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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 1073-1080

Impact of human cytomegalovirus on the response of chronic hepatitis C virus-infected patients to pegylated interferone and ribavirin combination therapy


1 Tropical Medicine Department, Faculty of Medicine, Menoufiya University, Shibin Al Kawm, Egypt
2 Department of Microbiology and Immunology, Faculty of Medicine, Menoufiya University, Shibin Al Kawm, Egypt
3 Department of Microbiology and Immunology, Shebin Elkowm Fever Hospital, Shibin Al Kawm, Egypt

Date of Submission02-Aug-2016
Date of Acceptance02-Oct-2016
Date of Web Publication31-Dec-2018

Correspondence Address:
Sammar A Hassan El-Said
Shebin Elkowm Fever Hospital, Shibin Al Kawm
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.248746

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  Abstract 


Objective
The aim of this study was to study the impact of human cytomegalovirus infection in response rates of patients with chronic hepatitis C virus infection to pegylated interferon and ribavirin combination therapy.
Background
Cytomegalovirus affects the liver and overall immunological status of the host body. In chronic hepatitis C virus patients, co-infection with Cytomegalovirus could be an additional threat to the host and may contribute to the complexity of disease outcome.
Patients and Methods
This study was conducted on 40 patients with chronic hepatitis C virus infection candidates for pegylated interferon and ribavirin combination therapy. They were classified into two groups according to response to therapy. Group I (non-responders): included 20 chronic hepatitis C virus patients with any form of non response to therapy. They were 12 males (60%) and 8 females (40%). Group II (responders): included 20 patients with adequate response to therapy at the end of treatment (48 weeks). They were 9 males (45 %) and 11 females (55 %).
Results
There were significant increases in the number of patients with positive polymerase chain reaction for Human cytomegalovirus DNA in non-responders when compared with responders (14 out of 20 patients versus 5 out of 20 patients respectively).
Conclusion
Human cytomegalovirus is one of the independent factors that may significantly affect response of chronic hepatitis C virus patients to pegylated interferon and ribavirin combination therapy.

Keywords: chronic hepatitis, hepatitis C virus, human cytomegalovirus, interferon, ribavirin


How to cite this article:
Mohamed HI, Ahmed Badawy AM, Salama AA, Hassan El-Said SA. Impact of human cytomegalovirus on the response of chronic hepatitis C virus-infected patients to pegylated interferone and ribavirin combination therapy. Menoufia Med J 2018;31:1073-80

How to cite this URL:
Mohamed HI, Ahmed Badawy AM, Salama AA, Hassan El-Said SA. Impact of human cytomegalovirus on the response of chronic hepatitis C virus-infected patients to pegylated interferone and ribavirin combination therapy. Menoufia Med J [serial online] 2018 [cited 2019 Jan 20];31:1073-80. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/1073/248746




  Introduction Top


Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide[1]. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC). The number of chronically infected persons worldwide is estimated to be about 160 million, but most are unaware of their infection[2]. In fact, Egypt has the largest epidemic of HCV in the world with an overall serum positive prevalence of 14.7% as reported by the Egyptian demographic health survey[3]. HCV genotype-4 is the most common variant of HCV in the Middle East and Africa, particularly Egypt[4].

The primary aim of HCV therapy is to achieve a sustained virological response (SVR)[5]. Until 2011, the combination pegylated interferone (Peg INF) and ribavirin (RBV) for 24 or 48 weeks was the approved treatment for chronic hepatitis C[2]. Because genotypes 1 and 4 are less responsive than genotypes 2 and 3, the low SVR in genotype 1 and the very poor response rates in subpopulations such as black patients and cirrhotics have driven the development of novel antiviral therapies[6].

Cytomegalovirus (CMV) is a ubiquitous B-herpes virus that affects 60–80% of the human population. Infection with CMV is more widespread in developing countries and in communities with lower socioeconomic status and represents the most significant viral cause of birth defects in industrialized countries[7]. The CMV infection is characterized by alternating periods of latency and reactivation. The infection of endothelial cells and macrophages plays an important role in the latency[8]. Reactivation of the virus is usually seen during periods of downregulation of the immune system[9].

CMV can inhibit protein synthesis and liberate viral DNA to the nuclei, where its replication starts immediately. A strategy that it shares with other herpes viruses is the ability of stopping the immune response of the host by inhibiting RNA formation, blocking the presentation of antigenic peptides of the cell surface, and blocking apoptosis[10]. The infection potently inhibits major histocompatibility complex (MHC) I expression and downregulates endogenous interleukin (IL)-1 production in fibroblasts by up to 99%. Furthermore, it increases the production of transforming growth factor, which suppresses the immune system through several mechanisms, most notably the suppression of cytotoxic T lymphocyte and natural killer cells and counteracting IL-2 and tumor necrosis factor (TNF)[11]. In addition, different CMV proteins have been shown to suppress the apoptotic antiviral response induced by TNF. Moreover, infection with CMV was reported to disrupt the function of the JAK-STAT signal transduction pathway as CMV rapidly decreases the level of Jak-1 by enhanced protein degradation in CMV-infected fibroblasts[10]. As a consequence, the transcription of IFN-induced genes that play important roles in the antiviral activity of IFN will be inhibited[12].

Different studies reported that CMV affects the liver and overall immunological status of the host body. Specifically in HCV patients, co-infection with CMV can suppress the host immune system, affects the IFN-mediated antiviral pathway, and thus becomes an additional threat to the host and may contribute to the complexity of disease outcome in HCV infection[13].


  Patients and Methods Top


Search strategy

The study was approved by the ethical Committee faculty of medicine Menoufia university and the patient gave an informed consent. This study was conducted on 40 patients with chronic HCV infection who were candidates for Peg INF–RBV combination therapy. The patients were selected from Shebin El Kome Fever Hospital in the period between June 2014 and January 2015. There were 21 (52.5%) men and 19 (47.5%) women, their ages ranging between 21 and 55 years. They were classified into the following groups according to response to Peg INF–RBV combination therapy. Group I (nonresponders) included 20 chronic HCV patients with any form of nonresponse to therapy [complete nonresponse (10 patients) and breakthrough at week 24 (seven patients) and at week 48 (three patients)]. The patients in this group included 12 (60%) men and eight (40%) women, their ages ranging between 22 and 55 years with a mean age of 39.80 ± 8.60. Group II (responders) included 20 chronic HCV patients with adequate response to therapy at the end of treatment (48 weeks). There were nine (45%) men and 11 (55%) women, their ages ranging between 21 and 48 years with a mean age of 34.75 ± 8.04. All patients and controls were subjected to thorough history taking, complete clinical examination, laboratory investigations [including complete blood count, liver function tests, kidney function tests, blood sugar level (fasting and postprandial) and HbA1c, thyroid stimulating hormone, serum α-fetoprotein (αFP), antinuclear antibodies, latex for rheumatoid factor, anticyclic citrullinated peptide antibody as indicated, serology for schistosomiasis, HBsAg, pregnancy test in females in the child-bearing period, imaging study (abdominal ultrasound), ECG, liver biopsy, PCR studies; quantitative PCR for HCV-RNA and qualitative PCR for human cytomegalovirus (HCMV) DNA]. DNA amplification[14] was carried out in a thermal cycler (Biometra, Göttingen, Germany).

As regards cycling conditions, for the first round the thermal cycling protocol was as follows: denaturation at 94°C for 4 min, followed by 35 cycles of 94°C for 1 min, 60°C for 1 min, and 72°C for 1 min. A final incubation was carried out at 72°C for 7 min. For the second round the thermal cycling protocol was as follows: 1 min at 94°C, 1 min at 55°C, and 1 min at 72°C for 30 cycles.

Detection of the amplification products

The amplified PCR products were detected by using agarose-gel electrophoresis according to the method described by Zeuzem et al.[15].

Study selection

Inclusion criteria included the following: positive HCV antibody and HCV-RNA, male or female aged 18–60 years, white blood cell of more than 4000/mm3, neutrophil count of more than 2000/mm3, platelets of more than 100 000/mm3, Hb of more than 12 g for female and 13 g for males, prothrombin time of less than 2 s above upper limit of normal (ULN), direct bilirubin 0.3 mg/dl or within 20% of ULN (0.4 mg/dl), indirect bilirubin 0.8 mg/dl or within 20% of ULN (1.0 mg/dl), fasting blood sugar 115 mg or within 20% ULN (140 mg), albumin of more than 3.5, serum creatinine within the normal level, thyroid stimulating hormone within the normal level, HBsAg negative, antinuclear antibodies of less than 1: 160. In addition, if the patient is diabetic, the HbA1c had to be less than 8.5%. Alpha feto-protein less than 100 IU/ml, computed tomography is normal, female patient practicing adequate contraception, and a male patient's wife practicing adequate contraception. A signed written informed consent was obtained from patients before starting the treatment.

Data extraction

Data were collected for liver diseases other than HCV (by liver biopsy), decompensated liver disease, hypersensitivity to IFN or RBV, comorbid conditions, uncontrolled diabetes, retinal abnormalities, obesity (BMI) of more than 30, central nervous system diseases and psychiatric conditions, cardiovascular diseases, immunologically mediated diseases and immunosuppressive drugs, thyroid dysfunction, drug abuse, pregnancy, or breast feeding.

The data collected were tabulated and analyzed by using the SPSS (statistical package for social science), version 17.0 on an IBM compatible computer (SPSS Inc., Chicago, Illinois, USA).

Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and thus appropriate data analysis was carried out in addition to account for missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.


  Results Top


There was no significant difference between the studied groups as regards mean values of quantitative PCR for HCV-RNA and levels of viremia [Table 1] and [Figure 1].
Table 1: Pretreatment quantitative PCR for HCV-RNA in the studied groups (N=20)

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Figure 1: Pretreatment quantitative PCR for HCV-RNA in the studied groups.

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There was a significant difference between the studied groups as regards the stages of fibrosis (40% nonresponders were F3 vs. 15% responders, 55% nonresponders were F2 vs. 40% responders, and 5% nonresponders were F1 vs. 45% responders). However, there was no significant difference between the studied groups as regards the grades of necroinflammations [Table 2].
Table 2: Histopathological findings (grades of necroinflamations and stages of fibrosis) in the studied groups (N=20)

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There was a significant increase in the mean values of serum αFP in nonresponders when compared with responders, whereas there was no significant difference between the studied groups as regards BMI. None of the studied patients had obesity [Table 3].
Table 3: BMI and mean value of serum a-fetoprotein in the studied groups (N=20)

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There were significant increases in the number of patients with positive PCR HCMV-DNA in nonresponders when compared with responders (14 out of 20 patients vs. five out of 20 patients, respectively) [Table 4] and [Figure 2].
Table 4: Qualitative PCR for HCMV-DNA in the studied groups (N=20)

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Figure 2: Qualitative PCR for HCMV-DNA in the studied groups.

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Rising of serum αFP (5 ng/ml), higher stages of fibrosis, or positive serum qualitative HCMV-DNA were independant risk factors of nonresponses of chronic HCV patients to Peg INF–RBV combi nation therapy [Table 5]. Combination of two or all of the above factors as risks for a nonresponse could not be statistically assessed because of the small number of patients [Table 6] and [Figure 3].
Table 5: End point of treatment and type of nonresponse in the nonresponder group (N=20)

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Table 6: Univariate analysis of factors associated with nonresponse to treatment in hepatitis C virus-infected patients (N=20)

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Figure 3: Univariate analysis of all factors associated with response to treatment in HCV-infected patients.

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Ethidium bromide-stained agarose gel showed nested PCR results of HCMV-DNA in serum samples. Lane 1 showed the DNA ladder; lanes 3, 4, 9, and 11 showed a single band at 100 bp position and were considered positive. Other lanes (2, 5, 6, 7, 8, and 10) showed multiple bands at different bp positions and were considered as negative cases [Figure 4].
Figure 4: Ethidium bromide-stained agarose gel showing nested PCR results of HCMV-DNA in serum samples.

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  Discussion Top


In the present study, there was no significant difference as regards quantitative PCR for HCV-RNA and levels of viremia in the responder and nonresponder groups [Table 4]. The importance of HCV viral load on treatment response had been studied and various results were reported. Some of these studies agreed whereas many others disagreed with our results. Eldin and colleagues reported no effect of HCV viral load on the response rates of chronic HCV patients to the INF-based therapy[13],[16]. In addition, Izumi and colleagues reported that chronic HCV patients can achieve sustained virological response (SVR) even when the amount of virus before the treatment is quite large[17]. However, many previous studies reported that pretreatment with HCV viral load greatly affects the response of chronic HCV patients to the INF-based therapy. Zeuzem and colleagues, reported the low-basal HCV viral load to be significantly associated with early virological response and sustained virological response (EVR and SVR)[18],[19],[20].

The present study revealed significant difference between the studied groups as regards stages of fibrosis (40% nonresponders were F3 vs. 15% responders, 55% nonresponders were F2 vs. 40% responders, and 5% nonresponders were F1 vs. 45% responders). However, there was no significant difference between the studied groups as regards grades of necroinflammations. The importance of stages of fibrosis on liver biopsy as a determinant of response of chronic HCV patients to Peg INF–RBV combination therapy was studied in several studies and most of the results favored the negative impact of advanced fibrosis on the response of chronic HCV patients to Peg INF–RBV combination therapy, which is in agreement with our results. Hasan and colleagues found that patients with cirrhosis or severe fibrosis had significantly lower SVR rate compared with those with mild or no fibrosis[21]. Moreover, Torres and colleaguesdemonstrated that one of the independent factors associated with EVR was the noncirrhotic status of HCV patients[22]. Similarly, Gamil and colleagues reported that the higher the stage of fibrosis, the lower the achievement of EVR[23]. However, Al husseini and colleagues in their study aimed at finding more predictive markers that can help clinicians to choose the most effective treatment program for chronic HCV patients showed no significant relation to both histological activity score, which is in agreement with our results, and the degree of fibrosis with treatment response, which is in contrast to our results[24].

The present study revealed no significant differences as regards BMI and response of chronic HCV patients to treatment (none of the studied patients had obesity). The range of BMI was 19–29 kg/m with a mean ± SD of 27.01 ± 2.92 among the nonresponders and 23.04–29.68 kg/m with a mean ± SD of 27.0 ± 1.96 among the responders (P = 0.922). The importance of BMI and obesity as baseline predictors for response of chronic HCV patients to the INF-based antiviral therapy was a focus of a lot of studies with various results. Jacobson and colleagues and El din and colleagues reported that BMI did not significantly affect the response to treatment in their chronic HCV patients[13],[25]. Similarly, Mabrouk and colleagues selected their patients with a baseline BMI of less than 30 kg/m2 and reported no correlation between BMI and achievement of SVR, which is in agreement with our results[26]. On the other hand, Bressler and colleagues demonstrated that obesity, defined as BMI of more than 30 kg/m2, is a risk factor for nonresponse of HCV patients to antiviral treatment, regardless of the genotype and the presence of liver cirrhosis[27]. Qureshi and colleagues noted that patients weighing more than 70 kg showed poor response compared with those weighing 70 kg or less (the authors depended roughly on weight and did not calculate BMI in their patients)[28]. The authors suggested that the poor response in patients with heavier weight, either due to obesity or dose adjustment according to weight[28]. Many studies explained the possible mechanisms that might be responsible for nonresponse of chronic HCV patients to the INF-based therapy. Hickman and colleagues reported that weight loss plays an important role in HCV treatment because it downregulates liver enzymes and the progression of fibrosis[29]. Manns and colleagues reported that obesity itself is an associated factor for decreased efficacy of interferon-based therapies, and they suggested that obesity has been shown to be associated with an increased enhancement of suppressor of cytokine signaling family in the hepatocytes[30],[31],[32]. Imran and colleagues showed that BMI of more than 25 kg/m2 was linked with fibrosis and attributed the poor treatment response in these patients to altered metabolism due to cytokine production by adipocytes[33].

The present study revealed a significant difference as regards serum αFP in the responder and nonresponder groups. This is in agreement with Males and colleagues, who found that serum αFP levels should be added to the list of predictive factors for treatment responses[34], and also with Motawiand colleagues, who reported that serum αFP levels were significantly higher in the nonresponder group when compared with SVR patients in their study on predictor markers for response of Egyptian patients with chronic hepatitis C genotype-4 to the INF-based therapy[35]. Moreover, Faisal and colleagues found that the mean level of αFP was higher in nonresponders (3.2 ± 1.2 ng/ml) than in responders (2.3 ± 1.3 ng/ml), but this difference was statistically nonsignificant[20].

The present study revealed a significant increase in the number of patients with positive PCR for HCMV-DNA in nonresponders when compared with responders (14 out of 20 patients vs. five out of 20 patients, respectively). The importance of HCMV infection or reactivation in chronic HCV patients and its effect on the responses of these patients to Peg INF–RBV combination therapy was a focus in many studies and nearly all reports suggested the negative effect of HCMV, not only on the course of chronic HCV infection but also on the responses of these patients to the INF-based antiviral therapy. Gerakari and colleagues suggested that occult CMV and/or Ebestein bar virus infection has some influence on the clinicopathologic course of chronic HCV infection. In addition, these infections correlated with a worse response of their studied chronic HCV patients to the combination therapy[36]. Furthermore, Eldin and colleagues reported that HCMV infection inhibits the response of chronic HCV patients to Peg INF–RBV therapy and that there is a significant association between HCV response rate and CMV reactivation as CMV DNA was detected in 68% of the HCV-infected patients and the CMV viral load in HCV nonresponders was significantly higher [1.3 × 103 ± 6.22 × 102 genome-equivalents (GE)/ml] than in HCV SVR patients (5.2 × 102 ± 2.37 × 102 GE/ml) (P < 0.0001)[13].

Michelson and colleagues reported that HCMV potently inhibits MHC I expression and downregulates endogenous IL-1 production in fibroblasts by up to 99%. Furthermore, it increases the production of transforming growth factor, which suppresses the immune system through several mechanisms, most notably the suppression of cytotoxic T lymphocyte and natural killer cells and counteracting IL-2 and TNF[11]. In addition, different CMV proteins have been shown to suppress the immune response of the host by inhibiting RNA formation, blocking the presentation of antigenic peptides of the cell surface, and blocking the apoptotic antiviral response induced by TNF[10]. As a consequence, the transcription of IFN-induced genes, which play important roles in the antiviral activity of IFN, will be inhibited[12].

El Awady and colleagues studied the effect of IL28B polymorphism and HCMV as predictors for the response of Egyptian patients with chronic HCV type 4 to the INF-based combination therapy. The authors noted that co-infection with active CMV viremia induced severe failure to achieve acceptable rates of SVR and they suggested that infection with CMV has evolved multiple mechanisms for disrupting the IFN-stimulated JAK/STAT signal transduction: CMV co-infection appears to (a) inhibit IFN-α responsiveness by decreasing JAK-1 protein, which is an essential component of IFN-α signaling; (b) blocks IFN-stimulated gene factor 3 (ISGF3)-dependent (MHC class I, 2',5'-OAS, and MxA) and ISGF3-independent gene expression in infected cells; and (c) significantly decrease the essential component of ISGF3, protein 48. Therefore, the decreased JAK-1 and p48 protein would inhibit IFN-α stimulated signal transduction, transcription factor activation, and gene expression, and thus it is likely to globally block IFN-stimulated responses in HCV CMV co-infected patients. The dual analysis of both roles of IL28B single nucleotide polymorphism and CMV co-infection clearly showed that C/C (IL28B genotype) carriers not infected with CMV have a seven-fold higher rate of SVR than those C/C patients co-infected with CMV. When CMV invades the host cell, it inhibits protein synthesis, and liberates viral DNA to the nuclei, where its replication starts immediately[37].

Therefore, there have been several problems with Peg INF–RBV combination therapy concerning the poor response, high cost, and many side effects. Treatment of chronic hepatitis C virus is undergoing a radical change. This change of treatment results in fewer side effects and shorter duration. In addition, it turns out that the direct acting antiviral drugs are much more effective in eradicating HCV – in upwards of 85% of patients – in even those patients who have had poor responses to INF and RBV[38].

Whether HCMV co-infection will have an impact on the response of chronic HCV patients (of different genotypes) to recent direct acting antiviral drugs is an important question that may answered in the future.


  Conclusion Top


HCMV might be one of the many other independent factors that may significantly affect response of chronic HCV patients to Peg INF–RBV combination therapy as CMV viremia was detected in 70% of the nonresponders versus 25% of the responders. Other significant factors associated with nonresponse include higher stages of fibrosis and elevated serum αFP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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