Chronic HCV linked to vitamin A deficiency, nonresponse to antiviral therapy

Bitetto D. Hepatology. 2012;doi:10.1002/hep.26186.

December 21, 2012

A large number of patients with chronic hepatitis C are vitamin A deficient, and this deficiency is associated with nonresponse to treatment, according to recent results.

In a multicenter study, researchers compared the serum vitamin A and vitamin D levels in 199 treatment-naive patients with chronic hepatitis C, before receiving interferon (IFN)-based antiviral therapy, with those of 119 healthy controls.

Median vitamin A levels were significantly lower among patients with HCV than controls (256 ng/mL compared with 742 ng/mL, P<.0001 for difference). Vitamin A deficiency (200 ng/mL or lower) was observed in 42.2% of patients, compared with none of the controls, with severe deficiency (100 ng/mL or lower) present in 19.6% of cases. Vitamin D deficiency was present in 45.8% of 190 evaluable patients; severe deficiencies in vitamin A and vitamin D (20 ng/mL or lower) existed in 9% of cases.

Patients with severe vitamin A deficiency were more likely to be nonresponsive to treatment (36.1% of cases overall vs. 18.2% of those without severe deficiency, P=.019). HCV genotype 2-3 (P<.001), cirrhosis at baseline (P=.003), IL-28B polymorphism with at least one T allele (P<.001), gGT levels greater than 60 IU/mL (P<.001) and taking 80% or less of the assigned ribavirin dose (P=.002) were predictive of nonresponse.

Among patients with more difficult-to-treat genotypes, multivariate analysis indicated associations between nonresponse to antivirals and HCV RNA levels greater than 600,000 IU/mL (OR=4.39, 1.39-13.8), severe vitamin A deficiency (OR=3.68, 1.03-13.2), IL-28B T/* genotypes (OR=26.3, 4.34-159) and elevated baseline gGT levels (OR=5.24, 1.69-16.2) (95% CI for all).

A second model indicated that patients with low levels of vitamins A and D were at particularly increased risk for nonresponse (OR=12.9, 1.73-96.7). Patients with severe vitamin A deficiency and IL-28BB CT-TT were calculated at the highest risk for nonresponse in a third model evaluating the interaction between IL-28B genotypes and vitamin deficiency(OR=26.5, 2.91-242) (95% CI for all).

“A high percentage of patients with chronic HCV infection presented serum vitamin A deficiency,” the researchers wrote. “This condition is strongly associated [with] nonresponse to antiviral therapy, suggesting that vitamin A serum levels could modulate the responsiveness to IFN-based antiviral therapy. It will be of great importance to verify if vitamin A supplementation could restore the IFN sensitivity in nonresponders, because the success of new [direct antiviral agents] is still conditioned by IFN responsiveness.”

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DDW: Vitamin A Boosts Response to HCV Treatment

By John Gever, Senior Editor, MedPage Today
Published: May 05, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

NEW ORLEANS -- Early and sustained virologic responses to standard treatment for hepatitis C virus (HCV) infection were markedly improved when patients also received high doses of vitamin A, results of a small trial showed.
 
After 48 weeks of treatment with standard doses of pegylated interferon-alpha2b, ribavirin (Rebetol), and 30,000 IU/day of vitamin A, 61.7% of patients had achieved sustained virologic responses, compared with 42.9% of patients taking only the standard therapies without the vitamin, Shuichi Sato, MD, of Shimane University in Izumo, Japan, said here.

The addition of vitamin A also boosted early virologic response rates assessed after 12 weeks: 70% of patients taking vitamin A plus the standard drugs had no HCV genetic matter in circulation, whereas only about 40% of patients on standard therapy alone showed viral negativity at that point.

Despite the very high doses of vitamin A tested in the 42-patient trial -- the recommended daily intake of vitamin A in the U.S. ranges from 2,310 to 3,000 IU/day for adults -- Sato said it appeared to have no adverse effects in the trial.

"There is little or no risk in a high dose of vitamin A," he said at a press conference in advance of his formal presentation at Digestive Disease Week.

Sato and other researchers had reported in 2003 that retinoic acid compounds increased expression of interferon receptors on hepatoma cells in vitro. They followed that up last year with short-term clinical results suggesting that vitamin A increased the antiviral activity of interferon and ribavirin in patients with HCV infection.

At DDW, he will be presenting data on 42 patients who received a full course of PEG-interferon and ribavirin therapy in an open-label, multicenter study.

Patients with chronic hepatitis C were randomized to receive the high dose of vitamin A, or not, in addition to the standard therapy.

A little more than half the patients were men. Mean age was about 55 and 16 patients had previously received interferon treatment.

Study treatment lasted 48 weeks in most patients, although it was extended to 72 weeks in a few patients who achieved HCV negativity between weeks 12 and 36 of therapy.

About 5% of patients assigned to the vitamin A group and 10% of control patients failed to show a sustained response at week 48 but did achieve it by week 72, Sato reported.

Discontinuations were slightly more common in the vitamin A group but not significantly so: about 15% versus 10% in the control group.

Sato said a placebo-controlled trial is planned.

Press conference moderator Kelly Tappenden, PhD, of the University of Illinois in Urbana-Champaign, called the approach "promising" but said the findings need to be confirmed in a more rigorous study.

She said the very high vitamin A dose used in the trial was noteworthy and potentially a concern, as vitamin A is known to have toxic potential.

"They really need to look carefully at how to monitor the dosing schedule," Tappenden said. "It's an issue that needs to be sorted out for a practicing clinician who is not necessarily used to working with megadoses of vitamin A."
Primary source: Digestive Disease Week
Source reference:
Sato S, et al. "Retinol supplements antiviral action of pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C: Prospective pilot study" DDW 2010; Abstract T2004.

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