Vitamin D Increases Sustained Response to Interferon-based Therapy for Hepatitis C, May Improve Liver Fibrosis

Vitamin D Increases Sustained Response to Interferon-based Therapy for Hepatitis C, May Improve Liver Fibrosis

SUMMARY: Vitamin D supplementation increased the likelihood of sustained response to pegylated interferon plus ribavirin therapy for chronic hepatitis C, leading researchers to suggest that vitamin D deficiency may help explain well-known racial/ethnic disparities in treatment response, according to a presentation at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. A recently published related study found that low vitamin D levels were associated with more severe liver fibrosis and poor treatment response.

By Liz Highleyman

In the EASL study, S. Abu Mouch and colleagues from Israel assessed whether adding a vitamin D supplement to standard hepatitis C therapy using pegylated interferon plus ribavirin could improve rates of sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completion of treatment.

Vitamin D is a potent immune modulator that has a direct effect on T-cells and antigen-presenting immune cells, and can directly or indirectly influence the differentiation and activity of CD4 T-cells, the researchers noted as background. They hypothesized that vitamin D has an important role in innate immune response against HCV. In addition, some studies have shown that vitamin D improves insulin sensitivity (a predictor of better treatment response) and inhibits HCV replication.

The investigators first measured vitamin D levels in a group of 157 chronic hepatitis C patients treated at their liver clinic in Israel, and found that fully 84% had low levels, and one-third had "severe deficiency."

They then performed a randomized study of 67 patients. About half were men, the average age was 48 years, and most were of Russian origin, with only a few being of Israeli or Arabic origin.

Participants were randomly assigned to receive 1.5 mcg/kg pegylated interferon alfa-2b (PegIntron) plus 1000-1200 mg/daily weight-adjusted ribavirin for 48 weeks, with or without 1000-4000 IU/day vitamin D3, enough to bring serum levels up to 32 ng/mL. By chance, patients in the vitamin D group were more difficult to treat than those in the control group, having a higher body mass index and larger percentages with high baseline viral load and advanced liver fibrosis.

Results

	44% of participants receiving vitamin D achieved rapid virological response (undetectable HCV at week 4), compared with 18% in the control group (P < 0.0001).
	94% of participants in the vitamin D group achieved complete early virological response (undetectable HCV at week 12), compared with 48% in the control group (P < 0.0001).
	85% of patients in the vitamin D group achieved SVR, compared with 43% in the control group (P < 0.001).
	Adverse events were mostly mild and were typical of those associated with pegylated interferon/ribavirin (mainly flu-like symptoms).
	No serious adverse events were reported.

These findings led the investigators to conclude that adding vitamin D supplements to pegylated interferon/ribavirin therapy for treatment-naive genotype 1 patients with chronic HCV infection significantly improves SVR rates.

They further suggested that vitamin D deficiency may contribute to the strong racial/ethnic disparity observed in responses to antiviral therapy for HCV. People of African descent -- and to a lesser extent Latinos -- do not respond as well as whites and Asians to interferon-based therapy.

People with darker skin produce less vitamin D when exposed to the sun, and are therefore more likely have low levels. The 2000-2004 National Health and Nutritional Examination Survey (NHANES), for example, found that U.S. non-Hispanic whites had average vitamin D levels nearly 10 nmol/L higher than those of Mexican-Americans, who in turn had average levels more than 10 nmol/L higher than non-Hispanic blacks.

Treatment Response and Fibrosis

In the second study, published in the April 2010 issue of Hepatology, S. Petta and colleagues from Italy looked at the association between vitamin D levels and histological and virological response to interferon-based therapy.

Adding to the mechanisms described by Abu Mouch's group, the study authors noted that vitamin D also can potentially interfere with inflammatory responses and fibrogenesis (formation of fibrous scar tissue).

This study included 197 patients with genotype 1 chronic hepatitis C and 49 healthy HCV negative control subjects matched according to age and sex. Most of the hepatitis C patients (167) were treatment with pegylated interferon plus ribavirin.

Levels of 25-hydroxyvitamin D were measured using high-pressure liquid chromatography. Tissue expression of cytochrome P450 25-hydroxylating liver enzymes (CYP27A1 and CYP2R1) were assessed in 34 hepatitis patients and 8 control subjects.

Results

Serum 25-hydroxyvitamin D levels were significantly lower on average in chronic hepatitis C patients compared with healthy control subjects (25.07 vs 43.06 mcg/L; P < 0.001).

Lower vitamin D levels were independently associated with female sex and liver necro-inflammation.

Levels of CYP27A1, but not CYP2R1, were directly related to vitamin D levels and inversely correlated with necro-inflammation.

Independent predictors of severe liver fibrosis or cirrhosis (stage F3-F4) included:

	Liver necro-inflammation (OR 2.235);
	Older age (OR 1.043);
	High ferritin (a protein that stores iron) (OR 1.003);
	Low cholesterol (OR 0.981);
	Low 25-hydroxyvitamin D (odds ratio [OR] 0.942).

Overall, 70 patients (41%) achieved SVR.

In a multivariate analysis, factors independently associated with poor response, or failure to achieve SVR, included;

	Lower 25-hydroxyvitamin D (OR 1.039);
	Lower cholesterol (OR 1.009);
	Liver steatosis (fatty liver) (OR, 0.971).

Based on these findings, the study authors concluded, "Genotype 1 chronic hepatitis C patients had low [25-hydroxyvitamin D] serum levels, possibly because of reduced CYP27A1 expression."

"Low vitamin D is linked to severe fibrosis and low SVR on interferon-based therapy," they added.

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