Of course, I am hopeful that my hep c will clear with regular combo therapy. However, I recently came into contact with a girl from Romark whose mother has Hep C. Romark is trials both with Alinia in conjunction with interferon alone, as a monotherapy by itself, and as an adjunct to the the combo therapy. Alinia is an already on the books drug FDA approved for treatment of giardia, which I believe is a parasitic intestinal disorder. Which means that until the FDA approves it. treatment of Hep C outside the studies would, I suppose, be off-label. I am posting this info for those who relapsed after first tx to see if anyone else has heard about this tx/drug.
Alinia has been discussed here a few times.
Some think why bother there are better drugs around the corner.
Me I like the sound of it. Has something to do with the fact that its anti HCV qualities were found accidently.
You are right about Alinia being used to treat Giiardia and other intestinal parasites. Its found in the water supply btw.
I dont like what I here about the trials of it though. Mono anything doesnt work. The virus has a habit of building resistance to any single drug.
As you are still in the Acute stage your chance of SVR is excellent with the current drugs.
sorry, didn't know it had been posted before. I saw that it was being mono tested, but the good thing is they are now testing it with the combo therapy for those refractory to tx. Now obviously I also think my chances are excellent for clearence with combo alone due to being acute and low viral load. However, I had posted this for those who aren't in my shoes and ALSO just because I am looking down the road for myself just in case.
I was also thinking that since God knows how long it takes FDA to pass these things since this drug is already approved for one use, it is also worth mentioning that this drug is approved for another purpose. My mind wanders way ahead and I think of crazy things like, I could get my doc to give it to me for one thing and use it for another, just stupid stuff I know.
But, I don't like mono-therapy anything either. I am in absolutel agreement with you there. The girl my best friend ran into is a neat girl though my best friend's online college class in one of her courses. They were just all sharing one Unique thing about themselves and this girl - first name Grace - I won't for her confidentiality say her last name was saying she was excited about the new trial they are doing with the combo therapy plus her own company's Alinia because her own mother has entrenched Hep C that is refractory to the combo tx alone and since her mom is a family member of someone working for romark (her own company) I don't believe she was able to get her into her company's trials (Grace works for Romark). I have since spoken with her via email (as soon as my best friend found out about the research she got my permission to put us together, and I of course said yes [of course she emailed her, she didn't like post it in the class or anything]).
Anyway, very nice girl for a pharmaceutical company person, I guess I was expecting somebody really cold or something but she really believes in their work or seems too. I wanted to know if anyone else had heard about this drug and if anyone was in this study here but I didn't know it had been posted about before. I guess I can search archives on this site? Duh? Sorry lol
I think I have read just about every study on hep C that has been published in the past 10 years that I can find online but I had not heard of this particular drug prior to talking with her. It's a pretty interesting subject just from an academic standpoint, even if I weren't now an acute patient myself. I pretty much address any health issue in this manner (yeah. that's right, I'm a control freak lol ;)~ I know, I know - It just helps me FEEL in control the more knowledge I have even though I am not really IN any more control, you know?)
I think the Alinia research certainly looks promising. And it will be interesting to see the results of the STEALTH C-1 trail (though it is comprised striclty of geno 4's). The US Phase II (STEALTH C-2) is of geno 1 non-responders to current SOC - a tough group to re-tx, so the results from this will be very interesting (and skewed downwards, most likely, when compared to a tx-naive group). Perhaps they will a a tx-naive arm in any Phase III.
Also interesting is that they will start the patients off on 4 weeks of mono-Alinia, before moving on to full triple-tx. This, too, could very well skew the results downward given that hitting the virus up-front with all three at once would seem - in practicality - to be have the most potent approach.
yeah, I'm also in the alinia fan club. Any drug that's already cleared FDA hurdles, has minimal sides/toxicity and interferes with the HCV replication cycle looks interesting regardless of its monotherapy eradication potential.
Abstract 178 of the AASLD contains the results of a 48wk SOC vs 48wk Alinia plus 36wk SOC study. End of Treatment results are given as % 10Iu PCR negativity. 50 vs 93. 120 pt.Geno4. No added sides from Alinia. Results are quite astounding.
Abstract 178 of the AASLD contains the results of a 48wk SOC vs 48wk Alinia plus 36wk SOC study. End of Treatment results are given as % 10Iu PCR negativity. 50 vs 93. 120 pt.Geno4. No added sides from Alinia. Results are quite astounding.
Well hot damn!! I've heard about alinia, but only dribs and drabs in the background. I never had any idea it may have the kind of potential suggested in the references above. And really good to hear from you HR, thanks for the update! Man, Jeffrey Boger must be poopin' his pants right about now if this thing is what it looks like it might be. Got to keep an eye on vertex stock, I suspect this won't be good for it. If this doesn't turn out to be some kind of false alarm, it's history in the making!
Travelmom and dointime??? Take a gander at this stuff!!!
Good to see you contributing again. Do you have a link to the study, or to the AASLD abstracts?
I'm assuming that "90%" was a SVR rate from 48 weeks of Alinia followed by 36 weeks of SOC? Did they have a 24 week SOC group?
We need all the help we can get, but in weighing one treatment against another (of course they may end up combined) where I come out is that the least amount of time exposure to interferon the better. The thing that appears to stand out about Teleprevir is that it appears to work with only 24 weeks of SOC, and according to something recently posted here -- even less exposure to interferon (down to 12 weeks) may be possible for those with a very rapid viral response.
also, in case anybody is wondering and I think this info is useful, don't think he put it in his post, HR told me that it really doesn't matter what genotype you are, the Alinia works in a different way then SOC...
unless he's going to contribute again, which would be great, he told me that this was sent out to docs, whatever, and that it isn't widely published as of yet...and I think, don't quote me, it was the inverse, with the Alinia starting after SOC...hopefully, he'll come back on to answer you more thoroughly...
It makes more sense that they would have started with Alinia, but also of interest is whether these are SVR results and whether less than 36 weeks of SOC was tested in conjunction with Alinia and if so, what were the results. Hopefully HR will contribute cause I don't have as much time to research things out myself these days.
3arms : Randomized. First arm SOC 48wks. Second arm 12 wk Alinia mono then ADDED 36wks of Alinia +Peg2a. Third arm 12 wk Alinia mono then ADDED SOC (peg+riba) plus Alinia for 36wks. Results are End of Treatment response (EOT), defined as PCR negativity immediately after EOT. No SVR data available yet.
No link possible, you have to be subsribed to hepatology, this might change in a few days.
Thanks. But what's confusing is what appears to be 50% EOT negativity for SOC per your previous post. 50% is the approx SVR rate for SOC, and I would imagine that the negative EOT negativity rate would be closer to 80% for SOC with 30% then relapsing after the treatment drugs are stopped.
Yes, you might expect a higher EOT from SOC. I just quoted the facts as displayed in the abstract. There will be a presentation of this trial on Tue, Nov 6 in the Hynes Auditorium at 11:15.The auditorium will have questions like this to the presenter.
thanks for pointing this out. It does indeed look a very promising addition to the tool bag. The center where I see a liver specialist is one of the recruiting centers for the US study and I asked about participation but was turned down as a relapser rather than a non-responder. Given my interest in combo tx I have to ask why at this point wouldn't that study not also include a vx+soc+ntz branch?.
Anyway, it also looks like progress has also been made in determining the mechanism of ntz's anti-viral action. It seems surprising that the non-naive results are so different from the naive given that blocking viral protein synthesis is presumably independent of ifn resistance. The 50% SOC/EOT does looks a bit strange - I wonder is that just reflects the fact that these are ITT numbers and the completion stats are not given. The abstract and data below , hopefully with just enough mods to avoid copyright infringement:
Nitazoxanide (NTZ), a thiazolide anti-infective agent approved in the United States for treating emerging intracellular protozoan infections, blocks viral protein synthesis at a cellular level by selectively inhibiting dephosphorylation of eukaryotic initiation factor 2α (eIF2α). A randomized controlled clinical trial was conducted to evaluate the efficacy and safety of NTZ added to peginterferon α-2a (PegIFN) plus ribavirin (RBV) or PegIFN without RBV in treating chronic hepatitis C genotype 4.
Methods. 120 patients with chronic hepatitis C genotype 4 were enrolled in the trial at two centers in Egypt. Liver biopsy was obtained from each patient before enrollment. Patients were sequentially randomized to one of three treatment groups: (a) PegIFN-RBV for 48 weeks (standard of care),
(b) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN for 36 weeks, and
(c) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN-RBV for 36 weeks.
Eleven interferon-experienced patients were allowed to be enrolled in each of the two NTZ groups. NTZ was administered one 500 mg tablet twice daily with food; RBV was administered 1000 mg (weight <75kgs), or 1200 mg (≥75 kgs) daily in divided doses; and PegIFN was injected by clinical investigators once weekly (180 μg). Evaluations performed every 4 weeks during treatment included physical examination, standard laboratory hematologic and chemistry tests and determination of HCV viral load by RT-PCR. The primary endpoint of the study is SVR (HCV RNA <10 IU/mL 24 weeks following end of treatment). Secondary endpoints include RVR (HCV RNA <10 IU/mL after 4 weeks of combination therapy), EVR (≥2 log10 drop in HCV RNA after 12 weeks of combination therapy) and ETR (HCV RNA <10 IU/mL at end of treatment). Analysis is intent to treat.
Results. Baseline viral loads, BMI, fibrosis, age, sex and other demographic and disease-related characteristics were similar across the three groups. RVR, EVR and ETR rates are presented in the table below. Adverse events were similar across the three treatment groups except that the rate of anemia was significantly reduced
in the group that did not receive RBV. Conclusions. The addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates compared with PegIFN-RBV therapy without increase in adverse events. Patients are being followed to evaluate SVR rates. Further trials are being conducted in the United States in patients with genotype 1.
This suggests that genotype 4 is *more* responsive to treatment than genotype 1.
http://tinyurl.com/2xjbty Specificiallly 77 per cent EOT response and 68 per cent SVR with SOC. That puts it closer to genotype 2 in terms of response although apparently genotype 4 is understudied.
It will be interesting to see full-text on the study in question as to patient population, ribavirin dosage as well as compliance rates, etc. While I have no knowledge, I'm guessing the trial was held out of the country due to the low numbers of genotype 4's in this country.
JOHNS HOPKINS TEAM FINDS "ANCESTRAL" HEPATITIS-C VIRUS AT THE ROOT OF EVOLUTION IN ACUTE AND CHRONIC INFECTIONS
-- Scientists discover how virus evades immune system in acute and chronic infections; new vaccines may result
Researchers at Johns Hopkins have uncovered how a majority of the genetic changes in the hepatic-C virus, the most common cause of liver disease, allow it to evade the body’s immune system during infection. Hepatitis C infection can lead to cirrhosis, cancer and even death. In a series of experiments that describe the virus's transition from an acute to chronic infection, the Hopkins team found that one-half of the virus's changes in its genome are in sites under attack by the body's immune system. As the virus evolves and these changes weaken the body's immune response, a second set of changes at other sites in the genome are reverting back to an "ancestral" set of amino acids.
"We think this piecemeal exchange is helping the virus evade the body’s immune system," says study investigator and infectious disease specialist Stuart Ray, M.D., an associate professor at The Johns Hopkins University School of Medicine. "In a newly infected person, the virus may need to adopt new mutations to escape recognition by the immune system's T cells, which fight infection, but it may need to lose the mutations that had protected it in someone else. Despite pressure to change, the virus is always is restoring its shape."
The Hopkins findings, published in a pair of studies in the Journal of Experimental Medicine this week, are believed to be the first description of the precise genetic changes taking place in the virus during the acute phase of infection, when hepatitis C initially escapes the body's defenses and establishes itself in the body. As the infection moves into the chronic stage, the immune response becomes weak and less effective, but until now, no one could explain exactly why.
A second, related experiment produced similar findings when the Hopkins team partnered with researchers in Ireland to perform what is believed to be the first comparison of genetic changes across multiple genes in strains from chronically infected people to the original strain that infected them.
Ray, who served as senior investigator on the first study and led the second, believes the newly identified ancestral component of the viral genome, called a consensus sequence, could serve as the basis for development of a vaccine that is effective against both acute and chronic infections, thereby stemming the epidemic that currently afflicts more than 170 million people worldwide, including 3 million Americans.
"Hepatitis C is extremely difficult to treat if it becomes chronic," says infectious disease specialist Andrea Cox, M.D., Ph.D., an assistant professor at Hopkins who was lead author of the first study. "While approximately 30 percent of patients have a strong enough immune response to rid themselves of the virus during the acute phase, and current treatments are 90 percent effective at treating any remaining acute infections, these treatments are only 50 percent effective against chronic infections, which otherwise persist for life and can cause death."
According to Cox, the hepatitis C virus naturally mutates, or alters its genome, very rapidly. Its strains have two to three times more genetic variability, for example, than HIV, the virus that causes AIDS, and hepatitis C reproduces more than 100 billion times per day, 100 times faster than HIV. Compounding the problem, the infection is asymptomatic in the acute stage, making it less likely that diagnosis will be made early, when it is easiest to treat.
Conventional wisdom, the researchers say, was that the large numbers of mutations were simply random in the virus's ever-changing genome, but the new study suggests that Darwinian genetic selection is at play. That is, the virus's genome changes in ways that make it more reproductively "fit" in the face of each immune system it encounters, changing what is must to evade the immune system in one host, then restoring itself when the pressure is off.
What Ray's team found when the immune response weakens was that the virus naturally mutates toward a set of 3,000 common amino acids, what the researchers considered the virus's most preferred state. During the acute phase, Ray says, the virus is under severe pressure from the immune response and forced to drift away from the consensus sequence, using mutations to evade the immune response. However, the drift was reversible and, once the virus successfully evaded a particular immune cell, its amino acids reverted back to the consensus set.
To assess the genetic changes in the early stages of infection, the researchers decoded, or sequenced, the virus's genome, made up of RNA, which is very similar to the more widely known DNA that makes up the genome of most organisms. The RNA was gathered from eight newly infected patients in Baltimore, Md., all of whom were offered treatment and were participants in a larger study of infectious diseases in intravenous drug users. The sample group was unusual, allowing analyses before and during the early stages of infection. One patient self-recovered, while the rest proceeded to chronic infection.
Using advanced blood-sorting techniques, the Hopkins team extracted millions of immune system cells, including the system's principal fighters, called T cells, from blood samples taken between 30 days and six months after infection, when the body's initial immune response kicks in and subsequently peaks.
Immune responses were mapped using a series of more than 500 overlapping synthetic peptides, or strings of amino acids whose code was already known. This allowed the researchers to compare changes observed in the RNA sequence to corresponding shifts in the body's immune response to the infection.
When specifically recognized by T cells, the peptides trigger production of interferon gamma, a protein that acts as a signal to many other immune cells to respond to a new infection. Reductions in the production of interferon gamma would indicate, the scientists say, that the immune system was weakening in its response to the virus's mutations.
After analyzing the genetic changes in the sites, called epitopes, where the T cells specifically bind to the virus, the researchers found no changes had occurred during the one year of follow-up in the one patient who self-recovered. However, in the remaining seven patients, there were changes in 69 percent of T-cell epitopes, showing that the virus had mutated at key locations necessary for chronic infection to proceed.
Additional analysis showed that changes in T-cell epitopes were 13 times more frequent than changes in the remaining genome of the virus. The researchers examined the binding ability of T cells obtained early in infection to recognize 10 viral peptides known to have changed during the first six months of infection. Eight showed severely reduced capacity to stimulate production of interferon gamma, offering confirmation that the virus was mutating to evade the immune system.
Analysis of the viral RNA in the blood of seven patients with chronic infections revealed that eight of 16 changes in genome matched to the consensus sequence, confirming the presence of selective evolutionary pressure toward restoration of an ancestral form of the virus.
In the second study, using blood samples collected in Cork, Ireland, the researchers compared the genetic makeup of the virus in 22 chronically infected women to the original strain that had infected them more than 20 years before. The women were among hundreds accidentally infected in 1977 by a blood product tainted with hepatitis C, providing the researchers with unique access to the source of the infection, which came from a single donor unaware of having the illness.
Using computer analysis techniques developed at Hopkins, the scientists mapped these changes against the genetic makeup of the women's immune response. The researchers found that when viral mutations were clustered in epitopes specific to each woman's immune system, the changes were directed away from the consensus sequence, suggesting immune escape. However, when mutations were clustered in epitopes that were not specific, the mutations were reversions back to the consensus sequence.
When the individual genome changes in each woman were mapped on a grid, each woman formed a unique cluster indicating individual, evolutionary selection. However, some of the changes were shared, suggesting convergence, which would not have occurred had the virus simply mutated at random.
"Our results raise the possibility that a hepatitis-C consensus sequence could be the best practical option for a vaccine," says infectious disease specialist David Thomas, M.D., a professor of medicine at Hopkins who served as senior author of the study of Irish women. "If we can focus vaccine development on the common genetic element in chronically infected patients, then we may be able to make a more effective vaccine."
Funding for these studies, which took place from January 2002 to January 2005, was provided by the National Institutes of Health, including the National Institute for Allergy and Infectious Disease, and the National Institute on Drug Abuse.
Other Hopkins investigators in this research were Timothy Mosbruger; Qing Mao, M.D., Ph.D.; Zhi Liu, M.D.; Xiao-Hong Wang, M.D.; Hung-Chih Yang; Xiao-Hang Wang, Ph.D., Dale Netski, Ph.D.; and Drew Pardoll, M.D. Co-investigators in the first study also included John Sidney, Ph.D., and Alessandro Sette, Ph.D., from the La Jolla Institute for Allergy and Immunology, in San Diego, Calif. Collaborators in the second study, conducted at Hopkins and at Cork University Hospital in Ireland, were Liam Fanning, Ph.D., and Kelizaeth Kenny-Walsh, M.D.
Hepatitis C is the leading cause of liver disease in the United States, causing an estimated 10,000 to 12,000 deaths each year. Hepatitis C is transmitted when blood and possibly other body fluids of an infected person enter another person, primarily through injection drug use, exposures in health care settings, from an infected mother to her baby during birth, and occasionally through sexual exposure. Symptoms of hepatitis C may not appear for years after infection, and diagnosis must be confirmed by blood tests. However, in addition to liver inflammation and tumors, earlier signs of infection are persistent flu-like symptoms, including any combination of body aches, headaches, night sweats, loss of appetite, diarrhea, fatigue, rash, nausea and mild abdominal pain. Current treatments for hepatitis C involve weekly injections of pegylated interferon for one year, plus twice daily doses of oral ribavirin. While some patients recover on their own, with their immune system attacking the virus and clearing it from the body, most do not. Scientists have not yet determined why this happens in some patients and not in others.
HR - great to see you again! I hope all has been well with you and family. Thanks for posting the Alinia information. It appears to have almost come out of left-field to now have great potential to be added to the existing arsenal - and relatively quickly, too (hopefully).
willing - in the above Alinia results, they mention EVR as being "after 12 weeks of combination therapy". Has me wondering if the EVR results for the naive patients (22/29 + 26/29) are actually at week #24 of tx (12 weeks mono-Alinia + 12 weeks combo) or at week #12 of tx (12 weeks mono-Alinia)? If they are receiving those kind of EVR numbers (48/58 = 83%) on mono-Alina, that would be rather astounding - (to go along with the astounding 93% EOT response)!
Okay I just want to run something by all you guys. It might sound crazy - but to me it makes sense. As some of you may know, I am a geno 2b - tx was RVR - UND 4 weeks post and then relapsed.
Okay here comes the personal details that I have shared with a couple people from MH off forum....Just about everytime I have a bowel movement I see specks in my stool that freaked me out cause when I see specks like that in my dogs stool it always is indicative of worms(worm eggs.) I'm wondering if the Alinia is getting good results in part because it rids the body of parasites which may act as host for the HCV?
I had asked my NP during tx if she has ever heard of people with HCV being infected with worms and she just rolled her eyes at me, grinned and said no. I figured I was maybe just getting paranoid. Before telling my NP, I had told 2 other doctors, one doctor before I even knew I had hep and she sent out a sample and it came back neg. I still insisted I was right though but I dropped the subject. I thought maybe there are 'specific tests' for 'specific' parasites cause I still think these specks are eggs but I may be wrong and just paranoid at this point.
So now that I relapsed I am of course trying to figure out why (as if I would ever find out - but its only a natural reaction to sit and wonder what what wrong and grasp at straws for answers.)
So anyhow I DID find info that in some countries people that have HCV DO in fact have worms and the worms make the virus replicate and the worms MUST be treated.So now in finding out I wasn't as paranoid as I thought and there are people who do have worms with HCV - it would make sense I think (?) then that if the worms were left behind they would be a host for the HCV and it would be only a matter of time before relapse began.
So do you guys think that because ALINA rids the body of parasites that they may be the reason it is acheiving such good results? Maybe many people relapse because of worms?? HR - Could this be possible and if so, is there as specific test I should ask for as far as getting tested for worms or parasites?
I will be so upset if I find out that this is why I relapsed - WORMS. Though I have never been to these countries mentioned in the site- I am a 2b and I think(?) 2b is seen in some of these countries. If I have the blood of someone from an infected needle from years back and contracted HCV - couldn't I have gotten parasites also? Also I almost forgot.... my huband and I was to Antigua already- so maybe swimming or food contamination contracted parasites??
excert from article below in next post. I appreciate anyones opinion or thoughts along with hopefully hearing from HR if his schedule allows. thanks
Soluble egg antigen of Schistosoma Haematobium induces HCV replication in PBMC from patients with chronic HCV infection
"The present study suggests that SEA possesses potent in vitro proliferative activity on PBMC and provides the first evidence that SEA directly stimulates HCV replication in vitro . This may explain, at least in part, the higher morbidity observed in patients co-infected with Schistosomiasis and HCV."
There is alot of info in the article to read and didn't want to paste it all as to take up so much space- but it may of interest for you guys to read.
Your doctor can order a simple but thorough parasite panel that should clear up whether or not you have parasites in your stool. I had my doc order that panel (my symptons were ibs related) and it came out negative. No use guessing or speculating.
The numbers shown are different from other publications about genotyp 4 and responserates. http://tinyurl.com/ywf99s says the ETR is 77% for SOC, not 50%.
Nevertheless promissing news. However, I am a little bit hesitating to get crazy about the news, because we had a hype too often and many promissing new substances are not more than bitter history now. What we want to see is SVR, not laboratory cosmetics.
If you would be me (slow responder from SOC with > 2log drop in week 12 and UND around week 24, treating 37 weeks now, would you add Nitrozoxanide to the combo for the remaining 35 weeks?
The huge advantage of the substance is the availability in the pharmacies TODAY, not 2010 or later...
Jim, I did have a parasite test done and it did come back negative, but I still see specks and I am wondering if because Alinia rids the body of parasites if that could in fact be ONE of the reasons it is achieving good results. Thats all. And plus if parasites could be a reason I relapsed even if its 1% chance of me being right - I would want others to get tested for parasites as to maybe avoid relapse.
There might be a specific test for the type of worm that this is that is seen with HCV.
I agree not to get too excited re EOT versus SVR. Teleprevir mono, I believe achieved EOT negative in a very short period of time but needed other drugs to ahieve SVR. Not sure if that question is addressed to me or others, but not familiar with Nitrozoxanide.
geno-4 appears to be a bit of an oddball; unlike other genos for which subtype has no clinical relevance, geno 4 comes in various flavors, some significantly nastier than others. Here's an opening quote from that Roulot'07 study Goof referenced:
"Genotypes are of considerable clinical importance, because they affect response to antiviral therapy. While patients infected with HCV genotypes 2 and 3 respond much better to combination therapy with pegylated interferon alpha (PEG-IFNα) plus ribavirin than those infected with genotype 1 [17–19], data regarding HCV-4 response rates are limited and controversial. In Egypt and the Middle East, high sustained virological response (SVR) rates (67–70%) have been reported in patients infected with HCV-4 and treated with PEG-IFNα plus ribavirin for 48 weeks [20–22]. This resembles the rates of patients infected with genotypes 2 and 3. Similar findings have been reported for the subgroup of HCV-4-infected patients (n = 27), included in two international pivotal trials [17,18]. By contrast, a lower SVR rate (32%) was observed in a recent study where French patients were treated for 48 weeks . Altogether, these results suggest that SVR rates could differ in HCV-4-infected patients according to the geographical origin of the infection."
Unfortunately, there's no guarantee AASLD-presented abstracts will quickly get worked up into a publication, but with something this remarkable there's bound to be more to follow. It will be particularly interesting to find out more about "dephosphorylation of eukaryotic initiation factor 2α" - this sounds rather systemic, and I wonder what its long-term effects will be. We've never had mid-range artillery before. On the one hand there's ifn, the generic anti-viral car-alarm, that puts the body into an intruder-alert panic, on the other the carefully crafted swiss-watch approach of the protease inhibitors. Here's something that might be harder for the virus to evade than vx but not as hard on our system as ifn.
As best I can read this, the RVR/EVR times tolled after SOC started. There was no NTZ mono branch so I think the 48/58 refers to >log2 24 weeks in (12-ntz +12peg or soc).
on Alinia (and to be honest, some of it goes over my head, unless I really concentrate) I just think that this drug would be a good adjunct for SOC, no matter your genotype...I don't think it could hurt...
HR went to pains to explain why he thought this would help matters, raise the odds for me, because it acts on a different mechanism then SOC, which might have a lot to do with genetics in the way it operates in the system, etc...
As my pal Kittyface said on the other side (she went through a course of monotherapy with Alinia) the sides are negligible.....so I think I'm going to try to get some, and take it even before SOC begins, as HR recommends, he doesn't know why the trial decided to add on Alinia after SOC begins, that might of even lessened the effectiveness for the trial participants, but whatever...
Anything to possibly raise my odds, cause we all know the odds for SOC by itself, aren't spectacular for geno 1s......
And of course, if, God willing, if I did SVR, we wouldn't really know how much the Alinia had to do with it, but for my purposes, as long as I get some help...I'm okay with it...
Kittyface said that you can make a deal with the company, based on finances.... I might make too much money for that, but I'm going to really look into to this, even if I have to pay for this out of pocket, which I might not have to do ultimately...Just my take...
Given you have very little liver damage -- if I remember correctly -- why are you looking for an "adjunct for SOC" ? Especially one in preliminary trial stage? I don't dispute that Alinia has promise, but personally if I were in your position, I'd be focused more on the PI's like Teleprevir that have already proved significantly better SVR rates in half the time -- or if not proven yet, certainly by the end of this year we should have a very decent idea. Or, better yet, just wait until all these drugs (including Alinia) really wash out. No, you don't have anything to lose with Alinia -- not anything we know about -- but you do have something to lose with the SOC part. What does your doc think?
It is indeed a good point to see promissing results and little or no sides. So I too think it would be worth a try.
To all who have ideas about it: Knowing the design of the Alinia study (pre-treatment with Nitazoxanide), is there any theory suggesting NOT to add it to a running SOC at week 38? My chances for SVR with SOC are not the best, I am a slow responder.
Thank you in advance for your appreciated answers.
Since there is so little published out there on NTZ in relation to Hep C, it's pure speculation as to what it can or can't do when added to a slow responder's regime 38 weeks into the game. That being said, if I were in your shoes I'd research all I could on potential sx's (long and short-term), if any, of taking NTZ in the doses that are currently being rx'ed (by researching sx's for all uses of NTZ, that is, since there is a past history of it in other applications). And, assuming you come up with nothing to shoot things down, I'd add it to the mix for the duration of your tx. But I'd be sure to let my doc know what I was doing. And I'd also be asking for more frequent PCR's and other bloodwork to monitor things a bit more closely.
The following is from the romark website. Were I considering taking alinia - and could get to one of those clinics - I'd try to get a general consult from one of the referenced docs....
"We are excited to be participating in this clinical trial," said David Nelson, M.D., Associate Professor of Medicine, Medical Director of Liver Transplantation, and Chief of the Hepatobiliary Disease Section at the University of Florida. "There is a critical need for new therapies for patients with hepatitis C, particularly those who have already failed existing therapies."
The company's STEALTH C (Studies to Evaluate Alinia for Treatment of Hepatitis C) development program is being directed in collaboration with the Division of Gastroenterology and Hepatology at Stanford University School of Medicine by Emmet B. Keeffe, M.D., Jeffrey S. Glenn, M.D., Ph.D. and Dr. Rossignol who is also a Stanford affiliate.
Google Emmet Keefe..... one result: http://www.clinicalcareoptions.com/Hepatitis/Annual%20Updates/2006%20Annual%20Update.aspx
I basically agree w/ you...and if I were a bit younger (I'm a young 54 -in some respects, anyway :)) I'd totally do what you suggest...but everyone has their saturation level, and I just don't know if I want to go, yet, another year or two with this hitchhiker doing nothing...
I've played the waiting game probably more then most on this board, and in some ways I'm glad I did...they know a lot more about the meds, etc...then they did just a few years ago. I remember when everyone thought it was great if you cleared by week 12, that's not so much the case anymore. And better things are around the corner, that wasn't the case before either.
Even though I know many would not agree with my course of action (or inaction as the case may be)...Personally, I think my diet, mental attitude, supplemental regimen and lifestyle have played a part in why I'm doing pretty well w/ the disease, though others may disagree with that as well....
I weighed the various trials, etc and I just don't know that I want to partake in them at this stage of the proceedings...
the way I look at it, what I'm going to do is test how I react to the meds, if I don't clear, till say week 12.....personally, I think I'll get off the bus at that point, and wait till Vertex comes to market, which can only be at the most a few years now...or if if I have extreme reactions, I'll base my course of action on various contingencies...a very "individualized" treatment, I'd say....
I really hesitate to write this, cause I don't want to influence what others think of clearing at week 12, others have different circumstances to consider.....I'm in low liver damage stage with excellent labs, perhaps I can afford to experiment like this, know this is controversial as well. Maybe if I had kids, etc....I would of treated a while ago, I don't know....
I think I'm just going to play it by ear and see what the future brings me...I've already discussed this w/ my doc and he agrees with my course of action - for my case. I'm going to be taking 2 week pcr's in the beginning, so I can see just what's going on. Say, if I did clear by week 4 and went all the way, I could still consider getting off sooner then 48 weeks, I don't know.
And if the worst happened, and I didn't ultimately SVR, maybe I will have bought some time with the treatment anyway, to still wait for something better. Just think everyone has their saturation level, and I've pretty much reached mine. Course, there still is a few more tests I have to do....depending on what they say as well. As always, thanks for your concern and input, it's valuable to me.
agree that researching ntz in detail seems very advisable. My hunch is that you will find it difficult to find a Dr. who supports its use as an adjunct based on the scant information available , but they're not the ones facing a questionable tx..
If you hunt on the FDA site you'll see it has quite a long history and, as I recall, has already been turned down on one application for hiv-associated diarrhea. Unlike riba, it doesn't seem to raise any carcinogenic concerns. Obviously long-term use is the key question. There's quite a bit of information out there on elf2, for example:
I'm still completely ignorant on the topic, but my concern would be what else is not getting made along with the hcv proteins. If you look on pubmed you'll see that elf2 regulation seems to also play a role in various mental processes:
It is quite interesting that this comes down to translation - I've always suspected HCV's IRES-dependency will be its Achilles-heel.
Anyway, all the best. I'm sure we're all going to learn more about this topic..
I misspoke (like I said, was operating on little sleep) yesterday when I said HR said it would be optimal to start Alinia before starting SOC, he just now told me "ideally" it would be good to start both at the same time...the dosage was 2 x per day, at 500 mg...now this is for people who want to take the risk, he's not recommending that people do this or not....after all this, I just find the risk profile to be quite low, seeing this study where these participants took this for a year...
I just find it odd that with all your waiting, now that the promised land is in site, you're going to jump into SOC with a touch of something totally unproven. But regardless it's still SOC and it's still 48 weeks. The "harder" Teleprevir data HR talks about should be with us before the end of the year. Hopefully you will stay open until that time.
Not trying to butt in, but couldn't help notice you mentioning your decision to treat with SOC soon. As already discussed, with your minimal liver damage you have the very desirable luxury of waiting out the better stuff...and the better stuff really is "around the corner" now. Plus you're a type 1, committing to 48 weeks of SOC now is just asking for trouble unnecessarily. Why ask for trouble when you don't to? Plus you say you're going to try the drugs out...I wouldn't do that, I'd leave your virus in its pristine state. Leave it completely wild, untrained and undisturbed. Let it sleep in comfort, don't toughen it up. Wait for telaprevir and/or the alinia results to come out. Then in another year or two make your move, and make it big. If alinia turns out to be the shiznit, or is a serious part of the *shiznittian* process, then I could see taking it along with elevated doses of riba, along with IFN and maybe even Telaprevir for the first several weeks. My god a cocktail like that should bring the hordes of hades down on that virus, especially being a completely treatment naive/wild virus. You might even be able to get away with a mere 12 weeks of treatment with a maelstrom of drugs like that. Believe me, if I were you I would do whatever you can to shorten your course of IFN and riba. I'm SVR now and feel fabulous, but every morning I get up I hobble around for 5-10 minutes until my ankles and feet loosen up. Never had that prior to treatment, and maybe it'll go away in the months and years to come. But why potentially sign up to something like that (or worse even) if you dont have to? The longer you take IFN, the more likely something like that will happen too. Especially if you fail your first round of SOC and need to do another IFN based round of treatment. I know you already know this sorta stuff, but really - think it through. I knew I had HCV for 10 years prior to treating btw. When the VX950 trial came along, I knew it was my turn to move on it. Now that alinia is looking like a possibly good prospect and telaprevir certainly seems to be on the way, sure seems like a smart move to wait just a little longer; you almost certainly will not regret it.
I have to second Jim's and mremeet's recommendation that you wait for the good stuff. Are you treatment naive? If so, why not get into the phase III trial that will start in November. I don't think phase III trials are blinded or use placebos (none that I participated in were), so should be a good bet and it will start in another two months. If you live in LA, there should be a center near you that will participate.
drofi: apologies but I think the first of the two links in my post above, roberts'06, is not alinia-relevant. On closer read, the thrust of what they're reporting is that HCV can navigate around phosphorylation of eIF2alfa thereby evading the anti-translation environment created by the ifn response. On the other hand, the following review gives a nice summary of the tug of war between the cell and the virus as to whether the virus will or won't get to hijack the ribosome for its own nefarious purposes, and is probably more on point to alinia's mechanism of action:
4C: this is a bit presumptuous since I know you've thought this out very well but if you weigh the damage done by say 2 more years of that free-loading hitch-hiker vs the damage avoided by being able to safely cut your ifn time in half (which you can't today) I tend to think the scale tips towards waiting till the phase III is in. As for adding 12 weeks of alinia, it's really hard to see much risk in that. Per the Romark site "Nitazoxanide has been used for over ten years in more than twelve million patients worldwide, many of whom are children. ". The long-term dosing that drofi's contemplating, and I've also been mulling over as a maintenance strategy seems more suspect.
HR : if you have a chance, I would be very interested to hear your thoughts on
eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory
Cell, Volume 129, Issue 1, 6 April 2007, Pages 195-206
Is the eIF2-alfa phosphorylation site at aa 51 one of the ones targeted by NTZ's dephosphorylation inhibition? If so is it reasonable to anticipate some connection with memory or other cognitive function in long-term use?
I've been thinking about trying to get into a trial myself. In the end I find myself being torn between wanting to be clear of the virus .......and some second (and third) guessing about trying to achieve the best chances of clearing. I'm beginning to think now that even if I were to miss the Phase 3 Vertex trials there will likely be newer and even better opportunities that likely still will come. In a few years we may be looking at an improved SVR rate of 60-70%. Just as there continue to be SOC trials long after the drugs were approved we may also see other trials in which we won't even have a chance of getting a control arm short straw. OR even if you drew it it might be the triple therapy which may become the new "control arm". (the flip side and also correct view is that waiting may bring other unwanted HCV related health issues)
The long and short of it is that I often figure that the SVR rate is improving faster than I am unimproving. As others have said....... we all have to make our own call on when and how to treat. Good luck with yours.
That's why, after all of this, I'm willing to try treatment, knowing, that I might not get rid of this fatigue, and all the pitfalls. But I'm taking a risk that clearing up the virus might give me that ultimate energy (at least some of it back.) Though I'm not putting a lot into "expectations" a fools errand I know. Expectations can kick you in the a$$ big time, so I'm just hoping for "better." Even though I know there's a chance that I may be worse in the fatigue dept.
Something I wrote on another thread, thanks soooo much for your concern guys, but I think what I'm doing is going to be okay...I am trying to get in the next Vertex trial, see if I can...still awaiting a response from the trial coordiantor, she got a little pssed that I didn't go into to the last trial, so I'm hoping she doesn't think I'll flake on her, etc...it's bad that we have to still count on people and their prejudices for such major decisions, etc...love you guys...
As a 3a and 2x relapser with cirrhosis, I would be willing to try almost anything relatively safe and promising. I have got to clear next treatment as I am running out of time. I cannot wait for teleprevir. Now, Alinia is sitting out there and has few sides and looks promising, but I don't have parasites, so how to get a hold of it? My hep guy would never go for it, but it is MY decision. It is frustrating to see hope for us around the corner, but some of us can't wait that long. You bet I will take Alinia if I can figure out a way to get my hands on it!!
You wouldn't want to do Alinia as mono-tx - unless you are thinking of using it strictly in a maintenance application (of which there is zero information out there, so you'd truly be swimming alone). The concern with any mono-tx is the potential for resistant viral variants to arise (perhaps HR and/or willing could better address this possibility w/ Alinia), therefore rendering the drug possibly useless for you to use in a future combo tx. If you are attempting viral eradication w/ a goal of SVR, it would probably be best to place Alinia into a combo tx setting.
Given you circumstances - and failed tx history - you need to educate your current doc on the ongoing Alinia trials and tell him just how interested you are in it. Or, consider finding a new doc who would be more 'open' to experimentation (alot easier said-than-done, of course).
I would only use it as a suplemental to the combo prescribed. Hope I can find a way to get it. I cannot change docs again...I just finally got to see a real Hepatologist. Thank you for the blessing and back at you.
re the cell paper re blockage of the elongation factor and long term memory problems:
It should be enough of a concern to require psychometric testing in the US trials to show if such effect would exist in humans at the dosage used.
The effect if any does not seem strong enough to be obvious. Given that it would likely be temporary ( since rapid protein synthesis seems required for LT memory), this is a dynamic process that can be turned on or off and the drug disappears rapidly from the circulation - hence twice a day dosing.
Even if mildy present it might not be a real problem due to the temporary nature.
We can speculate, that the virus requires rapid synthetic activity more than the host and is therefore selectively impeded. The totally independent nature of this particular impediment to viral reproduction makes it likely to provide a truly synergistic effect with other treatment modalities.
I dont think there was any reason to do the 12wk monophase with NTZ other than to see its monopotential.Maybe there was hope for a stronger mono effect , that could strengthen the position in a future partnership. It would be very interesting to see a real from the start combotrial.
While NTZ blocks a host function, resistance is still possible by viral mutations reducing the reliance on such host function. This can only be tested, not reasonable predicted, like the quick resistance to nonnucleoside Polymerase inhibitors.
On a lighter note, consider the potential benefits of this memory effect in the combo: "How bad was your SOC Alinia combo treatment"? Patient: " As far as I remember, no problems, really".
Actually, if I lost all memory of events prior to 1987 or so, I would consider that a real plus! Anyway, I have read all I can find on this (not much yet); looks almost too good to be true. So many disappointments thus far with tx. BUT, it seems relatively safe and the risk to reward ratio for heppers in my position... well, I will run my own little study if i can I can get it in time!
HR : thanks for your thoughts on this; in fact the cognitive disorders, particularly poor-memory, associated with both untreated hcv and tx are a standing joke around here (makes one wonder whether Alberto Gonzales shouldn't be going in for an hcv test).
In light of that paper, perhaps both are at least in part due to ifn-induced phosphorylation of eIF2-alpha's Ser-51. The existence of a connection between such a fundamental cog in translational machinery and higher level brain function seems absolutely astounding to me!
I don't understand your comment about the "totally independent nature" of NTZ's mechanism: inhibition of eIF2-alfa dephosphorylation seems more complementary-to than independent-of ifn's action on that IF (I assumed that was part of why the non-naive results didn't look so great). Also, with regards to viral mutation, it'll be interesting to see what sort of NTZ resistance is reported, but I'm betting against the virus on this one. The ribosome is an ancient and very-conserved bit of machinery and no matter how adaptable the virus there's relatively little negotiating room if it wants to get its proteins translated. The Robert'06 study linked above seems to indicate that HCV has access to a "non-standard" way of binding eIF2-alpha (ie without the eIF2-alpah-GTP-Met-tRNA-Met TC complex) but presumably it still needs unphosphorylated eIF2 to get the job done.
ForeSee : yes, thanks-you! I'll be in touch. Sounds like you've got a good plan. For what it's worth, and I hope somebody proves me wrong if I'm off base on this, but I've never been much of a believer in developing ifn-resistance through tx. The ifn response is just too multi-faceted for the virus to wriggle out of, as it can with a single mutation in the case of vx. As far as I can tell, people have been poring over sequences of patients for whom tx did/didn't work for years now and haven't found anything convincing yet.
Gauf: if you decide to go that route it might be worth trying online pharmacies in Mexico/Canada. I found out a while back riba is apparently available over-the-counter in Mexico.
I just found out that the company that has Alinia, isn't really picky about it's form for getting it (as a financial hardship case) Hesitate to throw that out there, but this is a very serious situation, and sometimes we have to do what we have to do.
To piggyback onto what willing said: many, many moons ago - before I knew any better - I was considering taking riba as a mono-tx/maintenance. This was around 1996/97 after having failed mono alpha-interferon in 1992 (and getting somewhat tired and anxious of waiting for the promised 'next miracle'). At that point riba was relatively 'new' to the combo mix and was being tested in trials. The further I looked into it the more intrigued I became - and I took it to the point of finding potential suppliers in Europe and Canada where I could purchase it for import. But the more I learned, the more concerned I became about the potential for viral variants/resistance if I were to do riba as mono. And so that was the end of that.
The point of my little story is that Alinia, too, is out there and available, should you so desire - be it Mexico, Canada or Europe. I guess one of the biggest concerns in ordering it, though, would be in somehow trying to ascertain that you are receiving the real McCoy - and not the Alinia equivalent of baby laxative.
Hi, nice to see you. Well, a friend of mine got theirs in Mexico (another thing I'm hesitant to say) and it checked out pretty well. That's going into a pharmacy there, not online...I think they do a bang up business selling drugs to undercut drug prices here (so does Canada), so maybe they can't afford many quality control issues...When I went online to find out if I could get it from online pharmacies I found out I couldn't, but maybe I didn't know what I was doing. I don't know much about online pharmacy buying...where I'd be hesitant in buying drugs (and a few other things come to think of it) is China. Though I'm sure they are working on these issues.
just heard, on good authority, that you can get it from on=line pharmacies in Canada (though, I think, with a prescription), of very good quality, and at a much better price then here...for anyone concerned...
Very good to see you, too. Hope all is well these days with you and family.
Also good to see our friend back on here. He's a wonderful resource - and a darn good man, too.
As far as obtaining Alinia goes, I haven't looked into it. But there are all kinds of overseas/over-the-border opportunities out there. As an aside, a few years back I was able to get my Mom on an anti-dementia medication one year ahead of FDA approval, since it was already approved in Europe at that time. I found it to be relatively easy to obtain that particular drug at an on-line pharmacy and have it shipped here.
I used it for over a year of my 88 week treatment along with SOC. I was UND the last 68 wks of tx, the Alinia was easily tolerated, however I did relaspe. I'm type 1a geno.
Alinia seems to help genotypes 4 quite a bit in egyptian studies, and the Stealth trials also showed promise. However, based on what happen to me I'd conclude that it may have more to do with the strength of the strain you have, as well as your own genetic predictors as to whether you clear or not with type 1. (see Newleaf's journal for genetic predictors.
Not all hep C is created equal you see. Type 4 is the weakest and has a 80-90% success rate on 6 mo. of SOC where as type 1 has only 50% SVR on 1 year of SOC.
Certainly at this point it's hard to say for certain that Alinia will help everyone, however, if I was treating again today (which I would were the PI's were available,) I don't think adding it at the front end would be a bad idea.
It is well tolerated by most.
It does seem to help knock down viral loads more quickly in most patients, and that early viral response makes treatment success more likely. If I were to treat today, I would in an ideal world do the following:
A. get the Inovio vaccine to knock out 95-99% of the virus (not likely anytime soon)
B. pretreat with antidepressants and Alinia for at least one month prior to commencement.
C. Then do a SOC lead in of one month with weight based RIba and peg or Infergen
D. Then add boceprevir after the one month LEAD IN with SOC..
E. Add the procrit somewhere in that first month before anemia becomes debilitating.
(an ounce of prevention here is worth a pound of cure. Had it been added when I was at 12 I could have functioned, at 10 I barely could, and the procrit then only kept it from dropping lower it was not able to restore a functional level to me.)
F. Stay on the tx for at least 9 months even though some are saying 6 months ought to do it.
G. make sure my blood sugars and insulin resistance is kept under perfect control the whole time, whether having recieved a type 2 diagnosis or not.
Now that's based on my type, my stage, and what my ultimate wish list would be right now based on the current science. It is subject to change any day I find out more.
I am geno 4a/c , naive , VL 100K IU/ml (3weeks ago) FibroScan F2 , FibroSure F2
got Alina sitting on my desk both generic and brand.
I understand the argument anything mono won`t work . However the mono trial
did produce a 17.4% SVR (24wk after) in a very small group with very minor Sx.
The only reason not to try it mono would be creating resistance.
Now in laboratory tests the virus did not built up resistance to Nitazoxanide
and a hepatologist @ Romark says he has no reason to believe why it
should be any different in clinical use.
My concern still is that if I do mono first and than add SOC later if mono is unsuccessful
I am not 100% conform with trial data.
Here is what a doctor @ Romark said:
Is there any reason that speaks strongly against attempting an Alinia monotherapy (geno4, <400kIU/ml) of six months first
before trying the lead in + SOC treatment at a later date (health permitting) ?
This has not been formally tested, but I cannot think of any theoretical reasons why a course of Alinia monotherapy should have an impact on future combination therapy.
What bothers me is I saw some posts where geno 1s started with Alinia
mono and actually saw there VL go up from it initially.
By the way for geno 1s there will be new information from the ongoing Alinia+SOC
trials beginning 2010.
Orleans, I think you are right...getting my geno's a fuzzy, sorry. I read somewhere it's a little easier...but maybe it's 2 that's easiest.
I think the stealth studies said type 4 had a 60% success rate (better than 1's) but that alinia increase their SVR even higher.
It's hard to keep all these studies straight in my mind anymore...but Emett Keefe I believe is the one who did the Stealth trials...at Stanford so the abstracts are out there.
one group had about 20% improvement in Svr...i'll see if I can relocate that abstract.]
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