Response to Combined Pegylated Interferon and Ribavirin among Patients with Chronic Hepatitis C in Upper Egypt

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1 Med. J. Cairo Univ., Vol. 79, No. 1, September: , Response to Combined Pegylated Interferon and Ribavirin among Patients with Chronic Hepatitis C in Upper Egypt SAAD ZAKY, M.D.*; MAGDA SHEHATA, M.D.*; HOWAIDA ESMAEL, M.D.*; NASR K. KHALIL, M.D.**; HANY A. ALLAM, M.D.** and EKRAM M. ABD EL-KHALEK, M.D.*** The Departments of Tropical Medicine & Gastroenterology*, Pathology**; Public Health and Community Medicine***, Faculty of Medicine, Assiut University, Assiut**, Fever and El-Eyman Hospitals-M.O.H.-Assiut-Ministry of Health Abstract Background and Aim of the Study: Egypt has one of the highest prevalence of hepatitis C in the world. Combination therapy using pegylated interferon alfa 2a or alfa 2b plus ribavirin is now the established standard therapy for chronic hepatitis C. However, non-response to this therapy remains common and is associated with several factors. We aimed to assess the response rate and the factors affecting the response to pegylated interferon and ribavirin among patients with chronic hepatitis C in Upper Egypt. Patients and Methods: A clinical trial study was conducted in the center for treatment of chronic hepatitis C in Assiut Governorate included 400 patients with chronic HCV infection fulfilling the inclusion and exclusion criteria for treatment with pegylated interferon (PEG-INF) plus ribavirin. All the included patients were subjected to detailed medical history and complete clinical examination, detailed abdominal ultrasonogaphic examination, laboratory investigations including complete blood picture, complete liver function tests, blood sugar, serum creatinine, prothrombin time and INR, afp, HBsAg, ANA, T3, T4, TSH, quantitative PCR for HCV-RNA, fundus examination, ECG and liver biopsy with grading and staging with METAVIR Score. Results: The responses to PEG-INF plus ribavirin at 12, 24, 48 weeks and SVR were 292/400 (73.0%), 289/400 (72.2%) and 257/400 (64.2%) and 96/233 (41.2%), respectively. The high pretreatment viral load is associated with poor response at 12 and 48 weeks of therapy and sustained virological response (SVR). The high pretreatment weight and body mass index (BMI) were associated with poor response at 12 weeks while high pretreatment AST and lower WBC count were associated with poor response at 24 weeks of therapy. Early virological response (at 12 weeks of therapy) can significantly predict the response at 24 and 48 weeks and SVR ( p=0.000, p=0.03 and p=0.000, respectively). Conclusion: This study concluded that, SVR after combined PEG-INF plus ribavirin for patients with chronic HCV infection in Upper Egypt was 41.2%. The pretreatment viral load was the only significant predictor for SVR among those Correspondence to: Dr. Saad Zaky, The Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut. patients. Early virological response significantly predicted the response at 24, 48 weeks of therapy and SVR. Key Words: HCV PEG INF SVR Predictors of response. Introduction HEPATITIS C virus (HCV) is considered as a global health problem with approximately 3% of the world population, roughly million people are infected [1-3]. Approximately 70-80% of them develop chronic hepatitis, 20-30% of them develop liver cirrhosis [4]. In Egypt, the situation is quite worse. Egypt has one of the highest prevalence of hepatitis C in the world. According to government figures, about 10-15% of the Egyptians (8-10 millions people) are carrying hepatitis C antibodies, meaning that they either have or at one time had the virus. About 90% of them are genotype 4 [5]. Combination therapy using pegylated interferon alfa 2a or alfa 2b plus ribavirin is now the established standard therapy for chronic hepatitis C [6-9]. However, non-response to this therapy remains common and is associated with several factors [10]. Because of these therapies have important side effects and high cost, it is important to identify whom patients have the best chance to respond to this therapy [11]. Accordingly, the ability to accurately predict the response of patients to antiviral therapy is of great interest. In general, predictors of response may be clinical, biochemical or histological [3]. There are several patterns of response to therapy; non responders: Patients who are virologically non responders showing detectable HCV RNA levels throughout the treatment period, null responders: Patients who achieved less than 2 logs reduction of the baseline HCV RNA at weeks 12 of treatment, partial responders: Patients who achieved more than 2 logs reduction of HCV RNA at 12 weeks but detectable at 24 weeks, responders 369

2 370 Response to Combined Pegylated Interferon & Ribavirin among Patients (R): Those patients with negative HCV RNA at the end of therapy (after 48 weeks), sustained virological response (SVR): Those who have undetectable HCV RNA 6 months after discontinuation of therapy, relapse: Patients who have negative PCR for HCV RNA at the end of treatment and became positive at 6 month after discontinuation of therapy and breakthrough: Undetectable HCV RNA at some point of treatment but became detectable while on treatment [9,12]. There is great controversy regarding the response rate and the predictors of response to pegylated interferon and ribavirin among patients with genotype 4. In addition, there is insufficient data about the response to therapy in Upper Egypt. Aim of the study: The present study aims to assess the response rate and the factors affecting the response to antiviral combination therapy with pegylated interferon and ribavirin among patients with chronic hepatitis C in Upper Egypt. Patients and Methods A clinical trial study was conducted in the period from November 2007 to May 2010, in the center for treatment of chronic hepatitis C in Assiut Governorate which is sponsored by the National project for treatment of hepatitis C, Ministry of Health. Out of 825 patients with chronic HCV infection attending the center during the period of the study, 400 patients were selected randomly fulfilling the inclusion and exclusion criteria for treatment with pegylated interferon plus ribavirin. The drop out was due to several reasons; stop of treatment without cause, stop because of side effects, shift of the patient file to another center, lack of the PCR results at one or more stages during the treatment course. Inclusion criteria: Patients aged between 18 and 60 years, both sex, with positive PCR for HCV RNA, persistently elevated alanine aminotransferase (ALT) levels above the normal limit, liver biopsy consistent with chronic hepatitis C, negative HbsAg and antinuclear antibody (ANA), normal thyroid function tests, normal alfa fetoprotein ((xfp), normal blood glucose, normal ECG and normal fundus examination were included in this study. Exclusion criteria: The following patients were excluded from the study: Women who were pregnant or breast-feeders, those with concomitant infectious or metabolic liver disease, alcohol consumption more than 50g/day within the last year, any cause of liver disease other than HCV, decompensated liver disease or presence of hepatocellular carcinoma, any immunologically mediated diseases (systemic lupus erythromatosis and rheumatoid arthritis), poorly controlled diabetes mellitus, retinal abnormalities, neutrophil count <1500/mm 3 or platelet count < /mm 3, serum creatinin >1.5 times the upper normal limit, and medical history of psychiatric disease or uncontrolled depression at screening. Patients who stopped treatment during the study without reason or due to development of side effects were also excluded. Ethical consideration: Patient participation was voluntary and informed written consent was obtained from all patients. The study proposal was approved by the Ethical and Technical Review Committee. Formal administrative approvals were taken before the start of the work. All the included patients were subjected to the followings: 1- Detailed medical history taking and complete clinical examination. 2- Recording of the body weight, height and estimation of body mass index (BMI) according to WHO guidelines (1995) [13]. 3- Detailed abdominal ultrasonogaphic examination. 4- Laboratory investigations (complete blood picture, complete liver function tests, blood sugar, serum creatinine, prothrombin time and INR, (xfp, HBsAg, ANA, T3, T4 and TSH). 5- Quantitative PCR for HCV RNA. 6- Fundus examination. 7- ECG examination. 8- Liver biopsy and histopathological examination and scoring using METAVIR score [14,15]. Different personal, biochemical, virological and histopathological variables are evaluated as factors affecting the response to therapy. Enrolled patients were treated with pegylated interferon and ribavirin for 48 weeks. Pegylated INF-a2a (180mcg) (Pegasys; Roche, Switzeland) or INF-a2b (1.5mcg/kg) (PEG-Intron; Schering- Plough) subcutaneously weekly, plus ribavirin at a daily dose of 1000mg (if their body weight is 75kg or less) or 1200mg (if their weight exceeds 75kg) [9] divided into two oral doses. Treatment was discontinued or reduced in case of intolerance to the drugs due to development of severe side effects. Clinical and biochemical parameters were evaluated at the start of therapy, monthly during therapy and 6 months after the end of the treatment. Serum levels of HCV RNA were assayed at the start of therapy, after 12, 24, 48 weeks and 6 months after discontinuation of therapy. Patients who are still viremic (not achieved 2 logs reduction) after 3 months of treatment, therapy was discontinued and they were considered non-responders (NR).

3 Saad Zaky, et al. 371 Early virological responders (EVR) are those who have undetectable serum HCV RNA or a minimum of 2 logs decrease of the baseline level at week 12. (R) are those patients with negative PCR for HCV RNA at the end of therapy. SVR: Those who have undetectable HCV RNA 6 months after discontinuation of therapy. Relapsed patients: Those who have negative PCR for HCV RNA at the end of treatment and became positive 6 month after discontinuation of therapy. Breakthrough: Patients with undetectable HCV RNA at some point of treatment but became detectable while on treatment [9,12]. Liver biopsy: Ultrasound guided liver biopsies were obtained from all patients prior to therapy; all samples fixed in formalin and embedded in paraffin were stained with hematoxylin and eosin. Hepatic necroinflammation (activity) and fibrosis (staging) were assessed by the METAVIR scoring system. Fibrosis was staged on a scale of F0-F4 [14,15]. Liver steatosis was graded in accordance with Brunt et al. (1999) [16]. Statistical analysis: Data were collected and analyzed by using computer program SPSS (version 16). The frequencies, percentages, the mean and standard deviation were computed. To compare results between groups, Student's t-test was used for a Gaussian distribution; otherwise, the Mann-Whitney U-test was applied. An ANOVA was used to compare data with a Gaussian distribution from more than 2 groups. The chi square ( χ 2 ) test was used as a test of significant. p value <0.05 was considered to be statistically significant. Results The baseline characteristics of 400 patients including personal, biochemical, virological and histopathological are shown in Tables (1&2). The mean age of the studied sample was 41.8 yeas. Male respondents represented as 89.5%. The mean of BMI was The responses to PEG-INF plus ribavirin at 12, 24, 48 weeks and SVR were 292/400 (73.0%), 289/400 (72.2%) and 257/400 (64.2%) and 96/233 (41.2%), respectively (Fig. 1). The results of response at 6 month after discontinuation of therapy of 167 patients were not available, so the SVR was calculated from the results of 233 patients only. The high pretreatment viral load is associated with poor response at 12, 48 weeks of therapy and SVR. The over weight and BMI were associated with poor response at 12 weeks while high pretreatment AST and lower WBC count were associated with poor response at 24 weeks of therapy (Tables 3&4). Following the response to therapy, 50 patients (12.5%) developed breakthrough at 24 or 48 weeks of therapy (reappearance of HCV-RNA in the serum at 24 or 48 weeks of therapy after being absent at 12 weeks). Early virological response (at 12 weeks of therapy) can significantly predict the response at 24 and 48 weeks and SVR (p=0.000, p=0.03 and p=0.000, respectively). Out of 292 patients with negative PCR for HCV-RNA at 12 weeks, 271 patients (92.8%) had also negative PCR for HCV-RNA at 24 weeks. Similarly out of 272 patients showing negative PCR for HCV-RNA at 12 weeks, 244 (90.1%) also had negative PCR for HCV-RNA at 48 weeks. Out of 134 patients with negative PCR for HCV-RNA at 12 weeks, 90 patients (67.2%) developed SVR (Table 5) % weeks 24 weeks 48 weeks SVR Response 41.2 Fig. (1): Response to combined pegylated interferon/ribavirin among patients with chronic HCV, Assiut HCV Center, Table (1): Personal characteristics of patients with chronic HCV, Assiut HCV Center, Variable No. = 400 % Age: (Mean ± SD in years) 41.8±9.1 Gender: Male Female Weight: (Mean ± SD in Kg) 75.7± 12.7 Height: (Mean ± SD in cm) 166.2±5.7 BMI: Mean ± SD 27.4±4.4 Normal Overweight Obese

4 372 Response to Combined Pegylated Interferon & Ribavirin among Patients Table (2): Laboratory characteristics of patients with chronic HCV, Assiut HCV Center, Variable No. = 400 % AST: Mean ± SD 14.6± 11.2 Normal (12 U/L and less) Abnormal (>12 U/L) ALT: Mean ± SD 14.3 ± 11.9 Normal (12 U/L and less) Abnormal (>12 U/L) WBC: (Mean ±SD x13/cc) 6.0±2.0 Hb: (Mean ± SD in gm/dl) 14.3± 1.5 Platelets: Mean ± SD x13/cc) 210.8±51.1 HCV-RNA: Mean ±SD ± Liver biopsy Steatosis grade: Fibrosis stage: Inflammation grade: Table (3): Relation between personal characteristics and the response to combined pegylated interferon/ribavirin among patients with chronic HCV, Assiut HCV Center, Variable At 12 weeks 292 (73.0%) At 24 weeks 289 (72.2%) At 48 weeks 257 (64.2%) SVR Yes 96 (41.2%) No. % No. % No. % No. % Age: Mean ± SD 41.6 ± ± ± ±8.9 Gender Male Female Weight: Mean ± SD 72.6± 12.5* 76.9± ± ± 13.5 Height: Mean ± SD 166.4± ± ± ±7.0 BMI: Mean ± SD 26.4±4.3* 26.7± ± ±4.1 Normal Overweight Obese Unpaired t-test. * Significant.

5 Saad Zaky, et al. 373 Table (4): Relation between pre-treatment laboratory data and the response to combined pegylated interferon/ribavirin among patients with chronic HCV, Assiut HCV Center, Variable At 12 weeks 292 (73.0%) At 24 weeks 289 (72.2%) At 48 weeks 257 (64.2%) SVR Yes 96 (41.2%) No. % No. % No. % No. % A ST: Mean ± SD 14.5± ± 10.5* 14.1 ± ± 10.8 Normal Abnormal ALT: Mean ±SD 14.7± ± ± ± 11.7 Normal Abnormal WBC: Mean ±SD 6.0± ±2.1 * 6.0± ±2.7 Hb: Mean ±SD 14.2± ± ± ± 1.6 Plt: Mean ±SD 209.5± ± ± ±49.9 HCV-RNA: Mean ± SDo ± * ± ± * ± * Liver biopsy Fibrosis stage: No. % No. % No. % No. % Inflammation grade: Steatosis: No (no=318) Yes (no=82) Steatosis grade: 1 (n=67) (n=15) Chi-square test Unpaired t-test o Mann-Whitney test Table (5): Relation between the early treatment response and the response at 24, 48 weeks and SVR, Assiut HCV Center, Variable At 12 weeks r NR At 24 weeks of treatment: r (no=289) 271 (92.8%) 18 (66.7%) NR (n =30) 21 (7.2%) 9 (33.3%) Total At the end of treatment: r (no=257) 244 (90.1%) 13 (72.2%) NR (no=32) 27 (9.9%) 5 (27.8%) Total SVR: Yes (no=96) 90 (67.2%) 6 (6.1%) No (no=137) 44 (32.8%) 93 (93.9%) Total R:. NR: Non responders. p-value 0.000* 0.03* 0.000* Discussion Early studies reported that, patients infected with HCV genotype 4 responded poorly to conventional interferon alfa and to combined regular interferon alfa plus ribavirin therapy [17-20]. More recently, few trials on the treatment of HCV genotype 4 using PEG-INF alfa plus ribavirin showed highly variabl SVR rates ranging between 33% and 69% [21-30]. There are major controversies among different studies regarding the factors affecting the response to combined PEG-INF plus ribavirin. In the present study, 400 patients are evaluated for their response to pegylated interferon plus ribavirin. Their response rates were 73.0%, 72.2%, 64.2% and 41.2% at 12, 24, 48 weeks of therapy and SVR respectively. The low SVR in this study may be attributed to lack of the results of PCR for HCV RNA at 6 months after discontin-

6 374 Response to Combined Pegylated Interferon & Ribavirin among Patients uation of therapy (167 patients out of 400) and possible irregular use of ribavirin (some of the patients reduced the dose by their self or stopped treatment for some days due to financial causes). Several factors were identified as causes of this drop out, shift of the patient file to another center, lack of financial support, lack of interest, frustration following positive results. In the present study, the factors associated with poor virological response at variable stages of treatment course were high pretreatment viral load, weight, BMI, AST and lower pretreatment WBC count. No impact for age, gender, hieght, ALT, ALP, Hb level, platelet count, grading, staging and steatosis in liver biopsy on the response to therapy at any stage during the treatment course. Bressler et al., (2003) reported that, high body mass index but not steatosis was an independent risk factor for response to antiviral treatment [31]. A high BMI was also inversely correlated with sustained virological response to therapy [32]. El Makhzangy et al., (2009) concluded that, end treatment response to combined PEG- INF plus ribavirin and SVR were 69.5% and 61.1% respectively which is nearly comparable with end treatment response in our study but higher SVR. However, they identified different predictor factors for SVR including steatosis and fibrosis and no impact of the age, gender, weight, BMI, pretreatment ALT and viral load on the SVR [30]. Al Ashgar et al., (2009) reported response to combined PEG INF and rebavirin at 12, 48 and 72 weeks of 92.3%, 63.8% and 50.7%, respectively. They added that, the independent predictors of SVR were younger age, lower serum AST and being treatment naïve [33]. Similarly, researchers performed multivariate analysis of baseline factors and have identified lower baseline viral level as an independent predictor of sustained virological response regardless of genotype [32,34]. Cross et al., (2010) showed that, infection with genotype 1 or 4 and pretreatment weight were the only variables associated independently with sustained virological response [35]. In contrast to our results, Fried et al., (2002) found a significant negative correlation between male gender and sustained virological response on univariate analyses [8] while Shiffman et al., (2007) reported that younger age correlated significantly with a SVR [36]. Assessment of response after 12 weeks of treatment are used for many years and defined as early virologic response, viral load decline >_2 logs or undetectable HCV-RNA at week 12, and is used to be the mainstay of HCV on treatment decision making. According to Fried et al, up to 65% of patients responding at week 12, go on to develop a SVR which is similar to our result (67.2%). Conversely, if an early virologic response is not present, treatment should be stopped, because the chance of developing a sustained response of HCV eradication is less than 3% [8]. A study by Gad and his colleagues in 2008 about predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C concluded that severe firosis, severe steatosis, treatment with standard interferon and a high serum alpha fetoprotein level were all negatively associated with sustained virological response [37]. Breakthrough was reported among 12.5% of the patients of this study. Similarly, Hoofnagle and Seeff et al., (2006) reported 10% breakthrough [9]. This major controversy among studies evaluating the predictors of response to combined PEG- INF plus ribavirin stimulated the search for another underlying causes of the variable response in different geographic and sometimes in the same geographic areas. Several studies evaluated the underlying genetic predisposition for response or resistance to interferon and identified that 3 genes encoding IL29, IL28A, and IL28B [38-40], have been implicated in the response to PEG-IFN/RBV among patients infected with HCV genotype 1. The important genetic findings related to treatment response in patients with chronic hepatitis C will suggest the possibility of personalized medicine of treatment of this disease. Conclusion: This study concluded that SVR after combined PEG-INF plus ribavirin in Upper Egypt was 41.2% for patients with chronic HCV infection. The pretreatment viral load was the only significant predictor for SVR among those patients. 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