Association of Vitamin D Serum Levels and Its Common Genetic Determinants, With Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C Patients

S. Petta, S. Grimaudo, V. D. Marco, C. Scazzone, F. S. Macaluso, C. Cammà, D. Cabibi, R. Pipitone, A. Craxì

J Viral Hepat. 2013;20(7):486-493.

Abstract and Introduction

Abstract

Lower 25-hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

Introduction

The key issue in patients with chronic hepatitis C (CHC) is the progression of liver fibrosis as a consequence of various mechanisms of tissue damage caused by viral infection,^[1] with the ultimate development of cirrhosis and its complications.

Other than well known risk factors for fibrosis severity, like liver necroinflammation, older age, consumption of alcohol, duration of infection and viral coinfections,^[2] metabolic alterations, namely steatosis,^[3] insulin resistance (IR)^[4] and menopause (in females)^[5] can affect the degree of liver fibrosis.

In this complex and interesting interplay between liver and metabolic factors, growing evidence also suggest a role of vitamin D status on liver disease severity in patients with chronic hepatitis C. In particular, we firstly reported that fully compensated genotype 1 (G1) CHC patients are characterized by a higher prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency compared to a control population, also showing in this clinical setting an independent inverse relationship between 25(OH)D serum levels and liver fibrosis severity.^[6] These clinical data not only were further confirmed by other groups,^[7,8] but also their strength was supported by experimental studies showing that vitamin D, acting via its nuclear vitamin D receptor, exerts its protective effect by inhibiting stellate cell proliferation and their profibrogenic activation.^[9]

Vitamin D has therefore a relevant role in patients with CHC, and its metabolism is regulated by several environmental factors, in particular sunlight and diet. In addition, a recent genome-wide association study (GWAS), in a large screening population of about 30 000 European descent individuals divided in a training and a validation set demonstrated that serum concentrations of 25(OH)-vitamin D are influenced by variants near genes involved in cholesterol synthesis (7-dehydrocholesterol reductase -DHCR7), vitamin D hydroxylation (CYP2R1) and vitamin D transport (vitamin D-binding protein–GC).^[10]

With this in mind, in a cohort of biopsy-proven G1 CHC patients, we aimed to assess the association between vitamin serum levels and its genetic determinants, with the severity of liver fibrosis.

Materials and Methods

Patients

Two hundred and sixty consecutive patients with G1 CHC, recruited at the Gastrointestinal and Liver Unit at the University Hospital in Palermo and fulfilling all inclusion and exclusion criteria detailed below, were assessed. Patients were included if they had a histological diagnosis of CHC (any degree of fibrosis, including cirrhosis) on a liver biopsy performed within 6 months prior to enrolment. G1 CHC patients were characterized by the presence of anti-HCV and HCV RNA, with persistently abnormal alanine aminotransferase (ALT) levels, and by alcohol consumption of <20 g/day in the last year or more, evaluated by a specific questionnaire. Exclusion criteria were (i) advanced cirrhosis (Child-Pugh B and C); (ii) hepatocellular carcinoma; (iii) other causes of liver disease of mixed aetiologies (excessive alcohol consumption, hepatitis B, autoimmune liver disease, Wilson's disease, hemochromatosis, α1-antitrypsin deficiency); (iv) HIV infection; (v) previous treatment with antiviral therapy, immunosuppressive drug and/or regular use of steatosis-inducing drugs (corticosteroids, valproic acid, tamoxifen, amiodarone); (vi) therapy with medications known to affect vitamin D3 metabolism, including vitamin/mineral supplements; and (vii) active IV drug addiction.

The study was performed in accordance with the principles of the Declaration of Helsinki and its appendices, and with local and national laws. Approval was obtained from the hospital's Institutional Review Board and Ethics Committee, and written informed consent was obtained from all patients.

Clinical and Laboratory Assessment

Clinical and anthropometric data were collected at the time of liver biopsy. BMI was calculated on the basis of weight in kilograms and height (in metres), and patients were classified as normal weight (BMI, 18.5–24.9 kg/m²), overweight (BMI, 25–29.9) or obese (BMI ≥ 30). The diagnosis of arterial hypertension was based on the following criteria: systolic blood pressure ≥135 mm Hg and/or diastolic blood pressure ≥85 mm Hg (measured three times within 30 min, in the sitting position and using a brachial sphygmomanometer) or use of blood pressure–lowering agents. The diagnosis of type 2 diabetes was based on the revised criteria of the American Diabetes Association, using a value of fasting blood glucose ≥126 mg/dL on at least two occasions.^[11] In patients with a previous diagnosis of type 2 diabetes, current therapy with insulin or oral hypoglycaemic agents was documented.

A 12-hour overnight fasting blood sample was drawn at the time of biopsy to determine serum levels of ALT, total cholesterol, HDL and LDL cholesterol, triglycerides, plasma glucose concentration, insulin and platelet count. Insulin resistance (IR) was determined with the homoeostasis model assessment (HOMA), using the following equation:^[12] insulin resistance (HOMA-IR) = fasting insulin (μU/mL) × fasting glucose (mm)/22.5. HOMA-IR has been validated in comparison with the euglycemic/hyperinsulinemic clamp technique in both diabetic and nondiabetic patients.^[13]

The analysis of serum 25(OH) D was performed using a Chromosystem reagent kit and a chromatographic system equipped with a Waters 1525 Binary high-pressure liquid chromatography pump connected to a photo diode array detector, and detection was carried out at 265 nm. 25(OH)D serum levels <10 μg/L, from 10 to 30 μg/L, and >30 μg/L, were considered the threshold values for identifying deficiency, insufficiency and normality of vitamin D levels, respectively.

All patients were tested at the time of biopsy for HCV RNA (RT-PCR homemade; limit of detection: 12 IU/mL). Genotyping was performed by INNO-LiPA, HCV II, Bayer.

Genetic Analyses. DNA was purified using the QIAmp blood Mini Kit (Qiagen, Mainz, Germany), and DNA samples were quantified using spectrophotometric determination.

Genotyping for IL28B (rs12979860), PNPLA3 (rs738409), CYP2R1 (rs 10741657), NADSYN1(rs 12785878) and GC (rs 2282679) was carried out using the TaqMan SNP genotyping allelic discrimination method (Applied Biosystems, Foster City, CA, USA). Commercial genotyping assays were available for the SNPs: rs738409 (cat. C_7241_10), rs 10741657 (cat. C_2958430_10); rs 12785878 (cat. C_32063037_10); rs 2282679 (cat. C_26407519_10). Instead, a custom assay has been created by AB for rs12979860.

The genotyping call was performed with SDS software v.1.3.0 (ABI Prism 7500, Foster City, CA, USA). Genotyping was conducted in a blinded fashion relative to patient characteristics.

Histology

Slides were coded and read by one pathologist (D.C.), who was unaware of the patient's identity and history. A minimum length of 15 mm of biopsy specimen or the presence of at least 10 complete portal tracts was required.^[14] Biopsies were classified according to the Scheuer numerical scoring system.^[15] The percentage of hepatocytes containing macrovescicular fat was determined for each 10× field. An average percentage of steatosis was then determined for the entire specimen. Steatosis was assessed as the percentage of hepatocytes containing fat droplets (minimum 5%) and evaluated as a continuous variable. Steatosis was classified as absent-mild at <20% or moderate–severe at ≥20%.

Statistics. Continuous variables were summarized as mean ± standard deviation and categorical variables as frequency and percentage. The Student's t-test and analysis of variance were used when appropriate. Multiple linear regression analysis was performed to identify independent predictors of 25(OH)D serum levels as a continuous dependent variable. As candidate risk factors for low serum levels of 25(OH)D, we selected age, sex, body mass index, baseline ALT, platelet count, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood glucose, insulin, HOMA score, diabetes, arterial hypertension, DHCR7,CYP2R1 and CG SNPs, HCV RNA levels, steatosis and activity score.

Multiple logistic regression models were used to assess the relationship of fibrosis to the demographic, metabolic, genetic and histological characteristics of patients. In the model, the dependent variable was severe fibrosis coded as 1 = F3–F4 in the fibrosis score versus 0 = F1–F2. As candidate risk factors, we selected the same independent variables included in the 25(OH)D model and added 25(OH)D serum levels as an additional independent variable.

In all analyses, DHCR7 SNP was evaluated as TT/TG vs GG, CYP2R1 as AA/AG vs GG, and CG as TT/TG vs GG, according to published data on genotypes associated with lower vitamin D levels.^[10]

Variables associated with the dependent variable at univariate analyses (probability threshold, P < 0.10) were included in the multivariate regression models. Regression analyses were performed by SAS.^[16]

Results

Patient Features and Histology

The baseline features of the 260 patients are shown in . Most of our patients were in the overweight to obesity range. One patient in four had fibrosis of at least three by Scheuer score, with a high prevalence of moderate/severe necroinflammation (grading 2–3). One patient in three had histological evidence of steatosis of moderate/severe grade.

Table 1.  Demographic, laboratory, metabolic and histological features of 260 patients with genotype 1 chronic hepatitis C

Variable	Chronic hepatitis C genotype 1 (n = 260)
Mean age (yrs)	52.8 ± 11.9
Gender
Man	128 (49.2)
Woman	132 (50.8)
Mean body mass index (kg/m2)	26.8 ± 4.8
Body Mass Index (kg/m2)
<25	90 (34.6)
25–29.9	124 (47.6)
≥30	46 (17.8)
Arterial hypertension
Absent	203 (78.1)
Present	57 (21.9)
Type 2 diabetes
Absent	222 (85.4)
Present	38 (14.6)
Alanine aminotransferase (IU)	95.0 ± 78.9
Cholesterol (mg/dL)	174.0 ± 35.2
HDL Cholesterol (mg/dL)	54.7 ± 17.7
LDL Cholesterol (mg/dL)	100.8 ± 32.6
Triglycerides (mg/dL)	100.3 ± 51.1
Blood glucose (mg/dL)	97.7 ± 31.1
Insulin (μU/mL)	13.6 ± 7.6
HOMA score	3.37 ± 2.23
25(OH)D (μg/L)	24.5 ± 8.4
25(OH)D
Normality	64 (24.6)
Insufficiency	195 (75.0)
Deficiency	1 (0.4)
HCV RNA (UI/ml)	1,490,677 ± 2,542,912
DHCR7
TT	114 (43.8)
TG	133 (51.2)
GG	13 (5)
CYP2R1
AA	29 (11.1)
AG	109 (41.9)
GG	122 (46.9)
GC
TT	149 (57.3)
TG	94 (36.2)
GG	17 (6.5)
Histology at biopsy
Steatosis:	12.0 ± 16.6
-Continuous variable
-Categorical variable
<20%	180 (69.2)
≥20%	80 (30.0)
Stage of fibrosis
0	12 (4.6)
1	52 (20.0)
2	122 (46.9)
3	45 (17.3)
4	29 (11.2)
Grade of activity
1	44 (16.9)
2	144 (55.4)
3	72 (27.7)

yrs, years; IU, international units; HOMA, homoeostasis model assessment; HDL, high-density lipoprotein; LDL, low density lipoprotein; HCV RNA, hepatitis C virus ribonucleic acid; DHCR7, dehydrocholesterol reductase; GC, vitamin D-binding protein.

Mean serum values of 25(OH)D were 24.5 ± 8.4 μg/L. Accordingly, vitamin D deficiency, insufficiency and normality were observed in 0.4%, 75% and 24.6% of G1 CHC patients, respectively.

DHCR7 rs12785878 TT genotype was present in 114 (43.8%) patients, compared to 133 (51.2%) and 13 (5%) with TG and GG variants, respectively. The CYP2R1 rs10741657 AA genotype was observed in 29 patients (11.1%) compared with 109 (41.9%) and 122 (46.9%) with AG and GG variants, respectively. Finally, GC rs7041 TT genotype was present in 149 patients (57.3%) compared with 94 (36.2%) and 17 (6.5%) with TG and GG variants, respectively.

Serum 25(OH)D Levels

Older age (P = 0.002), female sex (P = 0.03), DHCR7 GG (P = 0.003), GC GG (P = 0.05) and the severity of fibrosis (P = 0.001) were associated with lower 25(OH)D levels in G1 CHC, although only DHCR7 GG (P = 0.003) (P = 0.008) and the severity of fibrosis (P = 0.03) were independent factors in multiple linear regression analysis (). Figure 1 shows the distribution of serum 25(OH)D levels in relation to DHCR7 genotype.

Table 2.  Univariate and multivariate analysis of factors associated with vitamin D serum levels in 260 patients with genotype 1 chronic hepatitis C

Univariate analysis			Multivariate analysis
β	SE	P value	B	SE	P value
Mean age (yrs)	−0.192	0.043	0.002	−0.123	0.045	0.05
Male gender	−0.133	1.036	0.03	−0.107	1.031	0.08
Mean body mass index (kg/m2)	0.023	0.116	0.72	–
Alanine aminotransferase (IU)	0.058	0.007	0.35	–
Cholesterol (mg/dL)	0.045	0.015	0.46	–
HDL Cholesterol (mg/dL)	−0.096	0.032	0.15	–
LDL Cholesterol (mg/dL)	0.117	0.017	0.11	–
Triglycerides (mg/dL)	0.013	0.010	0.83	–
Blood glucose (mg/dL)	−0.102	0.017	0.10	–
Insulin (μU/mL)	−0.013	0.075	0.84	–
HOMA score	−0.049	0.023	0.43	–
Diabetes	−0.117	1.469	0.10	–
Arterial Hypertension	−0.097	1.257	0.11	–
HCV RNA	−0.038	0.001	0.64	–
DHCR7 TT/TG vs GG	−0.186	2.357	0.003	−0.161	2.317	0.008
CYP2R1 AA/AG vs GG	0.072	1.691	0.25	–
GC TT/TG vs GG	−0.118	2.100	0.05	−0.109	2.020	0.06
Histology at biopsy
Steatosis	0.036	0.031	0.56	–
Stage of fibrosis	−0.207	0.513	0.001	−0.135	0.532	0.03
Grade of activity	−0.099	0.779	0.11	–

yrs, years; IU, international units; HOMA, homoeostasis model assessment; HDL, high-density lipoprotein; LDL, low density lipoprotein; HCV RNA, hepatitis C virus ribonucleic acid; DHCR7, dehydrocholesterol reductase; GC, vitamin D-binding protein.

Figure 1.

25(OH)D serum levels according to DHCR7 genotype, in 260 patients with genotype 1 chronic hepatitis C.

Accordingly, all patients with DHCR7 GG genotype had vitamin D insufficiency/deficiency, compared to 74% with DHCR7 TT/TG genotype (P = 0.03).

Variables Related to Severe Fibrosis

The univariate and multivariate comparison of variables between patients with and without severe fibrosis (F3–F4) are reported in . Older age, male sex, high baseline values of ALT, low cholesterol, high triglycerides, high blood glucose, high HOMA, diabetes, low 25(OH)D, vitamin D insufficiency/deficiency, DHCR7 GG genotype, moderate–severe steatosis and moderate–severe necroinflammatory activity were associated with severe fibrosis (P < 0.10). Multivariate logistic regression analysis showed that the following features were independently linked to severe fibrosis (Scheuer score ≥3): older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). The overall area under the curve (AUC) of this model was good (AUC, 0.870). Figure 2 showed the prevalence of severe fibrosis, according to DHCR7 genotype.

Table 3.  Univariate and multivariate analysis of risk factors associated with severe fibrosis (F3–F4) in 260 patients with genotype 1 chronic hepatitis C

Variable	No severe Fibrosis (Scheuer score 0–2) n = 186	Severe Fibrosis (Scheuer score 3–4) n = 74	Univariate Analysis P value	Multivariate Analysis
				OR (95% CI)	P value
Age (yrs)	50.8 ± 12.4	58.0 ± 8.9	<0.001	1.056 (1.023–1.089)	0.001
Male gender
Male vs Female	89/97	39/35	0.48	–
Body mass index (kg/m2)	27.0 ± 5.2	26.1 ± 3.6	0.22	–
Alanine aminotransferase (IU)	78.1 ± 61.3	137.4 ± 100.1	<0.001	–
Cholesterol (mg/Dl)	178.1 ± 35.8	163.7 ± 31.5	0.003	0.984 (0.974–0.994)	0.002
HDL Cholesterol (mg/Dl)	57.0 ± 18.1	49.2 ± 15.6	0.004	–
LDL Cholesterol (mg/Dl)	104.9 ± 32.9	91.5 ± 29.9	0.005	–
Triglycerides (mg/Dl)	95.7 ± 43.6	112.0 ± 65.4	0.02	1.008 (1.002–1.015)	0.01
Blood glucose (mg/dL)	93.0 ± 28.9	109.5 ± 33.5	<0.001	1.008 (0.998–1.018)	0.11
Insulin (μU/mL)	13.3 ± 7.7	14.2 ± 7.5	0.41	–
HOMA score	3.18 ± 2.02	3.87 ± 2.64	0.02	–
Arterial Hypertension
Absent vs present	146/40	57/17	0.79	–
Type 2 diabetes
Absent vs present	169/17	53/21	<0.001	–
25(OH)D (μg/L)	25.5 ± 8.7	21.9 ± 7.0	0.002	0.958 (0.919–0.999)	0.04
25(OH)D insufficiency/deficiency
Absent vs present	51/135	13/61	0.09	–
HCV RNA (UI/mL)	1,501,661 ± 2,753,749	1,458,288 ± 1,812,436	0.92	–
DHCR7 TT/TG vs GG	180/6	67/7	0.03	4.222 (1.106–16.120)	0.03
CYP2R1 AA/AG vs GG	25/161	5/69	0.15
GC TT/TG vs GG	176/10	67/7	0.22
Histology at biopsy
Steatosis <20% vs ≥20%	139/47	41/33	0.002	2.588 (1.355–4.943)	0.004
Mild vs Moderate–Severe Grade of inflammation	39/147	5/69	0.006	2.437 (1.307–4.763)	0.001

yrs, years; IU, international units; HOMA, homoeostasis model assessment; HDL, high-density lipoprotein; LDL, low density lipoprotein; HCV RNA, hepatitis C virus ribonucleic acid; DHCR7, dehydrocholesterol reductase; GC, vitamin D-binding protein.

Figure 2.

Prevalence of severe liver fibrosis according to DHCR7 genotype, in 260 patients with genotype 1 chronic hepatitis C.

Discussion

In this study, we have shown that, in a cohort of patients with biopsy-proven G1 CHC, DHCR7 GG genotype, other than being associated with lower vitamin D serum levels, was also independently linked to the severity of liver fibrosis, together with well known risk factors for fibrosis, including lower vitamin D serum levels.

Different lines of evidence showed a relevant role of vitamin D status in patients with CHC patients, and with neoplastic and cardiometabolic disorders,^[6,17] prompting genetic, clinical and experimental research on vitamin D metabolism and actions.

In our study we showed that, in G1 CHC patients, lower levels of serum 25(OH)D were independently linked to the DHCR7 GG genotype. Our data are in agreement with the GWAS study of Wong and colleagues on a cohort of about 30 000 subjects that identified the DHCR7 gene as able to affect vitamin D serum levels, with the lowest values in GG patients.^[10] In addition, the presence of lower vitamin D serum levels in patients with the DHCR7 GG genotype was also recently reported in a large cohort of Caucasian patients with chronic liver diseases due to different aetiologies.^[18] In our study, we did not identify a link between CYP2R1 and GC SNPs, also linked to vitamin D deficiency in the above quoted GWAS study,^[10] and vitamin D serum levels. This issue could be related to the demographic, clinical and biochemical characteristics of our studied population, like the very high prevalence of vitamin D deficiency, as well as to the relative low number of included patients.

This study offers the first evidence that the DHCR7 GG genotype, together with lower 25(OH)D serum levels, and with other known risk factors for fibrosis severity, such as older age, low cholesterol and high triglycerides levels, moderate–severe steatosis and high necroinflammatory activity, is independently associated with the presence of severe liver fibrosis in G1 CHC patients. Grünhage and colleagues,^[18] in a cohort of more than seven hundred patients with mostly clinically diagnosed chronic liver disease due to different aetiologies (60% HCV related), showed that, among subgroups of patients with liver stiffness measurement (LSM) lower than 7 kPa and lower than 9.5 kPa, the DHCR7 GG genotype was associated with higher LSM values. These data therefore suggested, with limits related to LSM use as surrogate marker of fibrosis, and to subgroups analyses, a potential association between severity of liver disease and the DHCR7 GG genotype. In this line, our study added further and relevant evidence about this issue, demonstrating the association between the DHCR7 GG genotype and severity of histological liver fibrosis, in a cohort of compensated, homogeneous and fully characterized biopsy-proven G1 CHC patients.

Another relevant finding of our study is that both the DHCR7 genotype and vitamin D levels were independently linked to the presence of severe liver fibrosis. This issue suggests that the association between the DHCR7 GG genotype and liver fibrosis is far complex. In fact, on the one hand, it is plausible that DHCR leads to fibrosis via lowering vitamin D serum levels.^[10] Experimental evidence in fact suggests that vitamin D, via interaction with VDR, is able to inhibit stellate cell proliferation and their profibrogenic activation.^[9] On the other hand, our results suggest that DHCR7 genotype could prompt fibrogenesis also via other direct/indirect mechanisms. However, literature data do not provide us with further help on this issue, and therefore, additional experimental work is needed.

The main limitation of this study lies in the low number of patients carrying the at-risk DHCR7 GG genotype. This issue could affect the interpretation of our results. However, the similar low prevalence of DHCR7 GG genotype reported in other studies,^[10,18] then our biologically plausible results^[9,10] and the presence in the literature of similar results^[10,18] makes us confident about the accuracy of our data, which obviously needs further validation in large cohort studies. Another limitation of our study is its cross-sectional nature and its inability to dissect the temporal relation between DHCR7 genotype, 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant.

In conclusion, this study showed that in a homogeneous cohort of compensated biopsy-proven G1 CHC patients, DHCR7 GG genotype, other than leading to lower vitamin D serum levels, is also associated with the severity of liver fibrosis, suggesting a complex interplay between liver damage, vitamin D and genetic determinants of vitamin D deficiency.

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Abbreviations
AUC, area under the curve; CHC, chronic hepatitis C; DHCR7, dehydrocholesterol reductase; G1, genotype 1; GC, vitamin Dbinding protein; GWAS, genome-wide association study; HCV, hepatitis C virus; HOMA, homoeostasis model assessment; IR, insulin resistance; LSM, liver stiffness measurement.

Contributors
S. Petta designed the study, contributed to data acquisition, was responsible for writing the manuscript and participated in statistical analysis. C. Camma', V. Di Marco and A. Craxì (Director of the GI and Liver Unit) were responsible for the project and writing of the manuscript. D. Cabibi, S. Grimaudo, F.S. Macaluso, R. Pipitone and C. Scazzone participated in patient management and data collection. All authors have seen and approved the final version of the manuscript.

J Viral Hepat. 2013;20(7):486-493. © 2013  Blackwell Publishing

Source

Patient perspectives on hepatitis C and its treatment

North CS, et al.

North CS, Devereaux R, Pollio DE, Hong BA, Jain MK.

Eur J Gastroenterol Hepatol. 2013 Jun 19. [Epub ahead of print]

aThe VA North Texas Health Care System Departments of bPsychiatry cSurgery, Division of Emergency Medicine dDepartment of Internal Medicine, Division of Infectious Diseases, The University of Texas Southwestern Medical Center eThe University of Texas Southwestern Medical Center, Graduate School of Biomedical Sciences, Dallas, Texas fThe University of Alabama School of Social Work, Tuscaloosa, Alabama gDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

OBJECTIVE: Much of the research to date on barriers to treatment for patients with hepatitis C has approached the problem from either the perspective of the medical provider or the healthcare system.

METHODS: To better understand these barriers from the patients' perspectives, nine exploratory focus groups of patients with hepatitis C (N=48) were conducted in 2008 and 2009, using a hybrid qualitative analysis.

RESULTS: Eight content categories emerged. Treatment-related issues, including barriers to care, were most emphasized, representing nearly one-half of the entire content. Need for accurate disease-related information was also extensively discussed. Social factors were important, including considerable focus on stigma. Participants described coping abilities including faith and perseverance.

CONCLUSION: Areas of concern expressed in these focus groups represent underexplored areas that may warrant additional attention or areas for intervention and investigation, such as exploring differences between perceptions of patients and providers regarding the hepatitis C treatment process and addressing barriers to care.

PMID

23788155 [PubMed - as supplied by publisher]

Source

HCV Care in VA Debated

Provided by NATAP

Download the PDF here

Download the PDF here

Download the PDF here

below are a series of 3 letters to the editor debating the quality of care of HCV for vets in the VA which followed from the publication of this study criticizing HCV care in the VA

from Jules:
This publication in the J of Hepatolog.....led to this letter below to the Journal by Cecil Bennet, which in return led to a response below by David Ross, Director of HCV treatment at the VA, and then again another response below back from Cecil Bennet.

Gaps in the achievement of effectiveness of HCV treatment in national VA practice - "overall effectiveness of HCV therapy is low in a national sample of veterans with chronic HCV"

http://www.natap.org/2012/HCV/012312_03.htm

"There is a chasm between efficacy and effectiveness of antiviral treatment in the VA......The lack of treatment in the remaining patients is potentially concerning......a majority of patients never received a biopsy as part of their evaluation process, and therefore their fibrosis stage remains unknown thus lack of significant fibrosis does not seem to explain the low treatment rates in this population of HCV patients.......Only 11.6% of patients had a liver biopsy in the VA during the two years before and two years after their HCV index date......The study highlights the sporadic testing for viral counts among patients started on antiviral treatment, which does not allow for classifying patients to the conventional randomized trial definition.......39.8% were not tested for genotype......HCV genotype was unknown in 8.8% of the patients who received treatment......Patients who were not tested for genotype were significantly less likely to receive any antiviral treatment (3.3% vs. 25.2%, p <0.0001)......Approximately 43% of patients who did not receive antiviral treatment had none of the contraindications to treatment listed in Materials and methods and in Table 1"

Click on picture to enlarge

Why 88% of US military veterans with HCV are not treated

Bennet Cecil
Jnl of Hepatology July 2013
Hepatitis C Treatment Centers, 1009A Dupont Square N, Louisville, KY 40207, USA To the Editor:

The article in the February issue of the Journal of Hepatology reported that less than 12% of American military veterans identified with HCV were treated with antiviral therapy [1]. The Veterans Administration does not want to spend adequate funds to cure patients with hepatitis C. Dr. Kenneth Kizer, Under Secretary for Health in the US Department of Veterans Affairs (VA), gave HCV a high priority but unfortunately he left the VA in 1999. Subsequent leadership has not shown enthusiasm for treating HCV.

The Director of Pharmacy and the Chief of Staff at my local VA hospital told me that I spent too much money treating HCV. Boceprevir and telaprevir are both on the hospital formulary but telaprevir prescriptions are routinely denied because it is more expensive. Patients must jump multiple hurdles before qualifying for antiviral therapy. No one would refuse to give coronary artery stents or bypass grafts to a veteran who smokes but veterans who do not completely abstain from alcohol for three months are refused antiviral therapy. In spite of difficulties, 585 of 1372 (43%) HCV RNA positive patients received antiviral therapy between 1998 and 2010 at our local VA hospital; 226 of 583 treated (39%) achieved SVR [2]. 36% of deaths were from HCC or liver failure. Veterans with sustained viral response had substantially improved survival. Effective antiviral therapy improves prognosis [3], [4]. Less than 2% of Americans die from liver disease, but more than one third of veterans with HCV die prematurely from complications of cirrhosis [2], [5]. According to a 2010 national VA report, deaths in veterans with HCV have more than tripled, "Between 2000 and 2008, the annual number of all cause deaths recorded for Veterans with chronic HCV rose from 1259 (1129 per 100,000 in VHA care) to 5967 (4049 per 100,000 in VHA care), respectively" [6].

Legislation should be passed allowing veterans with HCV to prequalify for their choice of Medicaid or Medicare so that they can obtain antiviral therapy in the private sector. Since Dr. Kizer is no longer in charge of the VA, it is very clear that the VA is not going to treat very many of them.

Treatment of veterans with hepatitis C in the United States Department of Veterans Affairs

Journal of Hepatology
July 2013

David Ross

To the Editor:
As Director of the National Hepatitis C Program for the United States Department of Veterans Affairs [VA], the largest provider of care in the United States for HCV, I would like to respond to the statements by Dr. Bennett Cecil in the October 2012 issue of the Journal of Hepatology about access to and quality of care for HCV-infected Veterans in VA care [1].

1.Dr. Cecil used data from 2005 [2] as the basis for his statement that only 12% of Veterans with HCV in VA care have received anti-viral therapy. However, two of the references he cited explicitly contradict that figure [3], [4]. In fact, the actual proportion treated is more than double that. As of September 30, 2012, internal VA data show over 25% of HCV-infected Veterans in VA care having received such treatment, compared to 17% in non-VA settings [5].

2.Dr. Cecil incorrectly states that both boceprevir and telaprevir are on the VA National Formulary; actually, only boceprevir is, with telaprevir available for use by VA providers as a non-formulary agent [6].

3.Dr. Cecil states that telaprevir is viewed as "too expensive" for use by VA but did not provide any evidence for this contention. In fact, a VHA policy memorandum issued in September 2011 stipulates that cost is not to be a factor in prescribing HCV protease inhibitors. Dr. Cecil did not provide an evidence-based rationale for his preference for prescribing telaprevir.

4.Dr. Cecil implies that he is responsible for anti-viral treatment of almost 600 HCV patients at the Louisville VA; however, multiple providers actually care for the patients with HCV infection at that facility. With regard to use of triple therapy at the Louisville VAMC, as of November 2012, 37 patients had initiated triple therapy (36 boceprevir, 1 telaprevir). Ten were on therapy at that time. Of the remaining 27, six (22.2%) had achieved an SVR, seven were discontinued for lack of efficacy, six were discontinued for toxicity, and eight for non-adherence.

5.The Louisville VAMC's screening/evaluation process includes a review by a clinical pharmacy specialist of drug/ drug interactions, current laboratory results, and monthly monitoring of prescription fills. Patients for whom treatment is appropriate attend a mandatory education class and provided information on HCV, anti-viral therapy, and drug side effects, as well as the importance of drug compliance and obtaining repeat laboratory tests. In addition, a treatment plan and follow-up clinic appointments are reviewed. This class is scheduled weekly, but also has been done at other times at the convenience of individual Veterans (M. Rothschild, personal communication).

Finally, and most importantly, Dr. Cecil's assertions that "VA has not shown enthusiasm for treating HCV patients" and that it is "not going to treat very many of them" are incorrect. Since FDA approved the first direct acting anti-virals in May 2011, VA has treated almost 4500 patients with triple therapy, spent over $100 million in antiviral drug acquisition costs, published updated treatment guidelines recommending use of regimens incorporating direct acting antivirals [7], trained hundreds of VA health care providers to deliver anti-viral therapy, championed integrated models to address treatment-limiting comorbidities [8], added dozens of clinical resources to its HCV Web site (www.hepatitis.va.gov), and moved aggressively to increase access to evaluation and treatment of HCV through teleconsultation models [9].

As a VA clinician who provides care for Veterans with HCV, I am proud of VA's HCV Program, which is recognized as a national leader in the integrated care of patients with this disease [10]. Although there is always room for improvement in any therapeutic service in any health care system, VA has been striving to deliver high-quality, evidence-based care to as many Veterans with HCV as possible, and will continue to do so.

Reply to: "Treatment of veterans with hepatitis C in the United States Department of Veterans Affairs"

Bennet Cecil

To the Editor:

I would like to thank Dr. Ross.

(1)Dr. Ross does not state how many veterans with HCV are currently receiving care at the Department of Veterans Affairs (VA). In 2008, VHA clinicians cared for over 147,000 veterans with chronic HCV [1]. Treating 4500 patients with HCV in 20 months is only 225 patients per month. The VA is currently treating less than 2% of infected veterans per year with boceprevir and telaprevir. It will take more than fifty years for the VA to treat all of their HCV infected patients. Evidence based care of an infectious disease is cure of the infection not the development of integrated models to address comorbidities. If 98% of patients with a curable infection are not treated each year, the VA's response is inadequate.

(2)The VA does a better job with the human immunodeficiency virus (HIV) treating 78% of veterans [2]. The number of patients on antiviral therapy clearly indicates that HIV is a high priority for the VA while HCV treatment is not.

(3)Telaprevir is not available as a non-formulary drug at the Louisville VA. Boceprevir is on the formulary there.

(4)More than 1800 patients with HCV antibodies have been identified at the Louisville VA over 19 years. They had multiple physicians providing care.

(5)$100 million for antiviral therapy over 20 months is $5 million per month. This is clearly inadequate to treat 147,000 veterans with hepatitis C. This is why legislation should be passed so that all veterans with HCV immediately prequalify for their choice of Medicaid or Medicare. They could then obtain antiviral therapy in the private sector instead of waiting for the VA to treat 2% of them each year. Now, many are trapped in the VA system while their curable infection progresses to liver cancer, liver failure and death.

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Emerging Therapeutic Targets for Hepatitis C Virus Infection

Provided by NATAP

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Clinical Gastroenterology and Hepatology
June 2013

ARUN B. JESUDIAN,* YPE P. DE JONG,*, and IRA M. JACOBSON*
*Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, New York-Presbyterian Hospital, Weill Cornell Medical College, New York; and Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, Rockefeller University, New York, New York

Summary from EASL 2013 for Hepatitis C - New HCV DAAs on their way soon: what do the phase III studies tell us? - written by Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany (05/16/13)

EASL: New Oral HCV Drugs at EASL - Report 4A

New HCV Drugs - EASL & Beyond - (05/11/13)

HCV at CROI - (03/17/13)

Conclusions: The era of DAA therapy in the treatment of hepatitis C is evolving rapidly. The leap forward from the initial proof of concept that HCV infection can be cured without IFN to showing that cure can be attained in an extraordinarily high proportion of patients has occurred more quickly than most observers had anticipated. We have an increasingly clear understanding of what components of an antiviral regimen are necessary to maximize SVR across patient groups. Whether a nucleotide-containing regimen requires 1 to 2 fewer drugs to optimize the chance of response, particularly across genotype 1 subtypes as suggested thus far, remains to be fully determined. Additional studies are needed to establish whether an optimized regimen in treatment-naive patients will suffice in prior nonresponders. Patients with cirrhosis who have impaired responses to interferon-based therapy, require evaluation to determine whether they require additional drugs or longer durations of therapy. Other groups requiring specific focus include HIV co-infected persons, decompensated cirrhotic patients, liver transplant recipients, and patients with renal disease. Allowing for some variability between HCV genotypes, it seems likely that there will be a transition period during which several new drugs will each be approved for use in combination with interferon and ribavirin, followed by the advent of interferon-free regimens which will become the standard of care for most, if not all, patients.

Therapy for hepatitis C virus (HCV) is a rapidly evolving field wherein traditional treatment with the nonspecific antiviral agents pegylated interferon (IFN)-alfa and ribavirin has been and will continue to be supplanted by combinations of targeted therapies against HCV with and without concomitant pegylated IFN and/or ribavirin, resulting in markedly superior rates of viral clearance. Exhaustive study of HCV structure and replication through the development of in vitro systems has enabled the development of numerous novel direct acting antiviral agents that currently are undergoing clinical trials. As our understanding of the HCV virus and its antiviral targets increases, the future of HCV therapy holds the promise of high rates of viral eradication in all patient populations, many or all of whom will be treatable with IFN-free combinations of all-oral agents.

Hepatitis C virus (HCV) is a member of the Flaviviridae family of positive-stranded RNA viruses that was identified as the cause of non-A, non-B hepatitis in 1989. It affects up to 200 million persons worldwide and approximately 4 million persons in the United States alone.1, 2 The viral genome encodes for a polyprotein that is cleaved into 3 structural and 7 nonstructural (NS) proteins by viral and host proteases. In 1999, the subgenomic replicon system was established, which is an in vitro system that allows for the replication of a partial genome in a human hepatoma cell line.3 The replicon system has led to the screening of small molecules that can inhibit viral replication, facilitating the development of many drugs that directly inhibit viral proteins, so-called direct acting antivirals (DAAs). Inhibitors of the viral protease NS3/4A, the polymerase NS5B, and the multifunctional protein NS5A have shown great promise in clinical studies and are discussed in detail later.

Inhibitors of other viral proteins, such as the NS2 and NS4B, or the helicase domain of NS3, are in preclinical or early phase clinical investigation and are discussed in detail elsewhere.4 Hampered by the lack of model systems, drugs directed against other parts of the viral life cycle could not be studied until the discovery of an infectious clone in 2005.5, 6 This cell culture system has proven indispensable in our understanding of the viral life cycle, including viral entry and innate immunity against HCV in hepatocytes, and may in the future lead to clinically useful interventions.7, 8 Last, experiments with chimpanzees, the only natural host besides human beings, have been used for in vivo studies. These experiments have led to a better understanding of the adaptive immune response against HCV, and the chimpanzee model, although costly and increasingly controversial, remains the best model for vaccine development.9, 10, 11 Targets that are the focus of currently available or investigational antiviral strategies are illustrated in Figure 1.

Current Standard of Care

Although the incidence of HCV infection is decreasing in the United States, the burden of liver disease resulting from chronic hepatitis C continues to increase.12 The goal of HCV therapy has been to achieve sustained virologic response (SVR), defined as an undetectable serum HCV RNA level at 24 weeks after conclusion of treatment, which portends a more than 99% likelihood of remaining HCV RNA-negative long term.13 Host factors influencing response include genetics, particularly interleukin (IL)-28B polymorphisms, race, obesity, insulin resistance, and severity of hepatic fibrosis, whereas viral characteristics include viral genotype and viral load at initiation of therapy.14, 15, 16, 17, 18 Genotype 1 HCV, the most common in the United States, has been more difficult to treat with interferon-based therapy than other prevalent genotypes.19, 20, 21 Until recently, the standard of care for patients with chronic HCV infection had been treatment with pegylated-interferon-alfa (Peg-IFN) in combination with ribavirin (RBV), given for 24 to 48 weeks, depending on viral genotype. SVR rates after treatment with Peg-IFN/RBV in genotype 1 HCV-infected patients have been 40% to 50%.22 A milestone in the evolution of HCV therapy occurred in 2011 with the approval of the first 2 DAAs: the NS3/4A serine protease inhibitors telaprevir (Incivek; Vertex, Cambridge, MA) and boceprevir (Victrelis; Merck, Whitehouse Station, NJ). The dramatic improvement in SVR rates when these agents are added to Peg-IFN and RBV has led to a new standard of care in patients with genotype 1 HCV infection.

Telaprevir

The ADVANCE (A New Direction in HCV Care: A Study of Treatment Naïve Hepatitis C patients with Telaprevir) study showed significantly higher SVR rates in treatment-naive patients who were given telaprevir-based regimens compared with those who received Peg-IFN/RBV alone.23 The duration of therapy was determined by viral response to treatment, a concept known as response-guided therapy (RGT). The REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial showed that treatment-experienced patients achieved higher SVR rates when telaprevir was added to the re-treatment regimen compared with Peg-IFN and RBV alone, with prior relapsers having higher rates of SVR than responders.24 The most significant side effects of telaprevir are anemia and rash.

Telparevir is now approved for use at a dose of 750 mg 3 times a day given in combination with Peg-IFN/RBV for 12 weeks followed by RGT (Peg-IFN/RBV for an additional 12 or 36 weeks, depending on viral response) in noncirrhotic treatment-naive patients and prior relapsers or followed by 36 weeks of Peg-IFN/RBV in prior partial or null responders, as well as patients with cirrhosis.25 Recent results from the OPTIMIZE study in treatment-naive patients showed that twice-daily dosing of telaprevir 1125 mg had equivalent efficacy to 3 times per day dosing.26

Boceprevir

The benefit of adding boceprevir to Peg-IFN/RBV in treatment-naive patients was established in the SPRINT-2 (Serine Protease Inhibitor Therapy) trial, and in prior partial responders and relapsers in the RESPOND-2 trial (Retreatment with HCV Serine Protease Inhibtor Boceprevir and PegIntron/Rebetol).27, 28 These trials also established the foundation for RGT with boceprevir treatment. The most significant side effect of boceprevir is anemia.

Boceprevir is now approved for the treatment of genotype 1 HCV at a dose of 800 mg 3 times per day in combination with Peg-IFN/RBV.29 All patients receive a 4-week lead-in period of Peg-IFN/RBV, and boceprevir in combination with Peg-IFN/RBV is added thereafter. Duration is determined by RGT based on the HCV RNA level at treatment weeks 8 through 24. Total treatment duration ranges from 28 weeks to 36 or 48 weeks based on prior treatment status and viral response.

Upcoming Direct Acting Antiviral Therapies

Telaprevir and boceprevir will be followed by other oral targeted therapies with various combinations of potency, barrier to resistance, side-effect profiles, and convenience of administration. These newer agents are being evaluated for use in combination with Peg-IFN/RBV and also in combination with other DAAs in IFN-free regimens. A recurrent theme with the protease and NS5A inhibitors is the difference in barrier to resistance and, in some cases, difference in potency between genotype 1 subtypes. HCV genotype 1a has a greater propensity to become resistant to either of these classes than genotype 1b, resulting in higher rates of response in patients with genotype 1b to several agents in these classes either combined with peg-IFN and RBV (including telaprevir and boceprevir) or in some IFN-free regimens studied to date. Nucleotide polymerase inhibitors have a higher barrier to resistance than the other classes of drugs enumerated earlier. The following is a brief summary of many of the most promising new DAAs currently in development, categorized by type of regimen, with emphasis placed on larger trials or those illustrating proof of concept.

One Direct Acting Antiviral Plus Peg-Interferon/Ribavirin

Regimens containing DAAs from several classes combined with Peg-IFN/RBV have resulted in SVR rates that are significantly higher than those attained by Peg-IFN/RBV alone. These classes include protease inhibitors, nucleotide polymerase inhibitors, and NS5A inhibitors. The most extensively studied class studied has been the protease inhibitors.

Simeprevir (formerly TMC435) is an NS3/4A protease inhibitor in an advanced stage of development. In the PILLAR study in treatment-naive patients, SVR rates were 75% to 86% across 4 arms of simeprevir-containing therapy vs 65% with Peg-IFN and RBV alone.30 In the ASPIRE study in prior treatment-experienced patients, simeprevir at a dose of 150 mg/d combined with Peg-IFN and RBV yielded an SVR in 85% of prior relapsers, 75% of partial responders, and 51% of null responders compared with 37%, 9%, and 19% with Peg-IFN/RBV alone.31 Simeprevir is administered once daily and is unassociated with incremental anemia or rash, which can complicate therapy with the currently available protease inhibitors. Hyperbilirubinemia associated with an effect of the drug on transporters may be seen. Phase 3 trials have been completed and results are pending at the time of writing.

Faldaprevir is a protease inhibitor administered once daily. Treatment-naive genotype 1 patients were evaluated in the SILEN-C1 study, yielding SVR rates of 71% to 83%, with the highest SVR seen in patients receiving 240 mg daily without a 3 day lead-in arm.32 The control group had an SVR rate of 56%. In the SILEN-C2 study of prior nonresponders (relapsers excluded), response rates ranged from 27% to 41% across 3 active treatment arms.33 Side effects of faldaprevir include rash and predominantly indirect hyperbilirubinemia. Phase 3 data are awaited.

Danoprevir is an NS3/4A protease inhibitor that was studied in the DAUPHINE trial in combination with Peg-IFN/RBV in treatment-naive genotype 1 and 4 HCV patients.34 When given at doses of 200, 100, or 50 mg boosted by ritonavir 100 mg twice daily for 24 weeks, preliminary undetectable HCV RNA at 12 wks after termination of therapy (SVR12) (now generally considered equivalent to SVR at 24 weeks) were 93%, 83%, and 67%, respectively, in genotype 1 (analysis with missing data excluded), and 100% in genotype 4. Rates of withdrawal because of adverse events were similar between the danoprevir and control arms.

Daclatasvir (formerly BMS-790052) is an NS5A replication complex inhibitor that is being studied in combination with Peg-IFN/RBV in treatment-naive patients with genotypes 1 and 4 HCV in the COMMAND-1 trial.35 When given at a dose of 20 or 60 mg daily in combination with Peg-IFN/RBV for 48 weeks, SVR rates were 64% to 65% in genotype 1 patients compared with 36% in patients receiving Peg-IFN/RBV alone. Higher SVR rates were seen in genotype 1b than in genotype 1a patients. The 60-mg dose has been selected for further development.

Sofosbuvir (formerly GS-7977) is a nucleotide NS5B polymerase inhibitor that combines potency with a high barrier to resistance that was studied in combination with Peg-IFN/RBV in the PROTON study, with a 90% rate of SVR with a response-guided regimen that resulted in nearly all the patients receiving 24 weeks of therapy.36 In the subsequent ATOMIC trial, when sofosbuvir was given at a dose of 400 mg daily in combination with Peg-IFN/RBV for 12 or 24 weeks in treatment-naive patients with genotypes 1, 4, and 6 HCV, SVR12 rates were 90% or greater.37 Sofosbuvir generally was well tolerated with no identified serious adverse events and low rates of discontinuation secondary to adverse events. A phase 3 trial of Peg-IFN, RBV, and sofosbuvir for 12 weeks is in progress.

Two Direct Acting Antivirals Plus Peg-Interferon/Ribavirin (Quadruple Therapy) Recent studies have demonstrated high SVR rates when a combination of 2 distinct DAAs with different protein targets are added to Peg-IFN/RBV in what is now referred to as 4-agent or quadruple (quad) therapy. Treatment-naive patients were treated with a quad regimen in the ZENITH study, which evaluated a combination of telaprevir and a non-nucleoside polymerase, VX-222, with Peg-IFN/RBV.38 Lower and higher doses of VX-222 resulted in SVR rates of 83% and 90%, respectively.

The results of quad therapy in prior nonresponders have been notable. When the NS5A replication complex inhibitor, daclatasvir, was combined with asunaprevir, an NS3 protease inhibitor, along with Peg-IFN/RBV in prior null responders with genotype 1 HCV, SVR rates were 90% to 95%.39 Danoprevir with ritonavir boosting and mericitabine, a nucleotide NS5B polymerase inhibitor, were combined with Peg-IFN/RBV in prior partial and null responders with genotype 1 HCV in the MATTERHORN study.40 In patients who received the 4-drug regimen, SVR rates were 86% and 84% in prior partial and null responders, respectively. These rates of response were significantly higher than in those patients who received only 3 drugs as opposed to quad therapy, whether it was Peg-IFN/RBV plus danoprevir or the 3 oral drugs without Peg-IFN. Response rates were higher in genotype 1b than in genotype 1a patients.

It has been speculated that quad regimens might find a place in the treatment of particularly difficult to cure populations with HCV infection. Recent developments with IFN-free therapy (see later) have seemingly made it less likely that quad therapy will occupy a durable position during the upcoming evolution of HCV therapy, but it remains a possibility. Peg-IFN-λ, the receptor for which has a less widespread tissue distribution than that for interferon-alfa, has shown early promise of at least equal potency to interferon-alfa with less hematologic toxicity.41 It is possible that this form of interferon could play a role in quad regimens in the future should there be a role for them.

Interferon-Free Regimens

Since its inception, IFN-based HCV therapy has been plagued by poor tolerability and significant side effects. Until very recently, patients with contraindications or an inability to tolerate therapy with Peg-IFN had no alternative options for treatment of their HCV infection. The development of DAAs has enabled investigators to pursue the most coveted goal in the history of HCV therapy, the ability to eradicate HCV without IFN in an all-oral combination of anti-HCV agents. The era of IFN-free therapy was ushered in by the INFORM-1 study, which showed marked viral suppression with 2 weeks of treatment when the protease inhibitor danoprevir was combined with the nucleotide polymerase inhibitor mericitabine.42

Lok et al43 showed proof of concept for the curability of HCV infection without IFN by combining the NS5A replication complex inhibitor daclatasvir with the NS3 protease inhibitor asunaprevir in 11 patients with genotype 1 HCV who previously had not responded to Peg-IFN/RBV. In this small phase 2a study, 4 patients treated with 24 weeks of the 2-DAA combination achieved SVR without IFN: 2 of 9 with genotype 1a and 2 of 2 with genotype 1b. Chayama et al44 validated these findings by showing a 100% SVR rate in 9 prior null responders with genotype 1b HCV who completed therapy with 24 weeks of the identical IFN-free regimen of daclatasvir and asunaprevir alone. In a larger cohort of null responders given 24 weeks of daclatasvir 60 mg once daily and asunaprevir 200 mg daily or twice daily, SVR occurred in 65% and 89% of genotype 1b-infected patients, respectively.39 In contrast, high rates of virologic breakthrough and low rates of SVR were observed in genotype 1a patients given the same regimen even when RBV was added. Another study showing markedly disparate results between genotype 1a and 1b patients was the INFORM-SVR trial, which evaluated a combination of danoprevir, mericitabine, and RBV for 24 weeks.45 Compared with an SVR rate of 71% in genotype 1b patients, SVR occurred in only 26% of those with genotype 1a. Along with the initial study by Lok et al,43 early evidence for the curability of HCV infection without Peg-IFN came from the ELECTRON study of the nucleotide polymerase inhibitor sofosbuvir.46 Forty patients with genotypes 2 or 3 infection received sofosbuvir 400 mg daily plus RBV for 12 weeks with varying durations of Peg-IFN in 3 arms, and, in 1 arm, no Peg-IFN. All (100%) of patients had SVR. In an additional group of 10 patients who received sofosbuvir monotherapy, all patients responded, but 4 patients relapsed, yielding an SVR rate of 60%. In 2 additional arms of the study evaluating patients with genotype 1 infection, 21 of 25 (84%) previously untreated patients had an SVR with 12 weeks of sofosbuvir plus RBV, whereas only 1 in 10 (10%) of prior null responders had SVR. Two additional studies of sofosbuvir plus RBV have yielded lower SVR rates in previously untreated patients. In the QUANTUM study, SVR rates of 59% were obtained, whereas in a study conducted at the National Institutes of Health the SVR rate was 72%.47, 48

The importance of both viral and host factors with some antiviral regimens targeting genotype 1 HCV was illustrated by the SOUND-C2 trial, which combined the NS3/4A protease inhibitor faldaprevir with the non-nucleoside NS5B inhibitor BI 207127 with and without RBV in treatment-naive patients with genotype 1 HCV.49 The SVR12 rate in patients given all 3 drugs for 28 weeks in the arm receiving the non-nucleoside agent twice daily was 69%, which was significantly higher than the SVR12 rate of 39% observed in those patients receiving the 2 DAAs without RBV. Response rates were much higher in genotype 1b than 1a patients (85% vs 43%), and much higher in genotype 1a patients with the favorable IL-28B CC genotype than the less favorable CT or TT genotypes. A subset analysis of cirrhotic patients showed encouraging rates of response.50 Further studies using various combinations of DAAs provided additional evidence for the importance of host factors in addition to viral factors in determining response to IFN-free regimens, including IFN nonresponsiveness and IL-28B genotype. When Poordad et al51 combined the NS3 protease inhibitor ABT-450 (combined with low-dose ritonavir) with the nonnucleoside NS5B polymerase inhibitor ABT-333 and RBV, treatment-naive patients had higher SVR rates (93%-95%) than prior nonresponders (47%).

In the initial wave of IFN-free trials suggesting that both viral and host factors were involved in mediating response to several regimens, it was particularly surprising that prior nonresponse to IFN-based therapy was an adverse predictor of response to IFN-free regimens. These observations posed the compelling question of whether optimized antiviral regimens could overcome the impact of both viral and host factors on response. The most recently studied regimens indeed appear to diminish the impact of both viral and host factors by showing extremely high SVR rates across genotype subtypes regardless of prior treatment status. Increasingly, it appears that such combinations of all-oral agents will attain SVR in most patients with HCV infection.

In the AVIATOR trial, studying the IFN-free combination of 3 DAAs (ABT-450/r, an NS3/4A protease inhibitor with ritonavir boosting + ABT-267, an NS5A inhibitor + ABT-333, an NS5B polymerase inhibitor) in combination with RBV in treatment-naive and prior null -responders with genotype 1 HCV, treatment with the all-oral, 4-drug regimen resulted in SVR12 in 98% of patients who received all 4 drugs (n = 75): 100% in genotype 1b patients and 96% in genotype 1a patients.52 SVR rates were 85% to 90% in patients who received ABT-450/r plus 2 of 3 of the other drugs, as well as in an arm containing all 4 drugs given for only 8 weeks. In prior null responders receiving all 4 drugs for 12 weeks, the SVR12 rate was 93%: 100% in genotype 1b and 89% in genotype 1a (42 of 45 patients). The nucleotide inhibitor sofosbuvir was studied in combination with the NS5A inhibitor GS-5885 and RBV in genotype 1 patients in an extension of the ELECTRON study.53 The 3-drug regimen achieved SVR4 in 100% (25 of 25) of treatment-naive genotype 1 HCV patients and also in 100% (9 of 9) of prior null responder genotype 1 patients.

The combination of the NS5A inhibitor daclatasvir with the NS5B polymerase inhibitor sofosbuvir, with or without RBV, has yielded equally remarkable SVR rates in treatment-naive patients.54 SVR24 was observed in 100% of treatment-naive genotype 1 patients treated with a 24-week course of the IFN-free regimen, with the exception of only 1 patient who appeared to be re-infected with a different virus at week 24, and in 93% of treatment-naive genotypes 2 and 3 patients treated with the 24-week course. In a group with genotype 1 treated for only 12 weeks, with or without RBV, SVR4 rates were 95% to 98%, with all 3 patients who failed to have SVR4 going on to have SVR12 (2 patients were missing data at week 4, and 1 patient had undetectable HCV RNA at post-treatment week 2 and low-level viremia at week 4). The implication of these results is that a 2-drug, RBV-free regimen can achieve nearly universal SVR with 12 weeks of therapy, at least in treatment-naive noncirrhotic patients. A study of this regimen in patients who have failed protease inhibitor therapy is ongoing. As with most of the studies cited here, cirrhotic patients were not included and further studies in these patients with IFN-free therapy are essential.

Alternative Strategies

Most patients are expected to respond to a combination of the 3 DAA classes described earlier. However, several hard-to-treat populations may require alternative or additional therapies. There are many alternative antiviral strategies under investigation, some of which already have progressed into clinical trials. These include DAAs directed against other viral proteins, drugs that interfere with host factors required in the HCV life cycle, and entry inhibitors. New DAA classes currently being studied are directed against NS2, the helicase domain in NS3 and NS4B. Of these, the NS4B inhibitor clemizole has been started in clinical studies, the results of which are pending, whereas NS2 and NS3 helicase inhibitors currently remain in preclinical development.55 A second strategy is to interfere with host factors that are essential for HCV replication. The most advanced in clinical studies is alisporivir (formerly debio-025), a cyclophilin A antagonist. Cyclophilins are a family of ubiquitously expressed peptidyl-prolyl isomerases that accelerate protein folding and assembly. Cyclophilin A is inhibited by cyclosporin A and subsequent investigations showed it to interact both with the NS5B polymerase to enhance its affinity for viral RNA and enzymatically modify domains 2 and 3 of NS5A.56, 57, 58 Alisporivir, a nonimmunosuppressive cyclosporin A analogue, was shown to have clinical efficacy and achieve an SVR rate of 75% when combined with Peg-IFN/RBV for 48 weeks in naive patients.59 Early observations also suggested activity of this agent in patients who had failed to respond to a previous course of Peg-IFN/RBV.60 Moreover, it also has shown promise against genotypes 2 and 3 in a trial in which the drug was administered with or without RBV, with Peg-IFN added (along with RBV in the RBV-free arm) from weeks 6 to 24 if HCV RNA was greater than 25 IU/mL at week 4.61 Somewhat fewer than half the patients continued without Peg-IFN through the end of therapy, with SVR rates up to 90% in these patients. A cluster of pancreatitis cases in the phase 3 development program containing interferon-based regimens resulted in this combination being put on hold. The high barrier of resistance and pangenotypic coverage of this drug leave open the possibility that it, or other drugs in this class, will be studied further in IFN-free regimens, even if studies of alisporivir with Peg-IFN/RBV are not resumed.

A different approach is represented by the antisense oligonucleotide miravirsen, which interferes with micro-RNA-122, a liver-specific micro-RNA that is essential for HCV replication.62 Miravirsen monotherapy was able to suppress HCV RNA in a dose-dependent fashion and at the highest dose, 4 out of 9 patients became undetectable.63 Irrespective of the amount of viral suppression no breakthrough was observed, illustrating that interfering with host factor may be less prone to viral escape.

Another potential strategy is the prevention of viral entry into hepatocytes, either through broadly neutralizing antibodies or by blocking one of the entry factors.64, 65, 66 One of these strategies led to the development of ITX-5061, a small molecule inhibitor of the entry factor SRB1, which currently is in phase 2 trials. These novel therapeutic strategies are unlikely to become standard of care, but may serve a need in certain difficult-to-treat subpopulations.

Safety Considerations

As we progress toward the removal of interferon from our treatment regimens, the safety features, pharmacokinetics, metablic pathways, and potential for drug-drug interactions of new drugs require close attention. Anemia, though less pronounced without interferon, will still be an issue in some patients if ribavirin is a component of therapy, along with the drug's teratogenicity.

Unlike telaprevir or boceprevir, the newer protease inhibitors do not appear to be associated with incremental hemoglobin declines, and rash is either less common or not seen with greater frequency than peginterferon and ribavirin alone. While cases of ALT elevation have been reported with certain investigational protease inhibitors, the isolated hyperbilirunemia induced by others in advanced development, related to a transporter effect and/or interactions with UDP-glucuronyl transferase, is of minimal clinical significance. The NS5A inhibitor class appears to combine potent viral suppression with an excellent safety profile thus far. The experience with INX-189, a guanosine nucleotide polymerase inhibitor which had its development halted because of cardiac and renal toxicity, has been a sobering reminder of how quickly a drug can fall from the perception of great promise to nonviability. The development of at least one other guanosine analogue, which had not been associated with toxicity thus far, was halted based on the experience with INX-189. Reassurance about the nucleotide polymerase class in general is provided by the favorable safety profile of sofosbuvir, a uridine analogue, after extensive studies. Another uridine analogue, VX-135, is earlier in development.

Conclusions

The era of DAA therapy in the treatment of hepatitis C is evolving rapidly. The leap forward from the initial proof of concept that HCV infection can be cured without IFN to showing that cure can be attained in an extraordinarily high proportion of patients has occurred more quickly than most observers had anticipated. We have an increasingly clear understanding of what components of an antiviral regimen are necessary to maximize SVR across patient groups.

Whether a nucleotide-containing regimen requires 1 to 2 fewer drugs to optimize the chance of response, particularly across genotype 1 subtypes as suggested thus far, remains to be fully determined. Additional studies are needed to establish whether an optimized regimen in treatment-naive patients will suffice in prior nonresponders. Patients with cirrhosis who have impaired responses to interferon-based therapy, require evaluation to determine whether they require additional drugs or longer durations of therapy. Other groups requiring specific focus include HIV co-infected persons, decompensated cirrhotic patients, liver transplant recipients, and patients with renal disease. Allowing for some variability between HCV genotypes, it seems likely that there will be a transition period during which several new drugs will each be approved for use in combination with interferon and ribavirin, followed by the advent of interferon-free regimens which will become the standard of care for most, if not all, patients.

Appendix

The following is a brief summary of some of the most notable studies presented at the 48th Annual Meeting of the European Association for the Study of the Liver (EASL) held April 24-28, 2013, in Amsterdam. References are online only (available at www.cghjournal.org).

Phase 3 data on simeprevir were reported in 2 studies in treatment-naive genotype 1 patients. In both trials, patients were given 24 or 48 weeks of simeprevir + Peg-IFN/ribavirin (PR) depending on response-guided therapy (RGT) criteria. Overall SVR12 with simeprevir was 80%-81% vs 50% with PR alone.1, 2 In a phase 3 trial of faldaprevir + PR in similar patients, either of 2 doses of faldaprevir resulted in SVR12 in 79%-80% vs 52% with PR alone.3 With both drugs, most patients were eligible to stop therapy after 24 weeks. There is no incremental anemia and at most slight increment in rash, with some increase in photosensitivity, with either of these once-daily protease inhibitors. Both can cause hyperbilirubinemia in the absence of hepatotoxicity.

Results from four phase 3 trials of sofosbuvir (SOF) were presented. In the FISSION trial, a 12-week regimen of SOF/RBV was compared to 24 weeks of PR in treatment-naive genotype 2 and 3 patients.4 The overall SVR 12 rate was 67% in both groups-97% and 78% with SOF/RBV and PR, respectively, in genotype 2 and 56% and 63%. Cirrhosis impacted upon SVR rates in genotype 3 patients, especially those with cirrhosis. In the FUSION trial, treatment-experienced genotype 2 and 3 patients were treated with 12 or 16 weeks of SOF/RBV.5 SVR12 rates were 86% and 94% with 12 and 16 weeks, respectively, and 30% and 62%, respectively, in genotype 3 patients. The largest increment in SVR from 12 to 16 weeks was in genotype 3 cirrhotic patients. In the POSITRON trial, IFN-ineligible, -intolerant, or -unwilling genotype 2 or 3 patients received a 12-week regimen of SOF/RBV.6 SVR12 rates were 93% in genotype 2, 61% in genotype 3, 81% in patients without cirrhosis, and 61% in those with cirrhosis, with cirrhosis having an impact only in genotype 3 patients. A common theme of SOF/RBV therapy was the universal attainment of viral suppression in all patients at week 12, with all virologic failures attributable to relapse and no resistant variants detected in samples from any relapsers. Adverse events of SOF/RBV were similar to those seen with RBV (eg, anemia). Studies assessing longer durations of treatment or the addition of a third agent to SOF/RBV in genotype 3 patients are ongoing. Finally, in the NEUTRINO study of 12 weeks of SOF/PR in genotype 1, 4, 5, and 6 patients demonstrated an overall SVR12 rate was 90% (80% in cirrhotic patients) with only 2% of patients discontinuing for adverse events, setting a new standard for IFN-based therapy.7

Several well-tolerated DAA combination regimens expanded upon the theme reviewed in this article of remarkably high SVR rates with IFN-free therapy. Moreover, the difference in response to DAA regimens between treatment-naive patients and those who had failed previous interferon therapy noted in earlier phase 2 studies appears to be overcome by sufficiently potent antiviral regimens. For example, the results of a 24-week course of daclatasvir combined with sofosbuvir with or without RBV were as dramatic in noncirrhotic genotype 1 telaprevir/boceprevir prior treatment failures as this combination had been in treatment-naive patients given 12-24 weeks of the same regimens (see review above). One hundred percent of a group of 41 patients who had failed protease inhibitor therapy had SVR12 (1 missing at week 12 had SVR24).8 Another NS5A inhibitor, ledipasvir, was combined with SOF and RBV and yielded SVR12 rates of 100% in 25 treatment-naive and 9 null-responder patients, respectively.9 An IFN-free regimen of ritonavir-boosted ABT-450, ABT-333, ABT-267 and RBV for 12 or 24 weeks resulted in SVR24 rates of 90-96% (ITT) in genotype 1 patients who were treatment naive or prior null responders to PR.10 An IFN- and RBV-free regimen of daclatasvir, asunaprevir, and the non-nucleoside NS5B inhibitor, BMS-791325 at 75 mg BID achieved SVR12 of 94% (ITT) when given for 12 or 24 weeks to treatment-naive genotype 1 noncirrhotic patients.11 Interim SVR4 rates in patients given BMS-791325 150 mg BID were similarly high.

Source

Treatment of primary liver cancer: SARAH study now available for all eligible patients throughout France

PARIS, June 24, 2013 /PRNewswire/ --

Launched by the Assistance Publique - Hôpitaux de Paris (AP-HP) in December 2011, SARAH, a French national collaborative randomized controlled trial of radioembolization with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma seeks to enroll 400 patients

To date, more than 150 patients have taken part in this study

PARIS (June 20, 2013) In patients with advanced HCC, sorafenib (Nexavar^®, Bayer HealthCare Pharmaceuticals, Germany), with which radioembolization is being compared, is now the standard treatment.  Its use is associated with an increased median overall survival (from 8 to 11 months in the SHARP trial) but 80% of patients also experience treatment-related adverse events. The SARAH trial is testing the hypothesis that radioembolization using yttrium-90 resin microspheres (SIR-Spheres^® microspheres; Sirtex Medical Limited, Australia) can increase the median overall survival with fewer side effects and/or a better quality of life in comparison with sorafenib.

     (Logo: http://photos.prnewswire.com/prnh/20130620/622575 )

Coordinated at the national level by Professor Valérie Vilgrain MD, PhD (Department of Radiology, Beaujon Hospital, AP-HP) - Principal Investigator of this large study, 19 specialist cancer centres throughout France (Angers, Bondy, Bordeaux, Caen, Clichy, Créteil, Dijon, Grenoble, Marseille, Montpellier, Nancy, Nantes, Nice, Paris, Poitiers, Saint Etienne, Strasbourg, Villejuif; cf. http://clinicaltrials.gov/ct2/show/NCT01482442) are currently accruing patients. The aim is to recruit 400 patients in France with the following inclusion criteria:^[1]

• Patients with advanced HCC with or without portal vein thrombosis or whose disease has progressed after chemoembolization or recurrence of HCC;
• No extrahepatic spread;
• Ineligible for:
• surgical resection;
• liver transplantation;
• radiofrequency ablation.

There is a growing medical interest in radioembolization using yttrium-90 resin microspheres in this patient population, based on a substantial number of open-label single-group studies as well as a large multi-centre European analysis^[2] of the long-term outcomes related to survival and safety of radioembolization using SIR-Spheres microspheres in patients with inoperable HCC. 

SIR-Spheres microspheres are approved for use in Australia, the European Union (CE Mark), New Zealand, Switzerland, Turkey and several other countries including in Asia (e.g. India, Korean, Singapore and Hong Kong) for the treatment of unresectable liver tumours.  SIR-Spheres microspheres are indicated in the U.S. for the treatment of unresectable metastatic liver tumors from primary colorectal cancer together with adjuvant intra-hepatic artery chemotherapy (IHAC) of FUDR (Floxuridine).

About Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs in people whose livers have become severely damaged or cirrhotic, due to conditions such as hepatitis and alcoholism.  It is one of the ten most-common cancers in the world, with nearly 750,000 cases diagnosed annually, and the third-leading cause of cancer deaths.^[3]  It occurs with greatest frequency in regions where viral hepatitis B or C are most often diagnosed, such as in Asia Pacific and Southern Europe. 

Hepatocellular cancer can be cured by surgery, either by resecting the diseased parts of the liver, or by transplantation with a liver from a healthy donor.  These interventions, however, are inappropriate for the great majority of patients, whose survival may range from a few months to two or more years depending largely on the state of their liver at the time of their diagnosis and the extent of tumour invasion.

About Selective Internal Radiation Therapy (SIRT)

SIRT, also known as radioembolization, is a novel treatment for inoperable liver cancer that delivers high doses of radiation directly to the site of tumours.  It is a minimally-invasive treatment, in which millions of radioactive SIR-Spheres microspheres (diameter between 20-60 microns) are infused via a catheter into the liver, where they selectively target liver tumours with a dose of internal radiation up to 40 times higher than conventional radiotherapy, while sparing healthy tissue. 

References:

1. SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma (SARAH): http://clinicaltrials.gov/ct2/show/NCT01482442.  
2. Sangro B, Carpanese L, Cianni R et al on behalf of European Network on Radioembolization with yttrium-90 resin microspheres (ENRY). Survival after ⁹⁰Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: A European evaluation. Hepatology 2011; 54: 868-878.
3. GLOBOCAN.  Liver Cancer Incidence and Mortality Worldwide in 2008.  http://globocan.iarc.fr/factsheets/cancers/liver.asp accessed 28 June 2011.

SOURCE SARAH trialists

Source