope you will make a full recovery.

Spittin'chips said...

Excellent stuff, George. Well done.

Tucker Goodrich said...

Fingers crossed! Although you'll have to find a new blog topic... ;)

Indy Jill said...

Excellent news George - you're such a brave person, even more so if you really do have hypochondriac tendencies (I can relate).

Fingers crossed that this turns out to be the cure you've been waiting for.

Angelo said...

I am so happy for you bro. I have been wanting to sit down and read your blog in detail and really consider your Paleo (perfect health diet). I will be doing that and I wish you the best of luck with a SVR.

George Henderson said...

Thanks everyone.
There were 2 symptoms that have improved completely since ding the trial:
1) gall bladder pain and URQ tightness
2) leg cramps. Leg cramps can be caused by cirrhosis
http://www.ncbi.nlm.nih.gov/pubmed/8591851
but can be relieved by zinc
http://www.ncbi.nlm.nih.gov/pubmed/10682870

Spittin'chips said...

Excuse my ignorance, George, but what's the story with Taurine? i.e why did you take it and why don't you need it anymore?

Cheers.

shtove said...

Interesting to see you so enthused.

I've been dropping in for 18 months or so and always find you digging up new information. Plus I liked your diet description, after Peter gave his.

I hope you can give us regular updates on this.

All the best.

Jack Kruse said...

Awesome news George.

George Henderson said...

@ Spittin'chips

I was taking taurine for gall bladder discomfort, which cleared up when the virus did.
Also on the principle I discussed in the NASH and cholesterol series, that unesterified cholesterol is a menace, and taurine gives it something to bind to. As my inflammatory markers (ALT, AST, ferritin and fibroscan) were higher than I liked, I thought this worth a try. Taurine is such innocuous stuff that they feed it to kids with their caffeine and sugar shots.

Dianne Kennedy said...

Do you think having a low viral load and inflammation markers pre-trial assisted with your excellent response?

lissjeanrosa said...

Fantastic news for you George...Ive been watching your progress with interest being a fellow HCV 3a and have tried all around our own nation to get on a trial. However I don't fit the strict criteria and at cirrhosis level are having to start SOC next month for 48 weeks. The only consolation I can concur from this is that I go into this tx with a great deal of knowledge now..thanks to your blog and others research. And should I fail the early marker load drops...I start at 6.4log....then the new drug combos are a welcome backstop down the track. Thanks for all the info and happy liver days ahead :-)

George Henderson said...

Here's the report from the 12-week phase 2 trial:

A second study, Study GS-US-342-0102 (Oral #111), is an ongoing randomized Phase 2 clinical trial in which treatment-naïve, non-cirrhotic patients with genotypes 1-6 HCV infection received a 12-week course of SOF plus the pan-genotypic NS5A inhibitor GS-5816. Patients received SOF 400 mg and either GS-5816 25 mg (n=77) or GS-5816 100 mg (n=77). In this study, 94.8 percent (n=73/77) of patients receiving the 25 mg dose of GS-5816 and 96.1 percent (n=74/77) of patients receiving the 100 mg dose achieved SVR12.

“The results of this study of sofosbuvir with a new pan-genotype NS5A inhibitor demonstrate the curative potential of this combination,” said Gregory T. Everson, MD, Professor of Medicine and Director, Section of Hepatology, University of Colorado, Denver, and principal investigator of Study GS-US-342-0102. “The combination was not only effective across all genotypes and patient subgroups, but also was well tolerated. These results warrant additional study in future trials, with the hope of providing a potent, pan-genotypic combination with few side effects and a high chance for cure.”

The most common adverse events occurring in more than 10 percent of patients were fatigue, headache and nausea. There were no treatment discontinuations due to adverse events, and no evidence of treatment-related laboratory abnormalities.

Additional information about ELECTRON2 and GS-US-342-102 can be found at www.clinicaltrials.gov.

Silvia Price said...

I don't think that fibrosis can regress that quickly. Did you have both Fibroscans while you were fasting? Because having a meal before the fibroscan causes some liver stiffness.

George...if you fail and want to retreat with a higher dose, have your doctor call the study's medical director and ask whether they would consider doing an extension study to retreat those that failed with a higher dose.

Tell them they could then prove that their med doesn't create resistance and people can retreat if for some reason they have to interrupt meds, etc.

The drug company may go for it because they don't have lots of time to do studies. They have to hurry to get their drug on the market. You're a compliant patient, they wouldn't have to redo all the initial testing which would save them money and adding an extension arm is easier to pass through the IRB than starting a new study for non-responders.

Or your doctor can ask them for med for you under "compassionate use".

Silvia Price said...

I don't think that cirrhosis can regress that quickly. Did you have both Fibroscans while you were fasting? Because having a meal before the fibroscan causes some liver stiffness.

Silvia Price said...

To lissjeanrosa:
Taking Metformin would increase your chances of SVR.

George Henderson said...

It's official; SVR12.

shtove said...

So no sign of the virus?

Help us out with some smilies.

annlee said...

http://www.medicalnewstoday.com/articles/275484.php
Currently, doctors treating hepatitis C patients with cirrhosis (liver scarring) can only offer treatments that rely on the drug interferon, which unfortunately, only works for less than half of patients. Now, a new study found that an interferon-free combination of drugs was safe, well tolerated and cured over 90% of 380 trial patients with liver cirrhosis in 12 weeks.

Apparently the combo of 4 drugs had very encouraging results.

Michael Sheldrick said...

George:

Love the blog, but don't have your email, so I don't have another way to send the following item to you. I assume you moderate comments. In general, I'm sure you are interested in CHC drugs. In particular, Sovaldi. It's stratospheric price has attracted attention here in the U.S.

http://www.sfgate.com/health/article/Cost-of-Gilead-s-hepatitis-C-pill-Sovaldi-spurs-5398315.php




Silvia Price said...

Your good news made me cry. I'm very happy for you.

I have good news of my own. I finally found a study that proved hepatitis transmission to MILITARY RECRUITS from a jetgun used to vaccinate them. Plus a beautiful paper that proves that not only is dose and route important in the kind of reaction an injection creates but also the SPEED at which it is given.

George Henderson said...

Michael, I'm sure that within a year or two there will be several copy-cat drug combos competing with Solvaldi, and prices will tumble.
Think of the benzodiazepines; first Librium, then Valium, after that the deluge of similar drugs with essentially similar effects (I can name about 20 of them, having taken every single on of them).
The high price will only last as long as Gilead have the advantage of being alone in the field.

George Henderson said...

Silvia, I know how long you've been looking for that - well done.
All scans were done when fasting.
Even if the first scan's 7.4 was inaccurate, the one a year or two before that was 6.4, and I had one done more recently (in week EOT+12) and it was 5.3, confirming the earlier score was accurate.
I blame zinc 30mg/day, plus clearing the virus.

shtove :)

constance weinholtz said...

Wonderful news George, i am like you, i have been waiting for the right treamtent since 1995 and doing alternative treatments... waiting for led/sof in the fall to be approved peace, connie

George Henderson said...

http://www.aidsmap.com/Sofosbuvir-new-GS-5816-NS5A-inhibitor-is-effective-against-hepatitis-C-genotypes-1-6/page/2847422/

This study included 154 previously untreated hepatitis C patients without liver cirrhosis. About 60% were men, most were white and the mean age was approximately 50 years. Nearly 30% had HCV subtype 1a, which is considered most difficult to treat. In addition, 7% had HCV subtype 1b, 14% had genotype 2, 35% had genotype 3, 9% had genotype 4, a single individual had genotype 5 and 6% had genotype 6. About one-third had the favourable IL28B CC gene variant associated with interferon responsiveness.

Participants in this open-label study were randomly assigned to receive 400mg once-daily sofosbuvir plus either 25mg or 100mg once-daily GS-5816 for 12 weeks. They were followed after finishing therapy to determine sustained virological response, or continued undetectable HCV viral load at 12 weeks post-treatment (SVR12), which is considered a cure.

SVR12 rates for people with genotype 1 were 96% using the 25mg GS-5816 dose and 100% using the 100mg dose. For people with genotype 2, the corresponding rates were 91% and 100%, respectively, while the cure rates for genotype 3 were 93% in both dose arms.

Turning to the less common genotypes – where the numbers were too small to draw meaningful conclusions – genotype 4 SVR12 rates were 100% and 86%, respectively, in the 25mg and 100mg dose groups. The single genotype 5 patient and all genotype 6 patients in both dose arms were cured. Across all genotypes, overall SVR12 rates were 95% using the 25mg dose and 96% using the 100mg dose.

Looking at the patients who did not achieve SVR12, three people relapsed after completing treatment: one person with genotype 1 taking 25mg GS-5816, one person with genotype 3 taking 25mg and one person with genotype 3 taking 100mg. In addition, one person with genotype 3 was a non-responder during treatment, one person with genotype 2 died during follow-up and one person with genotype 3 was found to be re-infected.

Genetic sequencing revealed that about one-quarter of people with genotype 1-3 had pre-existing resistance-associated NS5A viral variants. Among them, virological failure was more likely using the lower GS-5816 dose (5% vs 2%). However, most people with pre-existing variants were cured.

Treatment with sofosbuvir and GS-5816 was generally safe and well-tolerated. Four people had serious adverse events, three of them in the 25mg dose arms. However, no one discontinued for this reason. The most common side-effects reported by at least 10% of participants were fatigue, headache, nausea and constipation. No one developed anaemia, a side-effect often seen with ribavirin.

Fran said...

Hi George, Im Fran. I am Geno type 3. 4 weeks ago I began the Phase 3 trial for the sofo/GS5816 combo. one pill. I enjoyed your blog info. Im believing for SVR12 also. My drug time is 12 weeks with Dec 19th being the last dose for me. I do have to admit, I must be an anomaly. I have had various side effects. The most noticeable are constant leg twitches, I am on a potass and mag supplement daily and get checked regularly. I can, when my potass is low, do have twitches and irregular heart beats. But, I have regular blood draws and each time my potass and mag are good. The twitches are prominent. I also experience flickerings all over my body of the muscles. Spasms also and after a tough day of these sides I am sore and achy the next day. I have a had so much blood drawn to keep checking the levels, that i feel like a pin cushion. All my labs are good and Trial Dr. said there is nothing indicating that there is any damage or problems with my kidneys, etc. So I am chalking it up to side effects. A friend of mine who is an advocate for HepC said it is possibly neurological and will pass after the treatment is finished. I also have wanted to quit quite a few times. These sides did cause a panic attack and now if necessary I can take xanax. IF necessary. Im not big on taking drugs at all. My body always responds weirdly to meds so I avoid them as often as possible. I did get headaches, fatigue too. I am hoping that these 12 weeks will be worth it. I appreciate what you wrote. It gives me hope. I think I can make it through this for the reward. Oh I am on the 400/100 mg dose. Is there anything you are aware of that could help with the twitches...etc? Vitamins? I will hang tough though. I want this so badly. I am 56 and have fibrosis2. I wont know how to find your answer. Because someone posted this on my Hep C support group on FB. Could you "friend" me on FB? my name is Frannie Ford. my picture is a lady in a white sundress facing a mountain with my arms up in the air. Thank you. And Thank you for your post on this subject. Gives me understanding and hope!

George Henderson said...

Hi Fran,
This is the first report of this side effect I've seen with this combination; nausea, indigestion are fairly common, photosensitivity is possible. I definitely noticed something for the first month.
I can't think of much - massage and/or yoga would probably be the best thing. I found that zinc gluconate really helped with leg cramps. Maybe pyridoxine would help (about 10mg) if you don't take it already, indeed a B complex vitamin or multivitamin, doesn't have to be high dose, maybe better if it's not.

shend said...

After reading this it is the first time I am considering going back to the Hep C doctor. It's been a while and know I am in bad shape.

George Henderson said...

Here, I think is the trial report, and I'm the nut in the Sof + 25mg GS-5816 -
arm with a respiratory infection.
Pretty good results here.

http://www.natap.org/2014/AASLD/AASLD_13.htm

Sarah Burnage said...
This comment has been removed by the author.
Sarah Burnage said...
This comment has been removed by the author.
George Henderson said...

Hi Sarah,
I think vit C is useful, but just as part of an antioxidant regime. It's worth trying a higher dose at first to see what happens but this can cause problems (diarrhea and UTIs) if you overdo it. NAC is cheaper than glutathione and probably just as effective. Take it with a mixed-antioxidant supplement. l-carnitine is good too. I think zinc gluconate was very helpful to me at 30mg (also stopped leg cramps).
Definitely, take probiotics - this will really help.

This study used a low carb diet to reduce fatty liver, which sounds like part of your problem (especially if you have geno 3, but also with other genotypes). Reversing fatty liver with low carb doesn't need weightloss.


http://www.diabesityinpractice.co.uk/media/content/_master/4311/files/pdf/dip4-3-102-8.pdf

Foods I think are especially helpful are coconut oil and butter or ghee. Olive oil is OK too. Avoid other vegetable oils - get all the PUFA you need from a little nuts, seeds and fish (actually, eat a few brazil nuts every day for the selenium, that'll take care of your PUFA requirements too). Eat lots of green veges - whatever you can get, I like okra, spinach, leek, methi, broccoli - cooked in coconut oil or butter. Eat some unprocessed red and white meat, only eat cheese if you tolerate it, and above all -
avoid sugar, as sugar, honey, agave, coconut sugar, dried fruit, fruit juice - whatever. Don't eat this stuff unless or until you can use it very occasionally in tiny amounts.

Good luck Sarah, please let me know how you get on.

Sarah Burnage said...
This comment has been removed by the author.
jaza said...

Just looking here in case someone else has the generic drugs for treatment via Greg Jefferies from India.
Wanting to know about taking them with food or high fat as I have previously read.
Thanks.

George Henderson said...

Sorry to take so long - yes all DAAs as far as I know should be taken with fatty food. This may be more important with generics as they are not formulated to disperse so well (though data I've seen suggests there is probably little difference)

jaza said...

Thanks George - I will start taking it with nuts. I'm noticing eating high fats or rich food - (e.g. today the coconut cream in pumpkin soup) - I feel slightly nauseas - and yes I do have fatigue. Im also taking mag phos but still having lots of cramp at night so might look at the zinc.

George Henderson said...

Zinc is excellent for cramps related to liver disease. Mag Phos is not a good magnesium, Magnesium citrate is best, amino acid chelate (= Mg aspartate) is good; zinc gluconate is the best zinc form to supplement. I was taking both these during my Tx and I think zinc especially lowered enzymes and helped scarring resolve quickly during Tx.