Vitamin B12 supplements and hepatitis C treatment: an interview with Gerardo Nardone and Alba Rocco

Interview conducted by April Cashin-Garbutt, MA (Editor)Jul 26 2012

Please could you tell us a little bit about hepatitis C and the standard treatment for it?

Since its discovery in 1989, hepatitis C virus (HCV) has been recognized as a major cause of chronic liver disease worldwide. The most recent WHO estimate of the prevalence of HCV infection is 2%, representing about 150 million people. Every year, 3–4 million new people are infected with the hepatitis C virus, of those, approximately 60–80% develop chronic hepatitis, and 30% of them progress to cirrhosis and to end-stage liver disease.

The primary goal of HCV therapy is to cure the infection, which is achieved by eliminating detectable circulating HCV after cessation of treatment. The combination of pegylated interferon-a and ribavirin, which was the standard of care for HCV chronic hepatitis up to October 2011, eradicates the infection in 40-54% of patients infected with HCV genotype 1 and up to 80% of those infected with HCV genotypes 2 or 3. However, approximately 50% of individuals either do not clear the infection during antiviral therapy or relapse after treatment ends.

The recent introduction of the HCV non structural 3/4A protease inhibitors boceprevir and telaprevir, which are direct acting antiviral agents, has changed the treatment options for individuals infected with HCV. In fact, the American Association for the Study of Liver Diseases recommends their use in combination with pegylated interferon-a and ribavirin in patients with genotype 1 HCV infection. However, despite the impressive results of phase III clinical trials, several questions remain about the applicability of direct acting antiviral agents in “real-life” conditions, namely, the emergence of drug-induced mutations, selection of candidates to avoid unnecessary treatment, adverse events and additional costs to health-care budgets.

Moreover, these new drugs are not commercially available everywhere.

How did your research into giving B12 supplements originate?

The analysis of the data records of our HCV infected patients treated with interferon and ribavirin raised up the observation that those who needed chronic supplementation with vitamin B₁₂ due to concomitant diseases such as hematological disorders or previous gastrectomy, showed a high rate of sustained viral response.

Trying to explain this surprising observation we found that Lott and coworkers, in 2001, by using an in vitro system, demonstrated that vitamin B₁₂ inhibits HCV replication by directly interacting with HCV RNA. The evidence that chronic liver diseases, such as hepatitis and cirrhosis, are associated with an impaired liver storage of vitamin B₁₂ date back to Joske in 1963. Thus it seemed conceivable that restoring the vitamin B₁₂ liver storage it would have been beneficial for the treatment of HCV patients. Therefore, to test our hypothesis, we designed the pilot study.

Your research found that B12 supplements helped patients being treated for hepatitis C. Did your research indicate the mechanism behind this benefit?

Our study addressed the role of vitamin B₁₂ in the clinical setting and did not point out on the mechanism behind the beneficial effect of vitamin. However, the previous experimental evidence by Lott clearly demonstrated the “virostatic” role of the vitamin B₁₂ that inhibits HCV replication by directly interacting with HCV RNA.

Were B12 supplements beneficial to all hepatitis C patients being treated or were the effects particularly strong in certain types of patient?

The addition of vitamin B₁₂ to pegylated interferon-a and ribavirin produced a significant improvement of the response rates to anti-viral therapy at 12 weeks of therapy, end of therapy and especially at 24 weeks after stopping treatment, so called sustained viral response, which is the aim of HCV treatment and the closest it can be get to a cure. Overall, patients who received B₁₂ supplementation gained the sustained viral response 36% more frequently than those who were treated with pegylated interferon-a and ribavirin alone. More importantly, the most striking effect of vitamin B₁₂ supplementation in our study occurred in so-called difficult-to-treat patients, that is carriers of HCV genotype 1 and a high baseline viral load who get a rates of sustained viral response 41% and 38% higher in patients receiving B₁₂ supplementation than in patients treated with standard of care alone.

What form were the B12 supplements in your study given? Would it be possible for dietary changes to have a similar beneficial effect?

In our study we supplemented the patients by using vitamin B₁₂ at a dose of 5000 mg administered by intra-muscular injection every 4 weeks for the duration of the antiviral therapy. The therapeutic schedule was empirically determined since, until now, no reliable laboratory test exists through which we can accurately determine the entity of vitamin B₁₂ deficiency. It is unlikely that dietary changes alone would have a similar beneficial effect since process for gastrointestinal absorption of dietary vitamin B₁₂ in human is extremely complex and the bioavailability of dietary vitamin B₁₂ is significantly dependent on this gastrointestinal absorption. According to the Dietary Reference Intakes in the United States, it is assumed that only 50% of dietary vitamin B₁₂ is absorbed by healthy adults with normal gastrointestinal function and only few data are available until now on the bioavailability of vitamin B₁₂ from foods.

What foods are particularly high in B12?

The major dietary sources of vitamin B₁₂ are animal foods, that is meat, milk, egg, fish, and shellfish. However, cooking induces appreciable losses of vitamin B_12. Cooked meats lose about 33% of their vitamin B₁₂ content. Boiling for 2–5 min and 30 min bovine milk results in 30% and 50% loss of vitamin b₁₂ content, respectively and vitamin B12 concentrations in fermented milk decreases significantly during storage at 4°C for 14 days relative to the original milk. About 20%–60% of vitamin B₁₂ that is originally presented in milk is recovered in cottage cheese, hard cheese, and blue cheese. Vitamin B12 content in the whole egg is about

0.9–1.4 mg/100 g, mostly localized in the egg yolk. Vitamin B₁₂ intakes from the egg are generally large, because it is a popular food item. However, the bioavailability of vitamin B₁₂ from scrambled egg yolks, scrambled whole eggs, boiled eggs, and fried eggs averages only 8.2%, 3.7%, 8.9%, and 9.2%, respectively. Vitamin B₁₂ in eggs is generally poorly absorbed relative to other animal food products.

Do you have any plans for further research into this field?

Firstly, we are planning a large, randomized, controlled trial to confirm the findings of our pilot study.

Moreover, our future research plan is to determine the exact entity of vitamin B12 deficit in each hepatopathic patient, so that we can use a tailored schedule of vitamin B₁₂ supplementation. This approach could further improve the possibility to cure HCV infection. Finally, since vitamin B₁₂ inhibits HCV replication by using a site of attach to RNA different from that used by the currently available direct antiviral agent, it would be interesting to test a possible additive role of the vitamin also in this therapeutic setting.

How do you think the future of hepatitis C treatment will progress?

Research for antiviral drugs targeting HCV is growing very rapidly. Many compounds have been experienced and many others are likely to be approved within the next 5 years.

Hopefully it can be foresee that most chronic HCV infections will be cured by using all-oral, interferon free regimens. In this scenario, the addition of the vitamin B₁₂ to therapy could be useful to improve the rate of cure of HCV infection.

Where can readers find more information on this topic?

http://gut.bmj.com/content/early/2012/06/28/gutjnl-2012-302344.short?g=w_gut_ahead_tab

http://tier-im-fokus.ch/wp-content/uploads/2009/10/watanabe02.pdf

About Gerardo Nardone 

Gerardo Nardone was born in Benevento on January 23^th, 1956. In 1980 he graduated in Medicine at University “Federico II” of Naples, Italy. In 1984, 1988 and 1994 he obtained specialty degree in Gastroenterology, Nutrition and Internal Medicine at University “Federico II” of Naples, Italy.

In 1993, 1998 and 1999 he was a fellowship at Center for Basic Research in Digestive Disease, Mayo Foundation, Rochester, Minnesota focusing his research project on basic mechanism of epithelial carcinogenesis. Since 2001 he is Associate Professor of Gastroenterology at University “Federico II” of Naples and from 2006 Head of Gastroenterology Unit. He authored more than 100 full paper published in indexed journals and coordinated 3 national research projects. He is a well know scientist and his research group is actively employed in the main topics of gastroenterological researches.

About Alba Rocco

Alba Rocco was born in Castellammare di Stabia on November 15^th, 1964. In 1993 she graduated in Medicine at University “Federico II” of Naples, Italy and in 1998 and 2003 obtained specialty degree in Gastroenterology and Internal Medicine at University “Federico II” of Naples, Italy. In 2007 dr. Rocco got the PhD in “Nutrition and Health: biotechnology applied to gastrointestinal diseases”.

Since 2004 she is Physician at Gastroenterology Unit of the University “Federico II” of Naples.

Dr. Rocco authored about 60 full paper published in indexed journals and participated to 3 national research projects. She is scientist actively employed in the main topics of gastroenterological researches.