Skip Navigation LinksHome > January 14, 2013 - Volume 27 - Issue 2 > Low vitamin D levels are associated with impaired virologic...
AIDS:
doi: 10.1097/QAD.0b013e32835aa161
Clinical Science: Concise Communications

Low vitamin D levels are associated with impaired virologic response to PEGIFN + RBV therapy in HIV–hepatitis C virus coinfected patients

Mandorfer, Mattiasa; Reiberger, Thomasa; Payer, Berit A.a; Ferlitsch, Arnulfa; Breitenecker, Floriana; Aichelburg, Maximilian C.b; Obermayer-Pietsch, Barbarac; Rieger, Arminb; Trauner, Michaela; Peck-Radosavljevic, Markusa; the Vienna HIV & Liver Study Group

Free Access
Article Outline
Collapse Box

Author Information

aDivision of Gastroenterology and Hepatology, Department of Internal Medicine III

bDivision of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna

cDivision of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Styria, Austria.

Correspondence to Professor Markus Peck-Radosavljevic, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria. Tel: +43 140400 6589; fax: +43 140400 4735; e-mail: markus.peck@meduniwien.ac.at

Received 10 April, 2012

Revised 10 May, 2012

Accepted 21 September, 2012

Collapse Box

Abstract

Background: Low 25-hydroxyvitamin D [25(OH)D] levels are commonly found in HIV–hepatitis C virus (HCV) coinfected patients and are associated with liver fibrosis. No association between 25(OH)D levels and response to pegylated interferon α-2a/2b plus ribavirin (PEGIFN + RBV) has yet been reported for HIV–HCV coinfected patients.

Design: Epidemiological characteristics, HIV and HCV infection parameters, liver biopsies, as well as data on virologic response was available in 65 patients who received chronic hepatitis C (CHC) therapy with PEGIFN + RBV within a prospective trial. 25(OH)D levels were retrospectively assessed using stored screening serum samples obtained within 35 days prior to CHC treatment.

Methods: According to their 25(OH)D levels, patients were assigned to the normal (>30 ng/ml; D-NORM), the insufficiency (10–30 ng/ml; D-INSUFF), or the deficiency (<10 ng/ml; D-DEF) group. HCV-GT 1/4, high HCV-RNA load (>6 × 105 IU/ml), advanced liver fibrosis (METAVIR F3/F4), and IL28B rs12979860non-C/C were considered as established risk factors for treatment failure in HIV–HCV coinfected patients.

Results: Thirty-seven (57%) and 15 (23%) patients presented with D-INSUFF and D-DEF, respectively, whereas only 13 (20%) patients had normal 25(OH)D levels. Substantial differences in cEVR (D-NORM 92% vs. D-INSUFF 68% vs. D-DEF 47%; P = 0.008) and SVR (D-NORM 85% vs. D-INSUFF 60% vs. D-DEF 40%; P = 0.029) rates were observed between 25(OH)D subgroups. Especially in difficult-to-treat patients with multiple (three to four) established risk factors, low 25(OH)D levels were clearly associated with lower rates of SVR [patients without 25(OH)D deficiency 52% vs. D-DEF 0%; P = 0.012].

Conclusion: Low 25(OH)D levels may impair virologic response to PEGIFN + RBV therapy, especially in difficult-to-treat patients. Vitamin D supplementation should be considered and evaluated prospectively in HIV–HCV coinfected patients receiving CHC treatment.

Back to Top | Article Outline

Introduction

Liver disease is the second leading cause of death in patients infected with HIV [1]. When compared to hepatitis C virus (HCV) monoinfection, HIV–HCV coinfection, observed in 25–30% of European and US HIV-positive patients [2], was found to be associated with higher rates of liver fibrosis progression [3] and markedly higher risks of cirrhosis and end-stage liver disease [4]. In HIV–HCV coinfected patients, therapy-restricting contraindications, considerably lower rates of treatment initiation, and lower rates of virologic response to pegylated interferon-α-2a/2b plus ribavirin (PEGIFN + RBV) complicate chronic hepatitis C (CHC) therapy when compared to HCV monoinfection [5,6].

Low serum 25-hydroxyvitamin D [25(OH)D] levels were frequently found in both HCV monoinfected [7] and HIV–HCV coinfected [8] patients. Gal-Tanamy et al.[9] demonstrated in vitro that vitamin D acts directly as an antiviral agent by inhibiting HCV production in a human hepatoma cell line. Additionally, a synergistic inhibitory effect of vitamin D and interferon-α on HCV production was reported. In HCV monoinfected patients with recurrent hepatitis C after liver transplant, higher rates of virologic response were observed in those receiving vitamin D supplementation [10]. Finally, in a randomized prospective trial including only CHC treatment-naive HCV-genotype (HCV-GT) 1 patients, higher rates of virologic response were achieved in the group receiving vitamin D supplementation [11].

In the two studies on 25(OH)D levels in HIV–HCV coinfected patients published to date [8,12], low 25(OH)D levels were found to be associated with advanced liver fibrosis. However, none of these studies observed an association between 25(OH)D levels and virologic response.

Thus, the aim of our study was to assess the association of low 25(OH)D levels with virologic response to PEGIFN + RBV in HIV–HCV coinfected patients while considering established risk factors for treatment failure.

Back to Top | Article Outline

Patients and methods

Study population

A total of 65 HIV–HCV coinfected patients treated with PEGIFN + RBV at the Medical University of Vienna within a prospective trial were included in this study. Inclusion requirements consisted of the availability of a liver biopsy, 25(OH)D and HCV-RNA levels, interleukin 28B (IL28B) rs12979860 single nucleotide polymorphism (SNP), CD4+ T-lymphocyte counts as well as information on virologic response. All patients had compensated liver disease, were naive to pegylated interferon-α-based CHC therapy, and free of malignancies as well as significant cardiac, pulmonary or renal disease. None of the patients was receiving vitamin D supplements.

Back to Top | Article Outline
Blood sampling and interleukin28B rs12979860 SNP testing

25(OH)D levels were retrospectively assessed using stored screening serum samples obtained within 35 days prior to CHC treatment and a commercially available enzyme immunoassay (IDS; Boldon, Tyne and Wear, UK). In order to maintain comparability with the studies on 25(OH)D in HIV–HCV coinfected individuals published to date [8,12], patients were assigned to the normal (>30 ng/ml; D-NORM), the insufficiency (10–30 ng/ml; D-INSUFF) or the deficiency (<10 ng/ml; D-DEF) group. HCV-GT and serum HCV-RNA levels were determined using commercially available assays [VERSANT HCV Genotype 2.0 Assay (LiPA) (Siemens, Vienna, Austria) and COBAS TaqMan HCV Test (Roche, Vienna, Austria)]. High HCV-RNA load was defined as HCV-RNA levels more than 6 × 105 IU/ml. Serum CD4+ T-lymphocyte counts were determined using standard flow fluorocytometry. The IL28B rs12979860 SNP was analyzed as described previously using the Step One Plus Real Time PCR System (Applied Biosystems, Carlsbad, California, USA) and a Custom TaqMan SNP Genotyping Assay [13].

Back to Top | Article Outline
Liver biopsy

Liver fibrosis was assessed according to the METAVIR classification [14]. METAVIR F3 and F4 were denoted as advanced liver fibrosis.

Back to Top | Article Outline
Chronic hepatitis C treatment

All patients were treated with pegylated interferon-α-2a (180 μg) or pegylated interferon-α-2b (1.5 μg/kg body weight) once a week. HCV-GT 1/4 patients received 1000–1200 mg ribavirin, whereas HCV-GT 2/3 patients received 800 mg ribavirin daily. Treatment duration was 48 weeks, except for HCV-GT 1/4 patients without rapid virologic response (RVR), who were treated for 72 weeks. RVR, complete early virologic response (cEVR), and sustained virologic response (SVR) were defined as undetectable HCV-RNA at week 4 or 12 on treatment and 24 weeks after the end of CHC treatment, respectively.

Back to Top | Article Outline
Risk factors for treatment failure

In accordance with previous studies [15,16], HCV-GT 1/4, high HCV-RNA load, advanced liver fibrosis, and IL28B rs12979860 non-C/C SNP were considered as established risk factors for treatment failure.

Back to Top | Article Outline
Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics 19 (SPSS Inc., Armok, New York, USA). Continuous variables were reported as median (range), whereas categorical variables were reported as number (proportion) of patients with the certain characteristic. One-way analysis of variance (ANOVA) with Scheffe posthoc comparisons was used for group comparisons of continuous variables when applicable. Otherwise, Kruskal–Wallis one-way ANOVA and Mann–Whitney U-test with Bonferroni correction for posthoc comparisons were applied. Group comparisons of categorical variables were performed using Fisher's Exact Test. A P value of 0.05 was considered statistically significant.

Back to Top | Article Outline
Ethics

This study was conducted with the understanding and the consent of each participant and approved by the local ethics committee of the Medical University of Vienna (EKN 1099/2011).

Back to Top | Article Outline

Results

Patient characteristics
25-hydroxyvitamin D levels

Although 37 (57%) and 15 (23%) patients presented with D-INSUFF and D-DEF, respectively, 13 (20%) patients had D-NORM (Table 1). 25(OH)D levels varied seasonally between 18.4 (71.5), 26.1 (41.2), 18.8 (34.5), and 10.95 (24.2) ng/ml in quarters 1, 2, 3, and 4, respectively (P = 0.031).

Table 1
Table 1
Image Tools
Back to Top | Article Outline
25-hydroxyvitamin D levels and risk factors for treatment failure

The prevalence of HCV-GT 1/4 and high baseline HCV-RNA load did not vary statistically significantly throughout the 25(OH)D groups (P = 0.36 and P = 0.214, respectively) (Table 1).

The proportion of patients with IL28B rs12979860non-C/C SNP in the D-INSUFF group (81%) was higher than in the D-NORM group (39%) (P = 0.007), but did not differ significantly from the D-DEF group (53%) (P = 0.081). The frequency of patients with IL28B rs12979860 non-C/C SNP observed in the D-NORM group and the D-DEF group was not statistically different (P = 0.476).

Advanced liver fibrosis was found in 63% of 25(OH)D-deficient patients, 40% of 25(OH)D-insufficient patients and 13% of patients with D-NORM. Patients with D-DEF displayed a higher prevalence of advanced liver fibrosis than patients with D-NORM (P = 0.009), whereas the difference between patients with D-INSUFF and both patients with D-DEF and D-NORM was not statistically significant (P = 0.073 and P = 0.179, respectively).

Back to Top | Article Outline
25-hydroxyvitamin D levels and virologic response

The observed RVR rates did not differ statistically significantly between the 25(OH)D groups (P = 0.406) (Table 1).

Ninety-two percent of patients with D-NORM, 68% of patients with D-INSUFF and 47% of patients with D-DEF showed cEVR. Patients with D-DEF displayed lower cEVR rates than patients with D-NORM (P = 0.016), whereas the difference between patients with D-INSUFF and both patients with D-NORM and D-DEF was not statistically significant (P = 0.078 and P = 0.213, respectively) (Table 1, Fig. 1a).

Fig. 1
Fig. 1
Image Tools

SVR was observed in 85% of patients with D-NORM, 60% of patients with D-INSUFF and 40% of patients with D-DEF. When compared to patients with D-NORM, patients with D-DEF showed lower SVR rates (P = 0.024). Although substantial, the differences in SVR rates between the D-INSUFF groups compared to both the D-NORM and the D-DEF groups were not statistically significant (P = 0.173 and P = 0.234, respectively).

Back to Top | Article Outline
25-hydroxyvitamin D levels, virologic response, and risk factors for treatment failure

The study population was separated into two subgroups: patients with 0–2 risk factors and patients with 3–4 risk factors for treatment failure (HCV-GT 1/4, advanced fibrosis, high HCV-RNA levels, and IL28B rs12979860 non-C/C SNP) (Table 1, Fig. 1b).

Among patients with 0–2 risk factors, the SVR rates in patients with and without D-DEF were comparable (86 and 76%, respectively; P = 0.67). In contrast, patients with 3–4 risk factors and D-DEF showed lower SVR rates than their counterparts without D-DEF (P = 0.012). No patient with D-DEF obtained SVR, whereas SVR was obtained in 52% of patients without D-DEF.

The fraction of patients with D-DEF that carried 3–4 risk factors was comparable to patients without D-DEF (53 and 42%, respectively; P = 0.557).

Back to Top | Article Outline

Discussion

In line with previous studies, we observed a high prevalence of vitamin D insufficiency (D-INSUFF) and deficiency (D-DEF) in our study population of HIV–HCV coinfected patients [8,12].

Apart from low 25(OH)D levels in quarter 4, seasonal variation observed in this study was less pronounced when compared to studies on healthy white individuals [17]. This finding suggests that the modulating effect of sun exposure on 25(OH)D levels in HIV–HCV coinfected patients is not as pronounced as in healthy individuals because of other interfering factors.

Although several retrospective studies, as well as randomized prospective trials, in HCV-monoinfected patients reported a statistically significant association between both 25(OH)D levels and vitamin D supplementation and virologic response [7,10,11,18,19], none of the two retrospective studies in HIV–HCV-monoinfected patients found a statistically significant relationship [8,12]. However, potential limitations of both studies have to be considered. In the study by Milazzo et al.[12], the analysis of factors associated with SVR was performed in a relatively small group of 51 patients, of whom 20 were not naive to interferon-based CHC treatment, which further limits their conclusions and could explain the surprisingly low rate of SVR of 24%. Another study by Terrier et al.[8] analyzed factors associated with SVR in 189 HIV–HCV coinfected patients, whereas the applied treatment regimens were inconsistent. Ninety-four and 95 patients received interferon–ribavirin and PEGFIFN + RBV, respectively. The corresponding SVR rates were 27 and 38%, resulting in a modest overall SVR rate of 32%. None of the two previous studies reported data on IL28B rs12979860 SNP.

In the present study, the difference between both cEVR and SVR rates among patients with D-DEF and D-NORM was statistically significant. In absolute numbers, cEVR and SVR rates were about half as high in patients with D-DEF when compared to patients with D-NORM, reflecting a clinically relevant effect. Partially conflicting results have been reported on the association of RVR with 25(OH)D levels in HCV-monoinfected patients. Although a statistically significant association was found by Bitetto et al.[19], no such association was reported by Lange et al.[7]. Along with our findings, it might be concluded that the impact of 25(OH)D levels on RVR rates is less pronounced than on cEVR and SVR rates.

We demonstrated that the association between 25(OH)D levels and SVR rates is limited to difficult-to-treat patients with multiple risk factors for treatment failure. This hypothesis is supported by a study from Bitetto et al.[19] in HCV-monoinfected patients in which the combined influence of 25(OH)D levels and IL28B rs12979860 SNP on SVR was solely observed in patients with difficult-to-treat HCV-GT 1/4/5.

We have to acknowledge the potential limitations of our study such as the retrospective design and the potential lack of statistical power to detect differences in RVR rates.

In conclusion, our study demonstrates that low 25(OH)D levels are associated with considerably lower rates of cEVR and SVR in HIV–HCV coinfected patients. The latter finding was limited to difficult-to-treat patients with multiple risk factors for treatment failure. Thus, our findings, together with the evidence derived from the above-described prospective study in HCV-monoinfected patients [11], suggest that vitamin D supplementation may result in higher rates of virologic response in HIV–HCV coinfected patients. Prospective randomized trials on vitamin D supplementation in HIV–HCV coinfected patients receiving CHC therapy are highly encouraged.

Back to Top | Article Outline

Acknowledgements

Study concept and design (M.M., T.R., and M.P.R.), acquisition of data (T.R., B.A.P., A.F., F.B., M.C.A., B.S., and A.R.), measurement of 25(OH)D levels (B.O.P.), analysis and interpretation of data (M.M., T.R., M.T., and M.P.R.), drafting of the manuscript (M.M. and T.R.), critical revision of the manuscript for important intellectual content (M.M., T.R., B.A.P., A.F., B.F., M.C.A., B.O.P., A.R., M.T., and M.P.R.).

This work was supported by a grant from Roche Austria to M.P.R.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS 2010; 24:1537–1548.

2. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006; 44:S6–S9.

3. Reiberger T, Ferlitsch A, Sieghart W, Kreil A, Breitenecker F, Rieger A, et al. HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat 2010; 17:400–409.

4. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–569.

5. Reiberger T, Obermeier M, Payer BA, Baumgarten A, Weitner L, Moll A, et al. Considerable under-treatment of chronic HCV infection in HIV patients despite acceptable sustained virological response rates in a real-life setting. Antivir Ther 2011; 16:815–824.

6. Mehta SH, Lucas GM, Mirel LB, Torbenson M, Higgins Y, Moore RD, et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS 2006; 20:2361–2369.

7. Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011; 54:887–893.

8. Terrier B, Carrat F, Geri G, Pol S, Piroth L, Halfon P, et al. Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis. J Hepatol 2011; 55:756–761.

9. Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, et al. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology 2011; 54:1570–1579.

10. Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transplant 2011; 24:43–50.

11. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients. World J Gastroenterol 2011; 17:5184–5190.

12. Milazzo L, Mazzali C, Bestetti G, Longhi E, Foschi A, Viola A, et al. Liver-related factors associated with low vitamin D levels in HIV and HIV/HCV coinfected patients and comparison to general population. Curr HIV Res 2011; 9:186–193.

13. Payer BA, Reiberger T, Aberle J, Ferenci P, Holzmann H, Rieger A, et al. IL28B and interferon-gamma inducible protein 10 for prediction of rapid virologic response and sustained virologic response in HIV-HCV-coinfected patients.Eur J Clin Invest 2012; 42:599–606.

14. Theise ND. Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach. Mod Pathol 2007; 20 (Suppl 1):S3–S14.

15. Medrano J, Neukam K, Rallon N, Rivero A, Resino S, Naggie S, et al. Modeling the probability of sustained virological response to therapy with pegylated interferon plus ribavirin in patients coinfected with hepatitis C virus and HIV. Clin Infect Dis 2010; 51:1209–1216.

16. Neukam K, Camacho A, Caruz A, Rallon N, Torres-Cornejo A, Rockstroh JK, et al.Prediction of response to pegylated interferon plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients using HCV genotype, IL28B variations, and HCV-RNA load.J Hepatol 2012; 56:788–794.

17. Harris SS, Dawson-Hughes B. Seasonal changes in plasma 25-hydroxyvitamin D concentrations of young American black and white women. Am J Clin Nutr 1998; 67:1232–1236.

18. Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, Bono A, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010; 51:1158–1167.

19. Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, et al. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology 2011; 53:1118–1126.

Cited By:

This article has been cited 1 time(s).

American Journal of Clinical Nutrition
In HIV/hepatitis C virus co-infected patients, higher 25-hydroxyvitamin D concentrations were not related to hepatitis C virus treatment responses but were associated with ritonavir use
Branch, AD; Kang, M; Hollabaugh, K; Wyatt, CM; Chung, RT; Glesby, MJ
American Journal of Clinical Nutrition, 98(2): 423-429.
10.3945/ajcn.112.048785
CrossRef
Back to Top | Article Outline
Keywords:

coinfection; hepatitis C virus; HIV; liver disease; virologic response; vitamin D deficiency

© 2013 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.