Insulin Resistance as a Predictor of Early Virologic Response to HCV Therapy Among Chronic HCV...

Journal of Medical Virology 87:428–440 (2015)

Insulin Resistance as a Predictor of Early VirologicResponse to HCV Therapy Among Chronic HCVEgyptian Patients

Ekram W. Abd El-Wahab,1* Ashraf Mikheal,1,2 Fathallah Sidkey,3 and Hanan Z. Shatat1

1Tropical Health Department, High Institute of Public Health, Alexandria University, Egypt2Damanhour Fever Hospital, Ministry of Health and Population, Damanhour, Egypt3Department of Internal Medicine, Faculty of Medicine, Alexandria University, Egypt

Prior assessment of insulin resistance byHOMA-IR is emerging as an important mile-stone in the treatment of patients with chronichepatitis C. This cost-effective tool is recom-mended to individualize treatment duration, orto exclude those with low insulin sensitivityfrom being treated until ameliorating their stateof insulin resistance (IR). The present work aimsto elucidate further the effect IR state on earlyviral kinetic response to Chronic hepatitis Cvirus (HCV) therapy and the impact of HCVtreatment and viral eradication on insulin sensi-tivity. Insulin sensitivity was assessed using theHOMA-IR method. All enrolled patients weretreated with a dual therapy (pegylated inter-feron-alpha plus ribavirin) for 48 weeks andevaluated using qRT-PCR for early virologicresponse as well as the impact of treatment oninsulin sensitivity throughout the early period oftherapy. Of a total 392 chronic HCV cases, earlyvirologic response was achieved by 318 (81.1%).IR was detected in 241 (61.5%) chronic HCVpatient of which 73.4% responded to treatment.Early virologic response among patients with> 2.18 HOMA-IR value were significantly lowerthan those with HOMA-IR values �2.18(P< 0.0001). IR was significantly associated withhigh baseline BMI. Steatosis and fibrosis corre-lated with IR but neither independently pre-dicted early virologic response. PretreatmentIR< 2.18, low fasting blood glucose, low andintermediate HCV viral load, normal BMI, andnon-smoking were independent factors associ-ated with early virologic response. IR interfereswith early virologic response to the antiviralcare. Clinical application of pretreatmentHOMA-IR assessment could help in predictingearly treatment outcome and thus enable treat-ment regimens to be optimized and individuallytailored. J. Med. Virol. 87:428–440, 2015.# 2014 Wiley Periodicals, Inc.

KEY WORDS: hepatitis C; antiviral combina-tion therapy; insulin resistance

INTRODUCTION

Chronic hepatitis C virus (HCV) infection affectsapproximately 200 million people worldwide, compris-ing 3% of global population and is currently the mostfrequent cause for liver transplantation in the UnitedStates and Europe [Lavanchy, 2009; Tsoulfas et al.,2009; Bostan and Mahmood, 2010; World HealthOrganization, 2013].HCV infection is strongly associated with the

development of insulin resistance (IR) and predis-pose to the onset of type-2 diabetes irrespective ofliver disease severity through interactions withdifferent components of the insulin signaling path-way or with factors involved in its regulation.[Decock et al., 2007; Badar et al., 2012; Bugianesiet al., 2012]. Growing evidence from several studiessupports the central role of IR in response failure toantiviral therapy among HCV patients [Harrison,2006; Decock et al., 2007; Parise and Oliveira, 2007;Dai et al., 2009; Grasso et al., 2009; Khattab et al.,2010; Vachon et al., 2011; Brandman et al., 2012;Ziada et al., 2012; Ismail, 2013]. IR is stronglyimplicated in liver fibrosis and contributes to fibroticliver progression, steatosis, development of complica-tions, and response to HCV therapy [D’Souza et al.,2005; Svegliati-Baroni et al., 2007; Petta et al.,

Conflict of interest: The authors declare no conflict of interest.�Correspondence to: Ekram W. Abd El- Wahab, Tropical

Health Department, High Institute of Public Health, AlexandriaUniversity, Egypt.E-mail: [email protected]

Accepted 1 October 2014

DOI 10.1002/jmv.24092Published online in Wiley Online Library(wileyonlinelibrary.com).

�C 2014 WILEY PERIODICALS, INC.

2008]. Treatment of chronic HCV infection withPegylated-interferon alpha (PegIFN-a) and ribavirincombination therapy has favorable efficacy in geno-types 2 and 3 but a limited one among genotypes 1and 4 infected patients. The treatment is costly andinvolves severe side effects [Ghany et al., 2009]. Theprediction of non-response is thus of utmost interestfor both patient wellbeing and health care economy.A number of host-related factors have been reportedto interfere with HCV treatment response. Theseinvolve old age, male gender, ethnicity, obesity,advanced liver fibrosis or cirrhosis, high transami-nase levels, established state of diabetes, HLA class,and host genetic polymorphisms [Berg et al., 2003;Tarantino et al., 2006; Ge et al., 2009; McHutchisonet al., 2009; Suppiah et al., 2009; Alan, 2011]. Pre-treatment assessment of IR has emerged as animportant milestone in the treatment of patients.Elevated HOMA-IR was associated with a lowercure rate of patients with hepatitis C treated withPeg-IFN-a/ribavirin irrespective of the infecting gen-otype [Eslam et al., 2011]. Early virologic responseis a major determinant for identifying non-responderpatients and has a great impact on subsequent rapidand sustained virologic response, thus constitutesthe earliest treatment-stopping rule [Ghany et al.,2009].At present, no individualized treatment schedule is

tailored on the basis of any baseline predictor ofresponse. The present work aims to validate directlymeasured IR state as a pre-treatment clinical param-eter interfering with early viral kinetics in responseto HCV therapy and whether early treatment out-come could also be predicted at baseline virologic andhost characteristics. The impact of HCV treatmentand viral eradication on insulin sensitivity was alsoaddressed.

MATERIALS AND METHODS

Study Design and Patients

A prospective cross sectional study was conductedbetween October 2012 and February 2013 at theLiver Center of El-Qabbary Hospital affiliated toMinistry of Health and Population in Alexandria(Egypt). The study patients comprised chronic HCVpositive patients eligible for receiving pegyinterferon/ribavirin combination therapy. The criteria for inclu-sion were: age from 18 to 60 years, both sex, HCV-RNA positive PCR, liver biopsy showing Ishak stagefrom 1 to 4, complete blood picture within normalranges, HBV/HIV seronegative, and all eligible casesfor treatment according to international guidelines[Ghany et al., 2009]. Those with established diabetesmellitus (diagnosed according to the WHO criteria) orfemales with previous history of gestational diabetesand all cases found ineligible for the treatment wereexcluded from the study {Age under 18 or above60 years, history of major depression or psychosis,malignancy, coronary artery disease, solid organ

transplant, untreated thyroid disease, active sub-stance abuse, Wilson’s disease, hemochromatosis,a1-antitrypsin deficiency, and hepatic decompensa-tion, autoimmune hepatitis or other autoimmunedisease such as systemic lupus erythematosus, rheu-matoid arthritis, or auto immune hepatitis, uncon-trolled seizures, uncontrolled diabetes, uncontrolledhypertension, current or planned pregnancy for18 months following start of treatment, end stage renaldisease or serum creatinine greater than 1.5mg/ml,continued pattern of alcohol abuse >40g/day in thelast 6 month, WBCs< 3000/cmm, hemoglobin <10g/dl,platelet count <100,000/cmm, liver biopsy Ishak stagemore than 4/6, Retinopathy, concomitant schistosomamansoni, HIV, or HBV infection, and obese patients(Body Mass Index [BMI] >35)}.

Sample Size

Using a power of 80% to detect the prevalence of IRamong HCV seropositive cases¼ 50% [Harrison, 2006;Shaheen et al., 2007; Peres et al., 2013] with a precision¼ 5%, a¼ 0.05, the minimal required sample size wasfound to be 384 cases (Epi InfoTM version 7, Centers forDisease Control and prevention). A total of 401 (tocompensate for fellow-up loss effect) patients wereenrolled study using simple random selection. Patientswho terminated their antiviral therapy early (beforeweek 12) were excluded from the analysis (Fig. 1).

Clinical and Laboratory Investigations

All enrolled patients were interviewed using struc-tured predesigned questionnaire to collect sociodemo-graphic data and subjected to complete medicalexamination (general and abdominal) including esti-mation of the BMI. Baseline laboratory investigationsfor proper selection of eligible cases for treatmentcomprised: Complete blood count, fasting and post-prandial blood glucose, liver function tests (serumbilirubin, ALT, AST, alkaline phosphatase, prothrom-bin time, serum albumin), serum creatinine, anti-nuclear antibody, thyroid stimulating hormone, alphafetoprotein, viral markers including HBsAg, and anti-HCV (Enzyme-linked immunosorbent assay [ELISA];Adaltis1, Inc. Italy), HCV-RNA quantitation by Real-Time PCR using Taqman Real-Time PCR, AppliedBioSystem with a threshold of detection¼ 10 IU/ml,anti-shistosomal Ab: (Indirect hemagglutination test[IHA]; Fumouze Diagnostics, France). Abdominalultrasonography, ECG, and ocular examination weredone for all patients.HOMA-IR was assessed using the given mathemat-

ical equation; HOMA-IR¼ fasting insulin (mU/ml)�fasting plasma glucose (mmol/l)/22.5 [Bonora et al.,2000]. A HOMA value of �2.18, signifies IR (AUC¼ 0.63� 0.03, 95% CI¼ 0.56–0.69; P¼ 0.001, sensitiv-ity¼ 60%, specificity¼ 55%) (Fig. 2). A direct measureof IR using the hyperinsulinemic euglycemic clamp tocompare the sensitivity and specificity was not avail-able in this study.

J. Med. Virol. DOI 10.1002/jmv

Insulin Resistance and Early Viral Kinetics 429

Ultrasonography and Liver Biopsy

All patients underwent ultrasound-guided liverbiopsy before starting treatment. The biopsy speci-mens (not <15mm in length or with the presence ofat least 10 complete portal tracts) were analyzed by asingle experienced pathologist who was blinded tothe clinical and biological data). Necroinflammatoryactivity was graded and fibrosis was staged accordingto the histological activity index [Ishak et al., 1995].

Regimen of Combination Therapy

All enrolled patients received Peg-IFN-a-2a (Pe-gasys, Pegferon, Hoffimann-La Roche) or Peg-IFN-a-2b(Pegintron; Schering-Plough K.K., Kenilworth, NJ),

which was given in weekly doses adjusted to bodyweight according to the manufacturer’s instructions at1.5mg/kg/week, plus ribavirin (Rebetol; Schering–Plough K.K.), in two divided daily oral doses adjustedto body weight (800mg for weights <50kg, 1,000mg forweights 50–65kg, 1,200mg for weight 65–80kg, and1,400mg for weights >80kg). Laboratory investiga-tions, including complete blood count and liver functiontests were repeated at 4 and 12 weeks during treat-ment. At week 12 of treatment, all enrolled patientswere subjected to qRT-PCR for viral load to detect earlyvirologic response and re-assessment of HOMA-IR toevaluate the impact of treatment on insulin sensitivity.

Statistical Analysis

Data were collected, revised, coded, and fed to stat-istical software SPSS (Statistical Package for the SocialSciences) Version16.0 (SPSS, Chicago, IL). All statisti-cal analysis was done using two-tailed tests and alphaerror of 0.05 P-value. The means with standard devia-tion and percent were used to describe the scale andcategorical data, respectively. Numeric data were ana-lyzed using one-sample Kolmogorov–Smirnov test andMann–Whitney test. For categorical data, Pearson’s Chisquare test, Fisher’s exact test, Mont Carlo exact test,and Kruskal–Wallis test for several independentgroups. Multiple logistic regression analysis with thebackward stepwise variable selection was used to iden-tify the independent predictors of treatment outcome.

Ethical Statement

The study was approved by the institutional reviewboard and the ethics committee of the High Instituteof Public Health affiliated to Alexandria University,Egypt. The research was conducted in accordancewith the ethical guidelines of the 1975 Declaration ofHelsinki and the International Conference on Harmo-nization Guidelines for Good Clinical Practice. Allparticipants were invited to sign an informed writtenconsent after explaining the aim and concerns of thestudy. Data sheets were coded to ensure anonymityand confidentiality of patient’s data.

RESULTS

Patient Demographics

Of a total 392 enrolled chronic HCV cases, 55.6%were males, whereas females represented 44.4% with1.25:1M:F ratio. Their ages ranged between 19and 59 (mean�SD¼ 41.5� 10.2 years, median¼ 43,Q1¼ 30, Q3¼ 50). Most of the participants were fromrural areas (n¼ 322; 81.3%). Other sociodemographiccharacteristics are detailed in (Table I).

Factors Associated With Insulin Resistance (IR)in the Study Patients

Insulin resistance (HOMA-IR �2.18) was detectedamong 241 (61.5%) of the patients. The analysis of

Fig. 2. ROC curve for HOMA-IR cutoff value among studiedchronic HCV patients. Diagonal segments are produced by ties.

Fig. 1. Chart showing the enrolled chronic HCV patientsthroughout the treatment period distributed according to earlyvirologic response and insulin resistance state (IR).


430 Abd El-Wahab et al.

factors associated with insulin resistance using bi-nary logistic regression revealed that old age (50–59age group); (OR 95% CI¼ 2.9 [1.2–45], P¼ 0.021), lowprothrombin activity; (OR 95% CI¼ 3.5 [1.1–15.2],P¼ 0.037), high total serum bilirubin >2mg/dl; (OR95% CI¼ 1.9 [1.2–3.1], P¼ 0.009), prediabetics (Fast-ing Blood Glucose¼ 127–130mg/dl); (OR 95% CI¼ 77[4.2–125.7], P¼ 0.0001), high alpha fetoprotein(>10ng/dl); (OR 95% CI¼ 2.6 [1.3–5.6], P¼ 0.013),steatosis; (OR 95% CI¼ 1.9 [1.2–3.2], P¼ 0.014),normal and high insulin levels; (OR 95% CI¼ 19.2[1.1–158.3], P< 0.0001) and (OR 95% CI¼ 524.3[187.1–1257.3], P< 0.0001), respectively, Ishak scoresIII and IV; (OR 95% CI¼ 19.2 [1.1–158.3], P< 0.0001)and (OR 95% CI¼ 524.3 [187.1–1257.3], P< 0.0001]respectively are significant risk factors (Table I).Nevertheless, only pretreatment fasting blood glu-cose, total serum bilirubin, and higher Ishak scoringwere detected in a stepwise regression model (TableII). The same also applies among underweight andnormal weight subjects. Interestingly, although insu-lin resistance was higher among overweight andobese patients, high BMI was not a significant riskfactor for insulin resistance (OR 95% CI¼ 5.9 [0.36–97.7], P< 0.0001) and (OR 95% CI¼ 19.6 [0.79–87.6],P< 0.0001], respectively.

Early Virologic Response and Related HostCharacteristics, Viral, and Metabolic Factors

Early virologic response (defined as undetectableHCV-RNA levels in the serum estimated at the 12thweek of treatment) was achieved by 81.1% of thecases. Older patients (50–59 years) had the lowestresponse rate. However, the mean age of EV respond-ers was not-significantly lower than that of non-early virologic responders; (41.2� 10.2 vs. 42.5� 9.8).Although males responded slightly better than fe-males (81.6% vs. 80.6%) at 12 weeks of treatment;this was not statistically significant. Neither theplace of residence, marital status, education level northe occupation had significantly affected the earlyvirologic response. Smoking and higher BMI weresignificantly associated with lack of early virologicresponse at the 12th week of treatment (P< 0.0001)(Table III).Some viral and host baseline laboratory test levels

have significantly affected the early virologic re-sponse. This was evident for low initial viral load(P< 0.0001). The median initial viral load of respond-ers was significantly lower than that of non-respond-ers; (210,000 vs. 595,000). However, initial viral loadwas not significantly related to insulin resistancestate (P¼ 0.44). Elevated base line alpha fetoproteinlevel was significantly associated with non-responseat the 12th week of treatment (P< 0.001). Baselinehaemoglobin level, total leucocytes count, plateletscount, prothrombin activity, serum albumin, serumcreatinine, AST, ALT, alkaline phosphatase, thyroidstimulating hormone, and anti-shistosomal Ab were

not significantly related to early virologic response(Table IV).

Impact of Interferon Type, Pretreatment FastingBlood Glucose, Fasting Blood Insulin, andHOMA-IR on Early Virologic Response

Either type of interferon used (Peg-IFN-a-2a[n¼ 200] or Peg-IFN-a-2b [n¼ 192]) in the conven-tional therapeutic regimens had no significantimpact on early virologic response (P¼ 0.44). Asignificant association between baseline fasting bloodglucose and early virologic response was observed;the lower the pretreatment fasting blood glucose levelthe better was the response. The mean and medianfasting blood glucose were significantly lower amongresponders than non-responders (90.3� 11.3 vs.98.2� 13.4) and (88 vs. 95.5), respectively. Likewise,the median of pretreatment fasting blood insulin wassignificantly lower among responders than non-res-ponders (9.1 vs. 9.2) (Table V).

Impact of Some Histological Criteria onEarly Virologic Response

Low early virologic response was not significantlyassociated with the presence of steatosis and peri-portal fibrosis as detected by liver biopsy. On theother hand, higher stages of fibrosis in Ishakscoring were significantly associated with lack ofearly virologic response (P< 0.0001) (Table II).Stages l, ll, lll, and lV showed 96.7%, 85.6%, 47.4%,and 25% response rates, respectively (Fig. 3).Higher Ishak scoring was significantly associatedwith increasing alpha fetoprotein level (P¼ 0.003);mean�SD levels of 2.6� 1.8, 5.7� 12.1, 8.3� 9.7,8.4� 9.3 for stages l, ll, lll, and lV, respectively.High Ishak staging was also significantly associ-

ated with insulin resistance. About 49% of Ishakstage I had insulin resistance compared with 60%,84.2%, and 100% of Ishak stages ll, lll, and lV,respectively (Table VI).

Effect of Treatment on Glucose Metabolism andInsulin Resistance

HCV therapy was significantly associated withimprovement of glucose metabolism as evidenced byan increase in the number of patients with normalglucose and insulin, and decreased number of thosewith relatively high glucose and high insulin levels.The number of patients with insulin resistance haddecreased by fivefold (from 241 [61.5%] to 51 [13%])(Table VII).

Independent Predictors ofTreatment Outcome

Table VIII shows the result of multiple stepwiselogistic regression analyses for factors affecting re-sponse to chronic HCV therapy. The model includedall risk factors that were significantly, using



TABLE I. Factors Associated With Insulin Resistance

HOMA-IR categories

OR (95% CI) P- value

�2.18(no IR) >2.18 (IR)

No % No %

Age19� 26 44.8 32 55.2 1 0.02130� 46 45.5 55 54.5 0.97 (0.51–1.9)40� 52 40.0 78 60.0 1.2 (0.65–2.3)50�59 27 26.2 76 73.8 2.3 (1.2–4.5)a

GenderMale 88 40.6 129 59.4 1Female 63 36.0 112 64.0 1.2 (0.80–1.8) 0.35

ResidenceUrban 123 38.6 196 61.4 1 0.97Rural 28 38.4 45 61.6 1.0 (0.60–1.7)

EducationIlliterate 22 30.6 50 69.4 1.1 (0.35–3.7)Read and write 27 34.6 51 65.4 0.94 (0.29–3.1)Primary education 16 38.1 26 61.9 0.81 (0.24–2.8) 0.38Preparatory education 19 39.6 29 60.4 0.76 (0.23–2.6)Secondary education 62 45.3 75 54.7 0.61 (0.19–1.9)University education 5 33.3 10 66.7 1Smoking 31 33.3 62 66.7 1.3 (0.82–2.2) 0.24

BMI1_cat<18� 0 0.0 1 100.0 118� 120 90.2 13 9.8 0.11 (0.01–1.8)25� 26 14.4 154 85.6 5.9 (0.36–97.7) 0.000130þ 5 6.4 73 93.6 14.6 (0.79–87.6)

Viral loadVery low <10,000 13 50.0 13 50.0 1Low 10000–100000 37 40.2 55 59.8 1.5 (0.62–3.5)Intermediate 100000–1000000 73 38.6 116 61.4 1.6 (0.69–3.6)High >1000000 28 32.9 57 67.1 2.0 (0.83–4.9) 0.44

Hemoglobin levelBelow normal (10–12.9 g/dl) 133 38.4 213 61.6 1.0 (0.55–1.9) 0.93Normal (13–17.9 g/dl) 18 39.1 28 60.9 1

White blood cellsBelow normal (3.2–3.9 k/mm2) 12 32.4 25 67.6 1.4 (0.66–2.8)Normal (4–11k/mm2) 137 39.5 210 60.5 1 0.54Above normal (>11–13.5 k/mm2) 2 25.0 6 75.0 1.9 (0.34–9.8)

Platelet countBelow normal (24000–) 32 40.5 47 59.5 0.90 (0.54–1.5) 0.68Normal (150–404000k/mm2) 119 28.0 194 62.0 1

Prothrobin activityBelow normal (62–74%) 3 15.8 16 84.2 3.5 (1.1–12.2)a 0.037Normal (75–100%) 148 39.7 225 60.3 1

Total serum bilirubin<2 121 42.5 164 57.5 1>2 30 28.0 77 72.0 1.9 (1.2–3.1)a 0.009

Alpha feto proteinNormal (upto 10ng/ml) 142 40.7 207 59.3 1Elevated (>10ng/ml) 9 20.9 34 79.1 2.6 (1.3–5.6)a 0.013

Fasting blood glucoseBelow normal (50–69mg/dl) 3 75.0 1 25.0 1Normal (70–110mg/dl) 148 40.9 214 59.1 4.3 (0.45–42.1)Prediabetics (111–130mg/dl) 0 0.0 26 100.0 77.0 (4.2–125.7)a 0.0001

InsulinBelow normal <5uI unit/ml 15 100.0 0 0.0 1Normal 5–9uIUnit/ml 136 61.8 84 38.2 19.2 (1.1–158.3)a 0.0001Above normal >10uI unit/ml 0 0.0 157 100.0 524.3 (187.1–1257.3)a

Peri-portal fibrosis 61 39.1 95 60.9 0.96 (0.63–1.5) 0.84Steatosis 24 27.3 64 72.7 1.9 (1.2–3.2)a 0.014

Ishake scoreStage 1 31 50.8 30 49.2 1Stage 2 111 41.1 159 58.9 1.5 (0.85–2.5)Stage 3 9 15.8 48 84.2 5.5 (2.3–13.2)a 0.0001Stage 4 0 0.0 4 100.0 9.3 (4.5–82.6)a

aSignificance based on 95% confidence interval.



TABLE II. Stepwise Logistic Regression Model for Factors Associated With Insulin Resistance

95.0% CI for Exp (B)

B S.E. Wald df Sig. Exp (B) Lower Upper

Step 3 Ishak_score 0.729 0.214 11.638 1 0.001 2.1 1.4 3.2

Total serum bilrubin 0.873 0.405 4.637 1 0.031 2.4 1.1 5.3

Fasting blood glucose 0.076 0.013 35.725 1 0.000 1.1 1.2 2.1

Constant �8.619 1.279 45.401 1 0.000 0.000

TABLE III. Impact of Some Host Characteristics on EVR in Chronic HCV Patients Undergoing Therapy

EVR (n ¼ 392)

Responders Non-responders

(n ¼ 318) (n ¼ 74)

Variable Total no. (%) No. % No. % OR (95% CI) P-value

Age (years)19– 58 (14.8) 48 82.8 10 17.2 0.9 (0.38–2.1)30– 101 (25.8) 82 81.2 19 18.8 1.1 (0.5–2.6) 0.37740– 130 (33.2) 110 84.6 20 15.4 0.65 (0.3–1.5)50–59 103 (26.3) 78 75.7 25 24.3Mean�SD

41.2 � 10.2 42.5 � 9.8t¼0.9 7 0.334

GenderMale 217 (55.4) 177 81.6 40 18.4 0.9 (0.56–1.5) 0.802Female 175 (44.6) 141 80.6 34 19.4

ResidenceUrban 319 (81.4) 258 80.9 61 19.1 0.9 (0.5–1.8) 0.796Rural 73 (18.6) 60 82.2 13 17.8

Marital statusSingle 56 (14.3) 47 83.9 9 16.1 1.28 0.703a

Married 316 (80.6) 256 81.0 60 19.0Divorced 4 (1.0) 3 75.0 1 25.0Widowed 16 (4.1) 12 75.0 4 25.0

EducationIlliterate 72 (18.4) 58 80.6 14 19.4 0.7 (0.4–1.9) 0.956a

Read and write 78 (19.9) 61 78.2 17 21.8 1 (0.4–2.7)Primary education 42 (10.7) 34 81.0 8 19.0 1.4 (0.5–3.8)Preparatory education 48 (12.2) 41 85.4 7 14.6 1.1 (0.5–2.2)Secondary education 137 (34.9) 112 81.8 25 25.9 1 (0.2–3.9)University education 15 (3.8) 12 80.0 3 20.0 1

OccupationHealth care worker 2 (0.5) 2 100.0 0 0.0 1.801 0.996a

Employee 13 (3.3) 10 76.9 3 23.1Manual worker 24 (6.1) 20 83.3 4 16.7Farmer 67 (17.1) 56 83.6 11 16.4Housewife 165 (42.1) 132 80.0 33 20.0Trader 29 (7.4) 24 82.8 5 17.2Butcher 2 (0.5) 2 100.0 0 0.0Others 28 (7.1) 22 84.6 6 15.4Not working 62 (15.8) 50 80.6 12 19.4

SmokingNo 299 (76.3) 260 87.0 39 13.0 4 (2.3–6.9) 0.001b

Yes 93 (23.7) 58 62.4 35 37.6BMI

<18 under weight 1 (0.3) 0 0.0 1 100.0 0.4 (0.03–7.4) 0.001a,b

18� normal weight 133 (33.9) 121 91.0 12 9.0 4.4 (2.1–9.5)25� over weight 180 (45.9) 143 79.4 37 20.6 1.7 (1.1–3.4)30þ obese 78 (19.9) 54 69.2 24 30.8

aP-value based on Mont Carlo exact test.bP< 0.05 (significant).



TABLE IV. Impact of Baseline Viral, Host Metabolic Factors and Liver Histology on EVR of Chronic HCV Patient

EVR (n ¼ 392)


(n ¼ 318) (n ¼ 74)

Variable Total no. (%) No. % No. % 95% CI P

Viral load (IU/ml)Very low (<10.000) 26 (6.6) 26 100.0 0 0.0 3.8 (1.7–8.5)a 0.0001a

Low (<100.000) 92 (23.5) 82 89.1 10 17.4 1.9 (1.1–3.4)a

Intermediate (<1000.000) 189 (48.2) 152 80.4 37 19.6High (>1000.000) 85 (21.7) 58 68.2 27 31.8Median! 210000 595000 z = �4.472 0.0001a

Hemoglobin levelBelow normal (10–11.9 g/dl) 346 (88.3) 279 80.6 67 19.4 1.3 (0.6–3.1) 0.556Normal (12–18 g/dl) 46 (11.7) 39 84.8 7 15.2

White blood cellsBelow normal (3.2- k2/mm3) 37 (9.4) 28 75.5 9 24.3 1.1 (0.6–3.1) 0.261Normal (4–11–k2/mm3) 347 (88.5) 282 81.3 65 18.7Above normal (11–13.5 k2/mm3) 8 (2.0) 8 100.0 0 0.0

Platelet countBelow normal (24000–) 79 (20.2) 63 79.7 16 20.3 1.2 (0.7–2.3) 0.521Normal (150000–404000) 313 (79.8) 255 81.5 58 18.5

Prothrombin activityBelow normal (<75%) 19 (4.8) 13 86.4 6 31.6 1.6 (0.5–4.5) 0.223Normal (75–120%) 373 (95.2) 305 81.8 68 18.2

Serum albumenBelow normal (<3.5 g/dl) 4 (1.0) 3 75.0 1 25.0 1.4 (0.1–14) 0.647b

Normal (3.5–5.5 g/dl) 387 (98.7) 314 81.1 73 18.9 1.3 (0.03–53)Elevated (>5.5 g/dl) 1 (0.3) 1 100.0 0 0.0

Serum creatinine>0.5�mg/dl 322 (82.1) 256 79.5 66 20.5 0.5 (0.2–1.1) 0.0921–1.5mg/dl 70 (17.9) 62 88.6 8 11.4

ASTNormal (up to 37 U/L) 157 (40.1) 134 85.4 23 14.6 1.6 (0.9–2.8) 0.088Elevated (>37–330U/L) 235 (59.9) 184 78.3 51 21.7

ALTNormal (up to 40U/L) 156 (39.8) 127 81.4 29 18.6 1.03 (0.6–1.7) 0.906Elevated (>40–320U/L) 236 (60.2) 191 80.9 45 19.1

Alkaline phosphataseNormal (up to 92U/L) 124 (31.6) 104 82.9 20 16.1 1.1 (0.6–2) 0.406Elevated (> 92–380 U/L) 268 (68.4) 214 79.9 54 20.1

Total serum bilirubinNormal (up to 1mg/dl) 285 (72.7) 230 80.7 55 19.3 1.1 (0.6–2) 0.774Elevated (>1mg/ml) 107 (27.3) 88 82.2 19 17.8

Thyroid stimulating hormoneBelow normal (<0.35mIU/L) 11 (2.8) 10 90.9 1 9.1 1.1 (0.5–2.5) 0.676b

Normal (0.35–5mIU/L) 377 (96.2) 304 80.6 73 19.4Elevated (>5mIU/L) 4 (1.0) 4 100.0 0 0.0

Alpha feto proteinNormal (up to 10ng/ml) 349 (89.0) 293 84.0 56 16.0 3.8 (1.9–7.3)a 0.0001a

Elevated (>10ng/ml) 43 (11.0) 25 58.1 18 41.9Anti-bilharzial AbNegative 175 44.6) 143 81.7 32 18.3 1.1 (0.6–1.8) 0.797Positive 217 (55.4) 175 80.6 42 19.4

SteatosisNo 304 (77.5) 248 81.6 56 18.4 1 (0.9–1.8) 0.668Yes 88 (22.4) 70 79.5 18 20.5

Periportal fibrosisNo 236 (60.2) 194 82.2 42 17.8 1.1 (0.6–2) 0.501Yes 156 (39.8) 124 79.5 32 20.5

Ishak scoreI 61 (15.5) 59 96.7 2 3.3 88.5 (6.15–1272)a 0.0001a,b

II 270 (68.9) 231 85.6 39 14.4 17.8 (1.8–175)a

III 57 (14.5) 27 47.4 30 52.6 2.7 (0.2–27)IV 4 (1.0) 1 25.0 3 75.0

Interferon typeAlpha 2-a 200 (51.0) 159 79.5 41 20.4 1.2 (0.7–2.1) 0.4Alpha-2-b 192 (49.0) 159 82.8 33 17.2

Z: Mann Whitney test for two independent groups.! using median as the data are skewed (have high variability).aP< 0.05 (significant).bP value based on Mont Carlo exact test.



univariat analyses, among which the attached factorswere found to be significant, keeping other factorsconstant.As for pretreatment fasting blood glucose, the

increase by one unit was associated with decreased

probability of response by about 4%. Those withhigh HOMA-IR >2.18 have five times more risk ofbeing non-responder compared to those with HOMA-IR �2.18. Regarding viral load, those with pretreat-ment low and intermediate levels recorded 3.6 and 2times more chance for response respectively, com-pared to others with high pretreatment viral load.Concerning smoking, non-smokers had recordedfourfold more chance for response compared tosmokers.Likewise, those with normal BMI and those who

were overweight recorded 4 and 1.8 times more chancefor response respectively, compared to obese patients.

DISCUSSION

In May 2011, the FDA approved two new medica-tions (Boceprevir/Telaprevir) that are given withPEG-interferon/ribavirin for treatment of HCV. Thereis a limited availability of this triple therapy inEgypt. The previously recommended treatment forpatients with HCV genotypes 1 and 4 is pegylated-interferon plus ribavirin for 48 weeks. Such treat-ment remains suboptimal that yielded overall

TABLE V. Impact of Pretreatment FBG, Fasting Blood Insulin and HOMA-IR on EVR of Chronic HCV Patients

EVR (n ¼ 392)


(n ¼ 318) (n ¼ 74)

Variable Total no. (%) No. % No. % 95% CI P-value

Pretreatment fasting blood glucoseBelow normal (50– <70mg/dl) 4 (1.0) 4 100.0 0 0.0 0.84 (0.1–7.7) 0.034a,b

Normal (70–110mg/dl) 362 (92.3) 298 82.3 64 17.7 2.5 (0.2–25.7)Prediabetics (111–130mg/dl) 26 (6.6) 16 61.5 10 38.5

Mean�SD !90.3�11.3 98.2�13.4

Median (Range)!88 (53–130) 95.5 (72–130)

z¼�5.151 <0.001a

Q1, Q3 83, 96 90, 103.5Pretreatment fasting blood insulinBelow normal (<5uIUnit/ml) 15 (3.8) 14 93.3 1 6.7 1.2 (0.1–10) 0.316b

Normal (5–9uIUnit/ml) 203 (51.8) 167 82.3 36 17.7 0.2 (0.03–1.7)Above normal (�10uIUnit/ml) 174 (44.4) 137 78.7 37 21.3

Mean�SD !

15.3�27 11.5�8.2Median (Range)!

9.1 (3–270) 9.2 (4.8–58)z¼�2.168 0.030a

Q1, Q3 7, 12 7.8, 13.9Pretreatment HOMA-IRNo �2.18 151 (38.5) 141 93.4 10 6.6 4.6 (2.3–9.5)a <0.0001a

Yes >2.18 241 (61.5) 177 73.4 64 26.6Mean�SD!

3.46 � 5.9 3.1 � 2.3Median (Range)!

2.1 (0.57–51.7) 2.42 (1–19.2)z¼�3.71 <0.001a

Q1, Q3 1.56, 2.8 2.1, 3.33

Z: Mann Whitney test for two independent groups.! using median as the data are skewed (have high variability).aP< 0.05 (significant).bP-value based on Mont Carlo exact test.

Fig. 3. Impact of Ishak stage on early virologic response ofchronic HCV patients.



sustained viral response rates of 54–63% in random-ized controlled phase III clinical trials [Carrat et al.,2004; Aghemo et al., 2009]. However, treatmentresponses are not uniform across all patients, and aredependent on various viral and host factors [DiMarco et al., 2013]. Accordingly, prediction of treat-ment outcome at baseline would be highly beneficial.It is well-known that there are many factors that

affect a successful treatment outcome. These shouldbe considered when making a decision whether or notto treat an HCV patient.Early virologic response is a significant determinant

of final virologic response because of its higher predic-tive value [Kamal et al., 2007]. In the present study,81.1% became HCV-RNA negative by 12 weeks oftreatment. This was similar to that reported by Ismailet al., 2013 (85%) [Ismail, 2013], lower than thatreported by Kamal et al. (2007) (97%) [Kamal et al.,2007] but higher than results of Ziada et al. (2012)

(47%) [Ziada et al., 2012] for the same ethnic group,however their used sample sizes were relatively small.Age and sex are contributing host related factors to

treatment outcome [Di Marco et al., 2013]. Generally,people under 40 years old respond better to currentHCV medication than those over 40 [Khattab et al.,2010; Ziada et al., 2012]. In fact, the cellular,humoral, and innate immunity wane with age. Moreintact immune system at a younger age has betterability to fight the virus [Ginaldi et al., 2001]. Also,the longer that one has hepatitis C, the more thevirus can replicate and possibly causes liver damage.Women seem to respond better to current HCVmedications than males. The reason for this isunclear, but may be attributed to the positive effectsof estrogen especially in pre-menopausal females[Idrees and Riazuddin, 2009]. In the present study,no age or sex difference was observed among earlyresponders and non-responders. Other host related

TABLE VI. Relation Between Ishak Scoring and HOMA-IR

Ishak score

Stage 1 Stage 2 Stage 3 Stage 4

Insulin resistance Total (n¼392) N % N % N % N % X2 P

Normal 151 (38.5) 31 50.8 111 41.1 9 15.8 0 0.0 20.27 0.002*

High 241 (61.5) 30 49.2 159 58.9 48 84.2 4 100.0

*P< 0.05 (significant).

TABLE VII. The Effect of Treatment of Chronic HCV by a Combination of Pegylated Interferon Plus Ribavirin on GlucoseMetabolism and Insulin Resistance

Treatment phase

Pretreatment 12 week

Variable No. % No. % 95% CI P

Fasting blood glucoseBelow normal (50– <70mg/dl) 4 1.0 16 4.0 0.6 (0.3–1.4) <0.0001a,b

Normal (70–110mg/dl) 362 92.37 369 94.23Prediabetics (111–130mg/dl) 26 6.63 7 1.77

Mean�SD ! 91.8 � 12.1 83 � 10.1Median (Range) 89 (53–130) 81 (60–126) z¼�12.416 <0.0001a

Q1, Q3 84, 97 75.2, 90Fasting blood insulinBelow normal (<5uIUnit/ml) 15 3.83 4 1.0 8.4 (4.1–17.1) <0.0001a,b

Normal (5–9uIUnit/ml) 220 56.12 302 57.9Above normal (>¼10uIUnit/ml) 157 40.05 86 21.94

Mean�SD! 14.8 � 24.5 10.5 � 13.8Median (Range) 9.2 (3–270) 7.4 (4.5130) z¼�10.27 <0.0001a

Q1, Q3 7.1, 12.2 5.9, 9.6HOMA-IRNo �2.18 151 38.5 341 87.0 0.02 (0.01–0.04) <0.0001a

Yes >2.18 241 61.5 51 13.0Mean�SD! 3.38 � 5.4 2.18 � 3Median (Range) 2.15 (0.57–51.7) 1.58 (0.86–27.1) z¼�13.45 <0.0001a

Q1, Q3 1.62, 2.91 1.25, 1.85

aZ: Mann Whitney test for two independent groups.bP-value based on Mont Carlo exact test.



sociodemographics such as occupation, residence,education, and marital status did not affect treat-ment response. These results confirm the data re-ported in the literature [Berg et al., 2003; Khattabet al., 2010; Alan, 2011#39; Alan, 2011; Di Marcoet al., 2013].Smokers tended to have a significantly lower

response rate to IFN therapy at 3 months. Smokingwas also shown as independent risk in the stepwiselogistic regression model. This result was consistentwith El-Zyadi et al. (2004), who found a betterresponse rate among non-smokers who received IFNtherapy [El-Zayadi et al., 2004]. Smoking is hepato-toxic [Pessione et al., 2003] and increases the risk ofprogression to cirrhosis and hepatocellular carci-noma in viral hepatitis patients [Mukaiya et al.,1998] possibly due to oxidative stress associatedwith lipid peroxidation [Watanabe et al., 1995] orimmune impairment [Suzuki and Takahashi, 2007].Likewise, normal BMI was a good predictor of early

virologic response in agreement with Quershi et al.,(2011) [Qureshi et al., 2011].The present data confirms the inverse relationship

between BMI and early virologic response. Obesitydecreases IFN-a bioavailability, impairs of immuneresponse to HCV [McCullough, 2003], interfereswith lymphatic circulation, and hence lowers serumlevels of pegylated IFN [Banerjee et al., 2001].Viral load indicates viral replication [Ouzan et al.,

2005]. In concordance with the present findings, highviral load (>400,000 IU/ml; difficult to treat) wasconsistently reported to significantly correlate with alack of response [El-Zayadi et al., 2004; Romero-Gomez et al., 2005; Khattab et al., 2010#24; Vachonet al., 2011; Ziada et al., 2012]. Baseline viral loadhas been suggested as a predictor of sustainedvirologic response, but several cut-offs have beenproposed [Kau et al., 2008].Elevated baseline alpha fetoprotein level was sig-

nificantly associated with non-response at 12 weeks.

This reflected a significant correlation with advancedIshak stages as reported earlier [El et al., 2013].Conflicting to the present finding, Shaker et al.(2011) found no effect for alpha fetoprotein inresponse to HCV therapy in genotype four infectedpatients.Consistent with previous studies [Shaker et al.,

2011; Ismail, 2013], baseline hematological, and liverfunction profiles hemoglobin level, total leucocytecount, platelets count, prothrombin activity, serumalbumin, serum creatinine, AST, ALT, alkalinephosphatase, thyroid stimulating hormone, and anti-shistosomal Ab did not correlate with early virologicresponse. Nevertheless, normal [De Coreaga, 2006]and elevated ALT [Lee et al., 2002] levels werepreviously reported to favor response to HCV therapy.Incidence of insulin resistance in chronic HCV

infected patients was reported to be significantlyhigher than the general population [Miyajima et al.,2013]. HCV dysregulate intracellular factors thatresult in insulin resistance state. Hyper insulinaemiaassociated with IR interferes with INF-a inducedsignal transduction and thus inhibition of viralreplication [Decock et al., 2007]. In this study, baseline insulin resistance was significantly higher thanthat reported in earlier studies (23–34%) [Romero-Gomez et al., 2005; Svegliati-Baroni et al., 2007;Ziada et al., 2012] but similar to that reported byPeres et al., (2013). Several prior studies report IR asmeasured by HOMA-IR a predictor of lower sustainedvirologic response rate to anti-HCV therapy [Romero-Gomez et al., 2005; Dai et al., 2009; Merchante et al.,2009; Khattab et al., 2010; Eslam et al., 2011; Kimet al., 2011; Vachon et al., 2011; Brandman et al.,2012; Ismail, 2013]. IR was a prominent independentrisk factor in stepwise logistic regression model at3 months of treatment. The present results werecompatible with findings of Ziada et al. (2012) whoreported that early virologic response was signifi-cantly lower in HCV-IR cases although these results

TABLE VIII. Stepwise Multiple Logistic Regression Analyses for Factors Affecting Response to Chronic HCV Therapy

95.0% C.I. for Exp (B)

Predictors B S.E. Sig. Exp (B) Lower Upper

Step 3 HOMA-IR<2 1.629 0.358 0.000 5.098 2.663 10.290FBG (pre-treatment) �0.041 0.012 0.000 0.960 0.938 0.982Viral load 0.024Low 1.298 0.438 0.003 3.662 1.552 8.640Intermediate 0.673 0.331 0.042 1.960 1.023 3.752Non smoker 1.401 0.309 0.000 4.060 2.217 7.436BMI 0.028Normal 1.393 0.462 0.003 4.027 1.629 9.954Overweight 0.590 0.354 0.096 1.804 0.901 3.612Constant 4.340 10216.368 1.000 76.675P value for the model 0.000Classification accuracy 80.6%

SE, standard error; Exp (B), odds ratio; B, regression coefficient.P< 0.05 is significant.P< 0.05 (significant).



were limited because of the small sample size. In theaforementioned study, 18.3% of the responders and50.7% of the non-responders were HOMA-IR �2.18compared to 55.6% and 86.5%, respectively found inthe present study. IR appeared to improve with HCVtreatment at 12 weeks irrespective of viral eradica-tion. According to the results of the SENSITIZErandomized controlled trial [Harrison et al., 2012],modification of IR by prior therapy with pioglitazonedid not modify the early or sustained virologicresponse to therapy in patients with genotype 1.Such approach has been reported only for patientswith HCV genotype 4 in a single study from Egypt[Khattab et al., 2010]. However, this is not sufficientto claim that improving insulin sensitivity mayameliorate response to therapy. More recently,Younossi and co-workers found that baseline HOMA-IR correlated with sustained virologic response inunivariate but not multivariate analyses in patientschronically infected with HCV-1 and undergoingtriple therapy, suggesting other factors have a moredirect causal relationship with virologic response totelaprevir-based therapy than HOMA-IR [Younossiet al., 2013].IR was found in the present study to be associated

steatosis, but not hepatic fibrosis. This agrees withthe results of Ziada et al. (2012) but differs to someextent to the results of Kim et al. (2011) who foundno association between IR and hepatic fibrosis. Thesefindings could be limited by the very small samplesize (60 compared to 392 in the present study).Histological evidence of steatosis was significantly

associated with being high BMI. Early virologic re-sponse was not associated with steatosis or periportalfibrosis as detected by liver biopsy. This result contra-dicts reports in other studies that hepatic steatosis isan independent risk factor for poor response to IFN-atherapy [Monto, 2002; Negro, 2006].Higher Ishak scores were significantly associated

with poor early virologic response although liverfibrosis did not appear in the stepwise regressionmodel among the independent predictors of thelatter. High levels of insulin and glucose couldpromote fibrogenesis by stimulating the release ofconnective tissue (fibrogenic) growth factor fromhepatic stellate cells [Paradis et al., 2001].

CONCLUSION AND RECOMMENDATIONS

Both host-related variables including BMI, smok-ing, and metabolic state of IR and viral factors interms of high viral load are involved in the earlytreatment failure. Chronic HCV patient with no IRresponded more rapidly and more efficiently byachieving apparent early virologic responses thanthose having low insulin sensitivity state. Furtherstudies using randomized controlled trial for assess-ing early virologic response in patients with/withoutinsulin resistance treated for 16–18 versus 48 weeksare needed. Accordingly, treatment regimen of

48 weeks for early responders could be shortened toonly 16–18 weeks without compromising the outcome,thus avoiding side effects of unnecessary drug andsaving unaffordable costs. On the other hand, strat-egies to reverse or improve insulin resistance statebefore treatment initiation may have a positive effecton early and sustained viral kinetics in response toHCV therapy.The IR included in the present prediction models is a

cost effective tool, does not need a laborious methods toestimate, and is a potentially modifiable factor that couldbe improved. Pre-treatment assessment of insulin usingHOMA-IR may be used as a determinant for regimenoptimization and individualization in CHC patients.

LIMITATIONS OF THE STUDY

This study was limited by basing all findings ondual anti-HCV therapy, since access to novel treat-ments is limited in low resource countries includingEgypt. Relevant missing information is the determi-nation of the infecting HCV genotype and the IL28Bpolymorphism, two important factors that could affectthe treatment outcome.

ACKNOWLEDGMENTS

We would like to thank Dr. Shehata Farag,lecturer of Biostatistics, High Institute of PublicHealth, Alexandria University, Egypt, for his greathelp in data processing and statistical analysis.

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