D Increases Sustained Response to Interferon-based Therapy for
Hepatitis C, May Improve Liver Fibrosis
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
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
of participants receiving vitamin D achieved rapid virological
response (undetectable HCV at week 4), compared with 18%
in the control group (P < 0.0001).
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).
of patients in the vitamin D group achieved SVR, compared
with 43% in the control group (P < 0.001).
events were mostly mild and were typical of those associated
with pegylated interferon/ribavirin (mainly flu-like symptoms).
serious adverse events were reported.
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.
Response and Fibrosis
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.
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
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.
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).
vitamin D levels were independently associated with female
sex and liver necro-inflammation.
of CYP27A1, but not CYP2R1, were directly related to vitamin
D levels and inversely correlated with necro-inflammation.
predictors of severe liver fibrosis or cirrhosis (stage
necro-inflammation (OR 2.235);
age (OR 1.043);
ferritin (a protein that stores iron) (OR 1.003);
cholesterol (OR 0.981);
25-hydroxyvitamin D (odds ratio [OR] 0.942).
70 patients (41%) achieved SVR.
a multivariate analysis, factors independently associated
with poor response, or failure to achieve SVR, included;
25-hydroxyvitamin D (OR 1.039);
cholesterol (OR 1.009);
steatosis (fatty liver) (OR, 0.971).
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.
Mouch study: Hepatology Unit and Internal Medicine B, Hillel
Yaffe Medical Center, Hadera, Israel; Faculty of Medicine, Technion,
Haifa, Israel; Gastroenterology, Hillel Yaffe Medical Center,
Hadera, Israel; Liver Unit, Ziv Medical Center, Safed, Israel.
Petta study: Cattedra ed Unità Operativa di Gastroenterologia,
DiBiMIS, University of Palermo, Italy; Dipartimento di Biopatologia
e Metodologie Biomediche, University of Palermo, Italy; IBIM
Consiglio Nazionale delle Ricerche, Palermo, Italy; Dipartimento
di Biotecnologie Mediche e Medicina Legale Sezione Chimica e
Biochimica Medica, University of Palermo, Italy; Cattedra di
Anatomia Patologica, University of Palermo, Italy; Dipartimento
di Medicina e Gastroenterologia, "Alma Mater Studiorum,"
University of Bologna, Italy.
S Abu Mouch, Z Fireman, J Jarchovsky, and N Assy. Vitamin D
supplement improve SVR in chronic hepatitis C (genotype 1) naive
patients treated with peg interferon and ribavirin. 45th Annual
Meeting of the European Association for the Study of the Liver
(EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).
S Petta, C Camma, C Scazzone, and others. Low vitamin D serum
level is related to severe fibrosis and low responsiveness to
interferon-based therapy in genotype 1 chronic hepatitis C.
Hepatology 51(4): 1158-1167 (Abstract).