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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.