GUT: Vitamin B12 may improve SVR rates in HCV infected patients...

Study posted 7/18/12 via the journal GUT.  Researchers in Italy find a link between 5000 ug every 4 weeks of vitamin B12 and improved SVR... especially in the more difficult-to-treat genotype 1 patients with high baseline viral loads.  Researchers noted a 34% improvement in SVR in the arms containing B12 than in the arms that didn't. That's pretty cool in my book, but let's do a gut check all the same. OK, it's a small study, it's European (which means the patients have a higher probability of being Caucasian, lower BMI, CC alelle, genotype 1b, all that stuff that makes these patients more likely to respond to traditional pegylated interferon + ribavirin therapy than patient types over here in the States) but hey!! Vitamin B12 can be had on the cheap! Further prospective and larger clinical trials will have to be done to confirm or deny the seemingly extra added boost to SVR rates, especially with the new standard of care. Let's hope it's not another silymarin experience.

GUT
Vitamin B12 supplements may help treat hepatitis C

Safe and inexpensive option for boosting response rate to antiviral drugs

[Vitamin B12 supplementation improves the rate of sustained viral response in patients chronically infected with hepatitis C virus Online First doi 10.1136/gutjnl-2012-302344]

Adding vitamin B12 to standard hepatitis C virus (HCV) treatment significantly boosts the body’s ability to keep the virus at bay, indicates a pilot study published online in the journal Gut.

The effects were particularly strong in patients whose infection was proving difficult to treat effectively, the findings showed.

Between 60% and 80% of those infected with the viral liver infection HCV will go on to develop chronic hepatitis, and roughly a third of them will progress to cirrhosis and terminal liver disease.

Standard treatment of interferon (peg IFN) and ribavarin clears the virus in about 50% of patients infected with genotype 1 HCV and 80% of those infected with genotypes 2 or 3.   But this approach fails to clear the virus in around half of all those infected with HCV or the infection returns once treatment stops.  

While trials of new generation antiviral drugs show promise, they are expensive, and can make treatment more difficult. And questions still remain about how well they will work in practice, say the authors.

Experimental research dating back a decade suggests that vitamin B12 may have a role in suppressing HCV. The liver is the body’s primary storage centre for vitamin B12, but this capacity is impaired by diseases directly affecting the organ. The researchers therefore wanted to see if adding vitamin B12 to standard treatment would make a difference.

Ninety four patients with HCV infection were randomly allocated to receive standard treatment or standard treatment plus vitamin B12 (5000 ug every 4 weeks) for between 24 (genotypes 2 and 3) and 48 weeks (genotype 1).

The body’s ability to clear the virus was assessed after 4 weeks (rapid viral response), after 12 weeks (complete early viral response), at the end of treatment and at 24 weeks after stopping treatment (sustained viral response).

There was no difference between the two treatment approaches at 4 weeks, but there were significant differences in response at all the other time points, particularly 24 weeks after stopping treatment, which is the aim of HCV treatment and the closest it can be get to a cure.  

The effects were also significantly greater among those who carried the type 1 strain, which is particularly hard to treat, and those high levels of infection (high viral load) to begin with.

Overall, adding vitamin B12 to standard therapy strengthened the rate of sustained viral response by 34%, the findings showed.

The authors conclude that until clear eligibility criteria for treatment with the new generation antiviral drugs are established, standard treatment plus vitamin B12 is a safe and inexpensive alternative, particularly for those who carry a strain of the virus that is hard to treat.

They add: “This strategy would be especially useful in those countries where, owing to limited economic means, the new generation antiviral therapies cannot be given in routine practice.”

JAMA: Milk Thistle has no effect on serum ALT levels in HCV nonresponders...

Posted on 7/18/12 on the JAMA Network. Further evidence that Milk Thistle and Silymarin have no effect on serum ALT levels in patients with HCV. 

Original Contribution | July 18, 2012

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

Michael W. Fried, MD; Victor J. Navarro, MD; Nezam Afdhal, MD; Steven H. Belle, PhD; Abdus S. Wahed, PhD; Roy L. Hawke, PharmD, PhD; Edward Doo, MD; Catherine M. Meyers, MD; K. Rajender Reddy, MD; for the Silymarin in NASH and C Hepatitis (SyNCH) Study Group
JAMA. 2012;308(3):274-282.

Context:  The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy.

Objective:  To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy.

Design, Setting, and Participants:  Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011.

Intervention:  Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks.

Main Outcome Measures:  The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures.

Results:  After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo.

Conclusion:  Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.

Trial Registration  clinicaltrials.gov Identifier: NCT00680342

Milk Thistle shows no effect according to data presented at AASLD...

(From MEDPAGE.com: Data from AASLD concludes that silymarin. the active compound in the botanical Milk Thistle long believed to have antiviral and liver rejuvenating effects has neither compared to placebo. Important info for patients long misled by claims from unscrupulous vendors)

SAN FRANCISCO -- A botanical agent used in the treatment of liver disorders had no detectable effect on hepatitis C virus (HCV) disease activity in comparison with placebo in patients with previously treated chronic disease, results of a randomized trial showed.

Patients treated for six months with either of two doses of silymarin had little change in levels of the liver enzyme alanine transaminase (ALT). About 4% of patients in each silymarin arm and in the placebo group met the primary endpoint of a decline in ALT to ≤45 IU or at least a 50% decline from baseline.

"Similarly, symptom scores and quality of life measures were unchanged during silymarin treatment," Michael W. Fried, MD, of the University of North Carolina in Chapel Hill, reported here at the American Association for the Study of Liver Diseases meeting.

The trial was perhaps the first to use a single, well-described silymarin preparation, and the doses employed in the study were five to seven times higher than customary doses, he added.

Silymarin is an extract of milk thistle and has long been used as a treatment for various types of liver disorders. A mixture of flavonolignans, silymarin has demonstrated anti-inflammatory and immunodulatory properties in vitro, as well as activity against the HCV core and virus-associated gene expression.

The substance has been evaluated in clinical trials as a therapeutic aid for cirrhosis, alcoholic liver disease, and viral hepatitis. However, the results have been inconsistent.

"Previous studies have been confounded by a lack of well-defined efficacy endpoints, inclusion of heterogeneous populations of patients with liver disease, and use of nonstandardized silymarin preparations," said Fried.

To address some of the shortcomings of previous clinical studies, the investigators designed a trial to evaluate silymarin as a potential aid in the treatment of chronic HCV that had not responded to interferon-based therapy.

All of the 154 patients enrolled at four centers in the U.S. had a history of treatment with interferon-based therapy and had not achieved a sustained virologic response. The patients had quantifiable HCV RNA and a serum ALT ≥65 IU.

The silymarin preparation used for the trial is produced in the Netherlands under the brand name Legalon 140 and is approved as a prescription drug in some European and Asian countries. The customary dose is 140 mg three times a day.

Eligible patients were randomized to one of two doses of silymarin (420 or 700 mg) or placebo. Patients in the high-dose silymarin arm took five capsules of the botanical agent three times daily. Patients randomized to the standard dose took three silymarin capsules and two placebo capsules three times each day, and patients in the placebo arm took five matching capsules three times daily.

The high-dose arm was based on results from a phase I dose-finding trial "in order to provide the highest likelihood of finding a therapeutic benefit," said Fried.

The primary endpoint, measured after 24 weeks, was a decline in serum ALT to ≤45 IU (the upper limit of normal) or a decline of at least 50% from baseline and <65 IU (1.5 times the upper limit of normal).

The patients were randomized to the three treatment arms. The three groups did not differ with respect to baseline demographic and clinical characteristics. Median age was 55, about 70% were white, about 90% had HCV genotype 1, about a fourth of the patients had evidence of cirrhosis, and 40% to 45% had a history of milk thistle use.

Adherence was good, said Fried, as about 90% of the study participants consumed more than 80% of their medication doses.

After six months, one person in the placebo group had a serum ALT ≤45 IU, as did two patients in each of the silymarin arms. Additionally, two patients in the placebo and high-dose silymarin groups had at least a 50% decline in baseline ALT to <65 IU, as did one patient in the 420-mg silymarin arm.

The proportion of patients who met either definition of the primary endpoint was 3.8% (two of 52) in the placebo group, 4% (two of 50) in the 420-mg silymarin arm, and 3.8% (two of 52) in the high-dose silymarin arm.

The three groups also did not differ significantly with respect to the mean change in ALT, change in HCV RNA, or scores on a battery of quality-of-life instruments. A graph of serum ALT levels throughout the six months showed virtually superimposable lines for the three groups.

The placebo and silymarin groups also did not differ significantly in their adverse-event profiles. The most common types of adverse events were gastrointestinal, musculoskeletal, dermatologic, infection, and physical injury. Six patients in the 420-mg silymarin arm and five in the 700-mg arm had serious adverse events, compared with one in the placebo group.

During the discussion that followed the presentation, Fried expressed doubt that using even higher doses of silymarin might lead to better results, as suggested by a member of the audience.

AASLD president T. Jake Liang, MD, said the study is informative because the results showed not only that silymarin performed no better than placebo in a well-controlled clinical trial but also that the substance is not harmful for people who take it for liver conditions.