Journal of American Science 2013;9(3) http://www.jofamericanscience.

org

Apri As A Predictor For Sustained Virological Response In Chronic Hepatitis C Patients Genotype 4

Mohammad Yousri1, Medhat Assem1, Ahmed Helaly2, Gaser El Azab1 Wael Safwat3 Amgad Anas3 and
Manal Zahran4
1
Department of hepatology, National Liver Institute, Menofyia University, Sheben Al koom, Egypt.
2
Department of Medicine, Faculty of Medicine, Alexandria University, Egypt. 3Department of Hepato-
Gastroenterolgy, Theodor Bilharz Research Institute, Giza Egypt.
4
Department of Hematology, Theodor Bilharz Research Institute, Giza Egypt
[email protected]

Abstract: Background &Aim: To evaluate the aspartate aminotransferase (AST) to platelet ratio index (APRI) as a
predictive factor of sustained viral response in chronic hepatitis C naive patients with genotype 4. Patients
&Methods: We conduct this prospective study on chronic hepatitis C naïve patients who were evaluated to start
therapy with peg interferon a-2a (180 μg per week) and ribavirin (> 75 kg: 1200 mg and < 75 kg: 1000 mg) for 48
weeks and responders were followed for 24 weeks after end of treatment. Odds ratio (OR) and 95% confidence
interval (CI) were calculated to assess the relationship between each risk factor and the sustained virological
response (SVR). Results: One hundred and twenty patients were followed prospectively. The mean ± SD of age in
our subjects was 35.8 ± 12.5 years; weight 76 ± 12.7 kg , AST 63.8±44.7 IU/mL, alanine aminotransferase (ALT)
74.5± 60 IU/mL, creatinine; 0.96±0.26 mg/dl and platelets 202612±88343/mm3. The mean hepatitis C virus RNA
viral load was 3143683±6643988 IU/mL. APRI showed a significant positive correlation with increasing fibrosis
stage (r= 0.41, P < 0.05). By both univariate and multivariate analysis; initial viral load >600,000 iu/ml and
advanced hepatic fibrosis were negative predictors for SVR. Conclusion: APRI is a good estimator of hepatic
fibrosis. It could be used to decrease the number of liver biopsies; however it is not useful to predict SVR in patients
with chronic hepatitis C genotype 4.
[Mohammad Yousri, Medhat Assem, Ahmed Helaly and Gaser El Azab Wael Safwat Amgad Anas Manal Zahran.
Apri As A Predictor For Sustained Virological Response In Chronic Hepatitis C Patients Genotype 4. J Am Sci
2013;9(3):265-269]. (ISSN: 1545-1003). http://www.jofamericanscience.org. 50

Key words: APRI – HCV – Sustained virological response

1. Introduction fibrosis11,12,13.
Hepatitis C virus (HCV) is a major public Percutanous liver biopsy has been the gold
health problem that accounts for high proportion of standard for grading and staging liver disease;
liver diseases throughout the world1. According the recently however, non-invasive methods have been
WHO estimate 170 million individuals of the world developed to determine stage of hepatic fibrosis such
population are infected with Hepatitis C virus as transient electrograph, fibrotest, and the aspartate
(HCV)2. aminotransferase (AST) to platelet ratio index
HCV can result in progressive hepatic injury and (APRI)14,15 is one of several markers that have been
fibrosis, culminating in cirrhosis and end-stage liver anticipated to measure liver fibrosis. It is proposed as
disease. Chronic hepatitis C is a major indication for a simple and non-invasive predictor in the evaluation
liver transplantation and increases the incidence of of liver fibrosis status 14. APRI has been used in the
hepatocellular carcinoma3. evaluation of patients with CHC with high accuracies
The current treatment of choice for chronic in identifying the presence of significant fibrosis and
hepatitis C (CHC) is combination of pegylated cirrhosis14,15,16,17. Previous studies have not explored
interferon (Peg-IFN) and ribavirin (RBV)4. However, the usefulness of non-invasive tests like APRI to
non-response to this therapy remains common with assess liver fibrosis for the prediction of SVR in
approximately 50% of patients achieving sustained hepatitis C naive patients3.
viral response (SVR)5,6,7. Thus we designed the present study with the aim
Limited treatment efficacy, high costs, and to elucidate the role of APRI as a predictive factor of
significant side effects have prompted the SVR in Chronic hepatitis C patients with genotype 4.
development of methods to predict treatment
outcome8.9.10. Previous studies declared many 2. Methods & Patients:
negative predictors for SVR among HCV patients Patients eligible for HCV antiviral therapy
genotype 4 treated with peg interferon and ribavirin were recruited from National Liver Institute,
such as age, pretreatment viral load, and stage of Menofyia University, Egypt, in an ongoing,

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prospective trial from May 2007 to January 2009. Dose modifications

Treatment naive CHC patients were included if they Medications doses were modified based on
were between 18 and 60 years and had positive HCV the recommended manufacturers' guidelines for the
RNA by real time PCR (Cobas Amplicor HCV v2.0, treatment of Peg-IFN α-2a/RBV-induced
Roche Molecular Systems) with liver biopsy hematological side effects 19. Growth factors such as
consistent with chronic hepatitis and significant erythropoietin and granulocyte colony-stimulating
fibrosis. All patients were having HCV genotype 4. factor (G-CSF) were only used beyond the criteria of
Exclusion criteria included evidence for coexisting dose modification
liver disease, concurrent infection with hepatitis B Statistical analysis
virus or HIV, presence of hepatocellular carcinoma, Data was statistically analyzed using SPSS
decompensated cirrhosis, patients on hemodialysis, (statistical package for social science) program
significant systemic disorders, uncontrolled thyroid version 17 for windows. Quantitative data are
disease, a current or past history of alcohol abuse, presented as mean ± standard deviation. Qualitative
major psychiatric conditions, or previous liver data are presented as relative proportions. Student t-
transplantation. Patients with baseline anemia test and Mann-Whitney test were used to compare
(hemoglobin <13 g/dL for men and <12 g/dL for means for quantitative variables. The association
women), absolute neutrophil count (ANC) between the categorical variables was assessed by
<1500/mm3, platelet count <75,000 /mm3 or using the chi-square test or Fisher exact test. Odds
creatinine >1.5 mg/dL were also excluded. ratio (OR) and 95% confidence interval (CI) were
Pregnancy and lactation were not allowed calculated to assess the relationship between each risk
and the use of a reliable method of contraception factor. Logistic regression was used to assess the
during the period of combination therapy was significance of different variables on achieving SVR.
suggested. The study was conducted in conformance A p value < 0.05 was considered statistically
with the principles of the Declaration of Helsinki. The significant.
institutional review board of the hospital approved the
protocol and consent forms. All participants provided 3. Results
written informed consent. One hundred and twenty CHC patients (84
males, 70%) met the inclusion criteria; their mean
Treatment regime: ages were 39.9 ± 10.6 years. Seventy nine
They were treated with Peg-IFN α-2a 180 (65.8%) patients completed 48 weeks of treatment. 83
mcg weekly with ribavirin in dose of 1000 mg orally (69.2%) patients achieved EVR; 49 of them reached a
if patient was less than 75 kg and 1200 mg if the complete EVR and 34 showed partial EVR. 68
patient weighed greater than or equal to 75 kg. For 48 (56.7%) patients achieved ETR and 51 (42.5%)
ws patients achieved SVR. Basal patients’ characteristics
are shown in (Table 1).
Follow-up
All subjects were monitored during peg- APRI and fibrosis stage
interferon, ribavirin treatment in both groups and for a APRI showed a significant positive
further period of 24 weeks after the end of treatment. correlation with increasing fibrosis stage (r= 0.41, P
They had biweekly outpatient visits during the first = 0.009). Box plot of AST/ platelet ratio index in
month and monthly visits during the rest of the relation to the Metavir score is shown in (Figure 1).
treatment period as well as during the 24-week
follow-up period. At each visit, a physical Independent factors associated with SVR
examination was performed, the importance of Using the univariate analysis; HCV viral
treatment adherence was explained, adverse effects level above 600.000 IU/mL, and evidence of
were recorded, and biochemical tests and blood advanced fibrosis in liver biopsy (F4) were
counts were performed. The efficacy to standard anti significantly associated with low rate of achieving
viral therapy was defined as undetectable HCV RNA SVR (Table 2). This was confirmed by multivariate
level by PCR at 12 weeks (early virological response analysis (Table 3)
EVR),at the end of treatment (ETR) and after 24
weeks follows up (SVR). 4. Discussion:
APRI calculated according to the formula Recent studies have shown the importance of
proposed by Wai et al ., in 2003, namely, [(AST of APRI test to decrease the number of liver biopsies,
the sample/ reference AST) x 100] / platelets count particularly because patients with an APRI of less
(103/ dL)]18. Fibrosis was established if the APRI was than 0.40 have very little chance of having significant
≥ 1.2. fibrosis3. For our knowledge this was the first study

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to evaluate the APRI as a predictive factor of patients; but an indirect measure of fibrosis with
sustained viral response in patients with chronic APRI is not an option to predict viral response, in
hepatitis C genotype 4. addition, viral load still considered as a predictor for
We elucidate the possibility that biopsy viral response.
could predict treatment response in HCV infected

Table ( 1): B ase l i ne and demographic characteristic of patients’ cohort.

Variable Total patients (n = 120) SVR patients (n = 51) Non-SVR patients (n = 69) P value
Age (yr) 38.5 ± 12.5 36.9 ± 12.9 41.1 ± 11.8 0.424
Males (%) 84 (70%) 38 (74.5%) 46 (66.7%) 0.442
Weight (kg) 76.5 ± 12.7 73.7 ± 13.6 78.2 ± 12.1 0.301
Hemoglobin (g/dL) 14.1 ± 2.45 14.4 ±1.8 13.9 ± 2.81 0.511
Platelets (No/µL) 202,612 ± 88,343 212,132± 77,934 185,682 ± 94.113 0.133
Leucocytes (cells/µL) 5.2 ± 2.47 5.5 ± 2.1 4.9 ±2.6 0.512
Glucose (mg/dL) 103 ± 15.54 99 ±17.02 108 ± 13.7 0.243
Creatinine (mg/dL) 0.96 ± 0.26 0.97 ± 0.22 0.94 ±0.52 0.522
Albumin (g/dL) 4.4 ± 0.51 4.5 ± 0.41 4.3 ± 0.72 0.476
AST (IU/dL) 63.8 ± 44.7 59.9 ±41.5 72.2 ± 52.3 0.128
ALT (IU/dL) 74.5 ± 60 72.1 ± 56.2 77.2 ± 66.3 0.299
AP (IU/dL) 111.4 ± 37.4 107.2 ±40.3 113.3 ± 33.6 0.623
Baseline viral load (iu/mL) 3143683 ± 6643988 2448973 ± 7433292 3422776 ± 6217684 0.101
APRI 1.024 ± 1.89 0.911 ± 1.65 1.13 ± 1.94 0.092
Fibrosis stage
F1 26 (21.6%) 12 (23.5%) 14 (20.3%)
F2 37 (30.9%) 21 (41.2%) 16 (23.2%)
F3 38 (31.7%) 14 (27.5%) 24 (34.8%)
F4 19 (15.8%) 4 (7.8%) 15 (21.7%) 0.06
Data are presented as mean ± standard deviation
*P value is between SVR and non- SVR patients
AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; AP: Alkaline phosphatase; APRI: AST to platelet
ratio index.

Figure(1): relation of APRI score and Metavir fibrosis stage.

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Table( 2): Factors associated with SVR (Univariate analysis)

Parameter Odds Ratio 95% CI p value

Age (> 40 years) 0.75 0.52 - 1.11 0.61

Male gender 1.13 0.36 - 3.41 0.77
Body weight (BW) ≤ 75 kg 0.71 0.62 – 1.02 0.53
2
Body mass index (kg/m ) 0.78 0.34 - 1.09 0.74
AST (IU/L) 1.1 0.76 – 2.82 0.09
ALT (IU/L) 1.3 0.59 – 3.21 0.51
Platelets > 150 000/dL 1.9 1.02 – 2.9 0.24
Alkaline phosphatase (IU/L) 1.6 0.78 – 2.01 0.73
Bilirubin (mg/dl) 0.56 0.29 – 1.22 0.18
Viral load > 600 000 IU/mL 0.52 0.31 – 0.97 0.01
APRI 0.79 0.36 – 1.21 0.12
F4 Fibrosis stage 0.61 0.38 – 0.96 0.037
Ribavirin dose (mg/Kg body wt.) 1.73 0.92 – 2.91 0.22

Our findings are comparable with previous In conclusion, APRI, which is a simple non-
reports that evaluate predictors of sustained viral invasive index for the assessment of liver fibrosis, is
response in chronic HCV patients with genotype 4. associated significantly with the extent of fibrosis
Though our results might seem to differ with those of .However; APRI does not seem to be the index that
AL Ashgar et al ., 200920, who declared that young might replace the liver biopsy in the majority of
age, low AST, and treatment naïve were the predictor patients with chronic viral hepatitis, since it cannot
of SVR, their study was retrospective in nature with classify correctly 40–65% of cases21.
different ethnic and age groups from our study. Before the wide acceptance of any non-invasive
In their study, Akuta and colleagues concluded index in clinical practice, it should be evaluated by
than hepatocytes steatosis is a factor associated with other groups in several settings other than those in
virological non-response; however they measured which this index was initially applied, since the
liver steatosis by obtaining liver biopsy results are often found to be inferior to those reported
percutaneously, and did not use a non-invasive in the initial evaluation.
assessment of liver fibrosis21. We are not suggesting that the APRI replace
The APRI is a surrogate for liver fibrosis, and liver biopsy for individual patient management at this
although it seems to perform well, it may not be as time but, rather, that it may be a useful marker to
accurate as serial liver biopsies. The APRI is subject study liver disease progression longitudinally in
to fluctuations, because many factors influence AST large populations.
and platelet levels. It is notable that the APRI has a Acknowledgment: Authors would like to thank all
similar area under the curve (AUC) and positive the staff members in HCV clinic – National liver
predictive value for fibrosis as other noninvasive Institute, for their co operation in establishing this
markers22. work.
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