New study shows promise in using RNA nanotechnology to treat cancers and viral infections

New study shows promise in using RNA nanotechnology to treat cancers and viral infections

The research team on this study includes (L-R) Markey Cancer Center Director Dr. Mark Evers, Farzin Haque, Dr. Piotr Rychahou, Yi Shu, Dan Shu and Peixuan Guo.



LEXINGTON, Ky. (Sept. 4, 2012) — A new study by University of Kentucky researchers shows promise for developing ultrastable RNA nanoparticles that may help treat cancer and viral infections by regulating cell function and binding to cancers without harming surrounding tissue.

The study, published in Nano Today, was carried out in the laboratory of Peixuan Guo, the William S. Farish Endowed Chair in Nanobiotechnology at the UK Markey Cancer Center, in collaboration with Dr. Mark Evers, director of the UK Markey Cancer Center.

The study uses RNA (ribonucleic acid) as a building block for the bottom-up fabrication of nanostructures. Using the RNA nanotechnology pioneered by Guo, the researchers constructed ultrastable X-shaped RNA nanoparticles using re-engineered RNA fragments to carry up to four therapeutic and diagnostic modules. Their RNA nanoparticles can include small interfering RNA for silencing genes, micro-RNA for regulating gene expression, aptamer for targeting cancer cells, or a ribozyme that can catalyze chemical reactions.

The study demonstrated that regulation of cellular functions progressively increased with the increasing number of functional modules in the nanoparticle.

"RNA nanotechnology is an emerging field, but the instability and degradation of RNA nanoparticles have made many scientists flinch away from the research in RNA nanotechnology," Guo said. "We have addressed these issues, and now it is possible to produce RNA nanoparticles that are highly stable both chemically and thermodynamically in the test tube or in the body with great potential as therapeutic reagents."

The RNA nanoparticles displayed several favorable attributes: polyvalent nature, which allows simultaneous delivery of multiple functional molecules for achieving synergistic effects; modular design, which enables controlled self-assembly with defined structure; thermodynamically stable, which keeps the RNA nanoparticles intact in animal and human circulation systems, where they exist at very low concentrations; and chemically stable, which makes the nanoparticles resistant to RNase (an enzyme, which cleaves RNA) digestion in the blood serum.

"A major problem with cancer treatments is the ability to more directly and specifically deliver anti-cancer drugs to cancer metastases," Evers said. "Using the nanotechnology approach that Peixuan Guo and his group have devised may allow us to more effectively treat cancer metastasis with fewer side effects compared to current chemotherapy."

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In addition to Evers and Markey team member Dr. Piotr Rychahou, Guo's research team at UK also includes Farzin Haque, first author on the paper; Dan Shu; Yi Shu; and Luda Shlyakhtenko.

Best Approach Controversial in Early HCC

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

Best Approach Controversial in Early HCC

BY NEIL OSTERWEIL

IMNG Medical News

ORLANDO – Treatment centers and surgeons appear to play to their strengths when choosing therapy for patients with well-compensated cirrhosis of the liver and early hepatocellular carcinoma, investigators reported at a symposium sponsored by the Society of Surgical Oncology.

The choice of therapy for early HCC with well-compensated cirrhosis has been controversial; there is little agreement on when resection, transplantation, or radiofrequency ablation becomes the best approach.

A web-based survey has now shown that the specific choice of therapy for early HCC often depends on the surgeon’s repertoire of techniques and the therapeutic services the hospital offers.

The survey was completed by centers that had at least five HCC cases per year.

“This study demonstrates that nonclinical factors have an important effect on therapy for early HCC, and in particular, the choice of therapy depends in part on the surgeon’s portfolio of techniques, as well as the availability of transplantation services,” said Dr. Hari Nathan of the department of surgery, Johns Hopkins Hospital in Baltimore.

In a previous analysis of the data from their web-based survey, Dr. Nathan and colleagues found that surgeon specialty Best Approach Controversial in Early HCC was more important than certain patient- specific factors when determining treatment choice ( J. Clin. Oncol. 2011;29: 619-25).

“Differences in choice of therapy for nontransplant and transplant surgeons were not the result of an across-theboard preference for one therapy vs. another. Rather, some clinical factors impacted surgeons differently, depending on their specialty,” he said. In the new analysis, the authors used the survey data to assess the effect of surgeon and hospital factors on the choice of therapy for early, well-compensated HCC, and the effect of regional liver transplantation services on the surgeon’s choice of therapy.

The investigators defined early HCC according to the Milan criteria as a single tumor less than 5 cm in its largest dimension, or two to three tumors less than 3 cm.

Cirrhosis was considered to be well compensated if it was Child- Pugh class A, with no varices, ascites, or encephalopathy.

They presented respondents with case scenarios factoring in age, tumor number and size, type of resection required, etiology of cirrhosis (hepatitis B or C, or alcoholic), biological MELD (Model for End-Stage Liver Disease) score, platelet count, and anticipated transplantation waiting time. Of the 1,032 invitations they extended, 336 surgeons (33%) responded.

Of the respondents, 284 (85%) were in academic practices and 52 (15%) were in community practices for a median of 10 years (range, 4-17 years). Two-thirds (65%) were trained in liver transplantation.

Procedures performed for HCC included transplantation and radiofrequency ablation (41% of responders), transplantation alone (14%), or liver resection but not transplantation (45%).

Asked which procedures were available at their primary hospital (regardless of whether the respondent performed them personally), 100% said that resections were available, and 99% said that ablations were available. In contrast, transplantations were available at 71% of respondents’ hospitals.

The authors found that neither years in practice, surgical oncology training, nor liver transplantation training had a significant effect on treatment choice. Similarly, regional transplantation variables – such as number of procedures, percentage of transplant recipients with HCC, 30th percentile of liver transplantation wait time, and severity of illness by median MELD score – did not significantly predict treatment choice.

There was, however, significant variation in therapeutic choice based on practice type, adjusted for case presentation, with surgeons in academic practices favoring transplantation 57% of the time, compared with 47% for those in community practice.

Community-based surgeons were more likely to favor liver resection (45% vs. 38% for academic surgeons), and radiofrequency ablation (9% vs. 4%).

 In regression analysis that controlled for clinical factors, they found that surgeons in academic settings were significantly less likely than community-based surgeons to recommend ablation over liver transplantation (relative risk ratio [RRR], 0.41; P = .01).

But when they looked at the effect of practice types controlling for surgeons’ specialties, the significance of the practice type on treatment choice disappeared.

Regression analysis also showed that “highervolume surgeons prefer transplantation over resection more strongly than lower-volume surgeons,” Dr. Nathan said.

High-volume surgeons (defined as those performing 30 or more cases annually) were overwhelmingly transplantation surgeons; when the authors adjusted for whether the surgeon performed transplantations, the preference for transplantation disappeared.

Also, nontransplant surgeons who worked at hospitals where transplantations were available were more likely to recommend transplantation over ablation, compared with surgeons working at nontransplantation hospitals.

“Interestingly, they also favored resection over radiofrequency ablation more strongly.

This appeared to be a separate phenomenon than the one that we observed for the portfolio – that’s personally performed by each surgeon – and in regression analyses these effects were independent,” he said. Dr. Nathan reported no relevant financial disclosures.

Coauthor John F.P. Bridges, Ph.D., provided financial and administrative support for the study.

GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Adding Telaprevir to HCV Regimen Worthwhile

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

Adding Telaprevir to HCV Regimen Worthwhile

BY DIANA MAHONEY
IMNG Medical News
SAN DIEGO

"When considered in the context of the improved SVR, “the burden of the increased incidence of anemia and rash associated with telaprevir, of which few cases are severe, appears to be outweighed by the overall treatment response.” Addition of telaprevir to peginterferon/ribavirin therapy for chronic hepatitis C can exacerbate treatment- related side effects, but the triple combination does not diminish patient quality of life relative to the peginterferon/ ribavirin regimen alone, a study has shown."

Adding the protease inhibitor telaprevir “does not further diminish patient quality of life,” lead investigator Dr. Zobair Younossi, AGAF, explained at the annual Digestive Disease Week.

“The most important contributor to the quality of life measurement in interferon therapy is interferon itself, which is so overwhelming in terms of side effects, especially grade 4 and 5 effects, that it probably overshadows everything else.

” Studies have shown that addition of telaprevir to standard peginterferon alfa- 2a/ribavirin (PR) significantly improves treatment efficacy in treatment-naive patients with genotype 1 hepatitis C virus (HCV), but there is a perception that the additional side effect burden from telaprevir is prohibitive in some patients, said Dr. Younossi, chairman of the department of medicine at Inova Health System in Falls Church, Va.

Dr. Younossi and colleagues conducted post hoc analyses of data from the ADVANCE trial, in which adding telaprevir to the treatment mix significantly improved patients’ sustained virologic response compared with standard PR therapy.

In the ADVANCE study, 1,088 treatment- naive HCV genotype 1 patients were assigned to one of three treatment arms: 48 weeks of standard PR therapy; 12 weeks of telaprevir plus 24 weeks PR; or 12 weeks of telaprevir plus 48 weeks of PR.

Nearly 80% of patients in both telaprevir groups achieved sustained virologic response, compared with 46% of patients in the standard PR treatment group (N. Engl. J. Med. 2011; 364:2405-16). In terms of side effects, “across all phase III studies, the incidence of rash and anemia (which are the effects we’re talking about with the protease inhibitors) was 56% and 34%, respectively, among telaprevir-treated patients, and 36% and 17% in patients receiving standard treatment,” Dr. Younossi said.

To assess whether and to what degree these increases played a role in patient quality of life, Dr. Younossi and colleagues analyzed the results of EQ-5D quality of life questionnaires completed at baseline and at weeks 4, 12, 24, 36, 48, and 72 by 722 patients.

The investigators derived a summary index by calculating the percentages of patients reporting problems for each of the five health-related quality of life dimensions measured (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).

After adjustment for age and sex, the baseline mean index values for the EQ- 5D were 0.92 for the telaprevir plus 24- week PR group, 0.90 for the telaprevir plus 48-week PR group, and 0.91 for the 48-week PR-only group.

The percentages of patients reporting any problems in each of the five qualitative dimensions at baseline were 8.2% for mobility, 2.0% for self-care, 12.9% for usual activities, 25.7% for pain/discomfort, and 25.6% for anxiety/depression, he said.

Across all the treatment groups, the EQ-5D index scores worsened during the first 12 weeks of treatment initiation. Specifically, mean values were 0.80 for the pooled-telaprevir groups and 0.83 for the PR-only group, according to Dr. Younossi.

Also, the respective percentages of patients in the pooled-telaprevir and PR-only groups reporting any problems at week 12 were 56% and 50% for usual activities, 51% and 42% for anxiety/depression, and 60% and 63% for pain/discomfort, he said.

Change from baseline in terms of reported impact on mobility and self-care were small and not reported.

At week 48, the corresponding mean EQ-5D values were 0.93 for the telaprevir plus 24-week PR group, 0.83 for the telaprevir plus 48-week PR group, and 0.84 for the PR-only group.

By week 72 the EQ-5D index values returned to baseline levels, Dr. Younossi said.

Adjusted for age and sex, the mean EQ-5D index at week 72 was higher among the patients achieving sustained virologic response (SVR) compared with those who did not, with respective values of 0.90 and 0.86. “The 4% difference is within the range of published values for the minimal clinically important difference for the EQ-5D,” he said.

Furthermore, at week 72, there were fewer patients among those who experienced SVR and reported problems in each dimension, compared with those who did not experience SVR.

At week 72, after adjustment for the index at baseline, patient age, sex, race, advanced liver disease, self-reported comorbidities, and the number of adverse events during treatment, only SVR was a positive predictor of the EQ-5D index.

“We saw that [SVR] was a statistically significant and meaningful predictor of health-related quality of life,” he said. The study findings are consistent with the published research on the impacts of interferon-based regimens on health-related quality of life in this patient population, “and support the value of shorter treatment duration and [SVR] from a patient- reported outcomes perspective,” said Dr. Younossi. “We certainly cannot say that adding telaprevir causes fewer side effects.

It’s clear there are more side effects, but it appears that the most troublesome side effects are related to the interferon therapy,” he explained.

When considered in the context of the improved SVR, “the burden of the increased incidence of anemia and rash associated with telaprevir, of which few cases are severe, appears to be outweighed by the overall treatment response.”

This study was sponsored by Vertex. Dr. Younossi disclosed relationships with Biolex, Vertex, Salix, GlaxoSmithKline, and Tibotec.

GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Drug-Drug Interactions Added to Boceprevir Label

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

BY ELIZABETH MECHCATIE
IMNG Medical News

Drug-Drug Interactions Added to Boceprevir Label

New information about interactions between boceprevir and several other drugs has been added to the prescribing information for the antiviral drug, the Food and Drug Administration announced on Aug. 1.

Boceprevir (Victrelis), a protease inhibitor approved for treating hepatitis C in 2011, interacts with cyclosporine, tacrolimus (Prograf ), escitalopram (Lexapro), atorvastatin (Lipitor), and pravastatin (Pravachol), according to the FDA statement. The new information states that exposure to atorvastatin increases when given with boceprevir.

If the two drugs are used together, the lowest effective dose of atorvastatin should be used, not to exceed a daily dose of 40 mg, according to the FDA.

Dose adjustments of cyclosporine should be expected when it is given with boceprevir. Cyclosporine dosage “should be guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects.” When administered with boceprevir, exposure of escitalopram “was slightly decreased,” the statement said. Although selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, it may be necessary to adjust the dosage when it is administered with boceprevir.

Coadministration of boceprevir with pravastatin increases exposure to pravastatin, but pravastatin can be started at the recommended dosage when coadministered with boceprevir. “Close clinical monitoring is warranted,” the statement said. Giving tacrolimus and boceprevir together “requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects,” the statement said.

Boceprevir is manufactured in a capsule formulation by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., and is taken by mouth three times a day.

The drug-drug interaction data are from in vivo drug interaction trials, which the company conducted as part of its postmarketing commitments.

At a meeting in April 2011, an FDA advisory panel enthusiastically supported the approval of boceprevir for treating hepatitis C infection because of the antiviral’s efficacy, but emphasized that postmarketing studies on interactions with other drugs, including antidepressants, were needed. ■

The revised prescribing information is available at www.accessdata.fda . gov/drugsatfda_docs/label/2012/ 202258s001lbl.pdf ?source= govdelivery .

Serious adverse events associated with boceprevir should be reported to MedWatch at 800- 332-1088 or www.fda.gov/ medwatch
.
GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Disparities Affect Inpatient Mortality in HCC

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

Disparities Affect Inpatient Mortality in HCC

Compared with white patients,Asian Americans had 60% higher inpatient mortality

BY MITCHEL L. ZOLER IMNG
Medical News

SAN DIEGO –
African Americans and Asian Americans with hepatocellular carcinoma had significantly worse inpatient mortality than did white patients, and the data suggest that socioeconomic disparities in availability of health services may at least partially explain the difference.

In a multivariate analysis that also applied propensity-score matching, African American inpatients with hepatocellular carcinoma (HCC) were 30% more likely to die, compared with their white counterparts, and Asian Americans had a 60% higher inpatient mortality, compared with white Americans who had HCC.

The findings were based on data collected from 27,741 patients during 2002-2011 by the University Health Consortium, Dr. Sabeen F. Medvedev said at the annual Digestive Disease Week.

The data analyzed by Dr. Medvedev and her associates showed a broad range of disparities by racial and ethnic groups for type of medical coverage, disease severity at the time of hospitalization, presence of metastatic disease, and whether patients received invasive treatment or liver transplantation.

“Despite increased survival due to advances in surveillance and surgical interventions for HCC, we found racial disparities exist in prognosis and disease presentation,” said Dr. Medvedev of the division of gastroenterology and liver diseases at the George Washington University in Washington.

After propensity scores to mimic randomization of treatment options were used, a 60% excess mortality in African Americans, compared with whites, was reduced to a 30% excess, “indicating that the observed disparity in deaths might extend beyond disproportionate treatment allocation.

The take home message is, due to their insurance and economic status and lack of access to care, African Americans did not have as many treatment options,” Dr. Medvedev said. “We think this is a delivery-of-care issue,” she added in an interview.

The University Health Consortium includes 116 U.S. academic medical centers and 272 of their affiliated hospitals – about 90% of America’s nonprofit academic medical centers.

HCC patients who were treated during the 9 years studied had a median age of 61 years; 54% of them were white, 16% were African American
11% Asian, 9% Hispanic, and 10% were from other ethnic groups.

The white subgroup had the highest percentage of patients with private medical insurance (41%) and the lowest rate of Medicaid or uninsured status (15%). In contrast, among African Americans, 30% had private insurance, and 37% received Medicaid or were uninsured. Among Asian Americans, 38% had private insurance, and 30% had Medicaid or were uninsured.

An analysis of disease presentation and treatments applied showed that the African American and Asian American subgroups each had a 20% higher rate of HCC metastasis at the time of hospitalization, compared with the white subgroup.

African Americans also received significantly fewer liver transplants, resections, ablations, and transarterial chemoembolizations, compared with the white subgroup.

Asian Americans received significantly fewer transarterial chemoembolizations, compared with whites, but their rates for other types of treatments were similar to the rates seen in the white subgroup. The only treatment received significantly less often by Hispanic patients, compared with whites, was resection.

 Dr. Medvedev said that she had no disclosures.

GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Design help for drug cocktails

Design help for drug cocktails

Harvard researchers create a mathematical model that helps to design efficient multi-drug therapies

For years, doctors treating those with HIV have recognized a relationship between how faithfully patients take the drugs they prescribe, and how likely the virus is to develop drug resistance. More recently, research has shown that the relationship between adherence to a drug regimen and resistance is different for each of the drugs that make up the "cocktail" used to control the disease.
New research conducted by Harvard scientists could help explain why those differences exist, and may help doctors quickly and cheaply design new combinations of drugs that are less likely to result in resistance.

As described in a September 2 paper in Nature Medicine, a team of researchers led by Martin Nowak, Professor of Mathematics and of Biology and Director of the Program for Evolutionary Dynamics, have developed a technique medical researchers can use to model the effects of various treatments, and predict whether they will cause the virus to develop resistance.

"What we demonstrate in this paper is a prototype for predicting, through modeling, whether a patient at a given adherence level is likely to develop resistance to treatment," Alison Hill, a PhD student in Biophysics and co-first author of the paper, said. "Compared to the time and expense of a clinical trial, this method offers a relatively easy way to make these predictions. And, as we show in the paper, our results match with what doctors are seeing in clinical settings."
The hope, said Nowak, is that the new technique will take some of the guesswork out of what is now largely a trial-and-error process.

"This is a mathematical tool that will help design clinical trials," he said. "Right now, researchers are using trial and error to develop these combination therapies. Our approach uses the mathematical understanding of evolution to make the process more akin to engineering."
Creating a model that can make such predictions accurately, however, requires huge amounts of data.
To get that data, Hill and Daniel Scholes Rosenbloom, a PhD student in Organismic and Evolutionary Biology and the paper's other first author, turned to Johns Hopkins University Medical School, where Professor of Medicine and of Molecular Biology and Genetics Robert F. Siliciano was working with PhD student Alireza Rabi (also co-first author) to study how the HIV virus reacted to varying drug dosages.

Such data proved critical to the model that Hill, Rabi and Rosenbloom eventually designed, because the level of the drug in patients – even those that adhere to their treatment perfectly – naturally varies. When drug levels are low – as they are between doses, or if a dose is missed – the virus is better able to replicate and grow. Higher drug levels, by contrast, may keep the virus in check, but they also increase the risk of mutant strains of the virus emerging, leading to drug resistance.
Armed with the data from Johns Hopkins, Hill, Rabi and Rosenbloom created a computer model that could predict whether and how much the virus, or a drug-resistant strain, was growing based on how strictly patients stuck to their drug regimen.

"Our model is essentially a simulation of what goes on during treatment," Rosenbloom said. "We created a number of simulated patients, each of whom had different characteristics, and then we said, 'Let's imagine these patients have 60 percent adherence to their treatment – they take 60 percent of the pills they're supposed to.' Our model can tell us what their drug concentration is over time, and based on that, we can say whether the virus is growing or shrinking, and whether they're likely to develop resistance."

The model's predictions, Rosenbloom explained, can then serve as a guide to researchers as they work to design new drug cocktails to combat HIV.

While their model does hold out hope for simplifying the process of designing drug "cocktails," Hill and Rosenbloom said they plan to continue to refine the model to take additional factors – such as multiple mutant-resistant strains of the virus and varying drug concentrations in other parts of the body – into effect.

"The prototype we have so far looks at concentrations of drugs in blood plasma," Rosenbloom explained. "But a number of drugs don't penetrate other parts of the body, like the brains or the gut, with the same efficiency, so it's important to model these other areas where the concentrations of drugs might not be as high."
Ultimately, though, both say their model can offer new hope to patients by helping doctors design better, cheaper and more efficient treatments.

"Over the past 10 years, the number of HIV-infected people receiving drug treatment has increased immensely," Hill said. "Figuring out what the best ways are to treat people in terms of cost effectiveness, adherence and the chance of developing resistance is going to become even more important."

http://www.eurekalert.org/pub_releases/2012-09/hu-dhf083112.php

Video - NMA Viral Hepatitis C

National Medical Association holds seminar on Viral Hepatitis C during its Annual Convention and Scientific Assembly in New Orleans

Published on Aug 31, 2012 by louisianahometown

Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians

World J Hepatol 2012 August 27; 4(8): 242-247

World J Hepatol. 2012 August 27; 4(8): 242-247.
Published online 2012 August 27. doi: 10.4254/wjh.v4.i8.242.


Relationship between vitamin D and IL-23, IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians

Noha M El Husseiny, Hala M Fahmy, Waleed A Mohamed and Hisham H Amin.
Noha M El Husseiny, Hala M Fahmy, Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo 11111, Egypt
Waleed A Mohamed, Department of Chemistry, Cairo University, Cairo 12534, Egypt
Hisham H Amin, Clinical Pathology Department, Faculty of Medicine AL Azhar University, Cairo 15533, Egypt

Author contributions: El Husseiny NM did the statistics and wrote the manuscript; Mohamed WA put the idea of the research, collected the data and did the laboratory work; Fahmy HM participated in the idea of the research and participated in writing the manuscript; Amin HH participated in the laboratory work and data collection.

Correspondence to: Noha M El Husseiny, MD, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 11111, Egypt. dr_noha2002@yahoo.com
Telephone: +20-100-6803571 Fax: +20-223-667260
Received January 1, 2012; Revised August 6, 2012; Accepted August 23, 2012;

 

 

Discussion Only

 

 Full Text available at WJH World Journal Of Hepatology

 

The liver plays a central role in vitamin D metabolism. Vitamin D inadequacy is common in non-cholestatic chronic liver diseases and correlates with disease severity. The current study showed a significant reduction of vitamin D and its active metabolites in HCV genotype 4-infected patients compared to healthy controls. This reduction was more prevalent and severe in cirrhotic vs non-cirrhotic patients. This is consistent with previous studies done on patients with genotype 1, which showed that vitamin D deficiency is universal (92%) among patients with chronic liver disease, and at least one-third of the patients have severe vitamin D deficiency[^14-16].

 

Our results showed that IL-23 and -17 were markedly increased in HCV-infected patients in comparison to controls. Regulation of Th1 and Th17 responses in HCV-infected individuals was studied, and it was reported that TGF-β and IL-6 promote differentiation of naive murine CD4⁺ T cells into IL-17-secreting Th17 cells. In addition, it has been reported that other innate cytokines, including IL-1, IL-23, TNF-α, and IL-21, in different combinations or with TGF-β, are also involved in differentiation, amplification, or stabilization of the Th17 phenotype[^17,18].

 

Our study reported that there is a significant negative correlation between vitamin D and IL-17 and -23. Previous studies on mice showed that vitamin D is a strong inhibitor of Th17 polarization and Th17 cytokine expression of splenic CD4+ T cells. Furthermore, Th17 differentiation from naïve T cells was affected by vitamin D. These data implicate a regulatory mechanism on Th17 cells by vitamin D, through the reduction of RORgt expression[¹⁹].

 

The effect of vitamin D on the behavior of Th17 cells was investigated in different diseases and it was found that vitamin D suppressed the expression of IL-17 and -23[^20-23].

 

We reported a positive correlation between IL-23 and -17 with viral load, a finding which further support our suggestion regarding the link between vitamin D and both IL-17 and -23 in immune regulation in HCV genotype IV-related chronic liver disease. These findings may support our suggestion that increased IL-17 and -23 could be, at least in part, involved in the role of vitamin D in the immune response in HCV genotype IV-related liver disease and explain how vitamin D deficiency plays a role in increasing liver fibrosis.

 

Our results revealed HCV-infected males and females had no differences with respect to vitamin D levels. In contrast with our results, Arteh et al[²⁴] who reported that African American females with chronic liver disease are at higher risk of vitamin D deficiency.

Our study showed that the viral load mean value was 1.28 × 10⁵ ± 28 × 10³ IU/mL. A significant negative correlation was reported between vitamin D and active vitamin D and viral load (P = 0.0001 and P = 0.001, respectively).

 

Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and SVR rates in HCV as reduced 25-hydroxyvitamin D levels and CYPB27-1260 promotor polymorphism with reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotypes 1-, 2-, and 3-infected patients[^9,25]. Our HCV patients with genotype IV need further follow up to confirm the effect of vitamin D deficiency on their responses to treatment.

 

There was a significant increase in level of MCP-1 in our patients with all grades of hepatic affection in comparison to controls. Similar results were reported by Camps et al[²⁶]. However, Panasiuk et al[²⁷] reported a decrease in the MCP-1 level in liver cirrhosis in comparison to the controls and did not reflect any inflammatory process in liver cirrhosis. More studies are needed to explore this point of controversy.

 

Our results also revealed a significant negative correlation between vitamin D and MCP-1. This supports the role of decreased vitamin D in inflammation and fibrosis. No previous work in hepatic patients studied this relationship. However, Zehnder et al[²⁸] reported that reduction of the vitamin D hormonal system in kidney disease was associated with increased renal inflammation and fibrosis. Zehnder et al[²⁸] reported a significant negative correlation between vitamin D and MCP-1. Logistic regression analysis with urinary MCP-1 as a binary outcome showed that a 10-unit increase in serum 1,25(OH)₂D or 25OHD resulted in lower renal inflammation[²⁸].

 

On classifying HCV-infected patients according to sonar finding into four groups, vitamin D and active vitamin D were shown to be lower in cirrhotic patients and much lower in patients with HCC, and this difference was highly significant (P = 0.0001). IL-17 and -23 and MCP-1 were higher in advanced liver disease) and the differences were highly significant (P = 0.0001). These findings are concomitant with previous results which indicate that vitamin D inadequacy is common in non-cholestatic chronic liver diseases and correlates with disease severity[¹⁴]. The difference in viral load among these groups may explain in part the difference in levels of inflammatory cytokines.

 

In conclusion, vitamin D deficiency is prevalent in HCV genotype IV-infected patients and viral load is negatively correlated to vitamin D. Whether or not this deficiency is related to HCV-induced chronic liver disease or predisposing factor for higher viral load is a matter of debate. In view of the immune function of vitamin D, vitamin D status may be assessed and supplements may be considered to achieve a SVR with IFN-based therapy. The negative correlation between vitamin D and IL-23 and -17 and MCP-1 may highlight, at least in part, how these cytokines might be involved with vitamin D in immune responses in HCV genotype IV-related liver disease and may explain how vitamin D deficiency plays a role in increasing liver fibrosis.

 

http://www.wjgnet.com/1948-5182/full/v4/i8/242.htm