Published online Oct 7, 2016. doi: 10.3748/wjg.v22.i37.8406
Peer-review started: June 28, 2016
First decision: July 29, 2016
Revised: August 9, 2016
Accepted: August 23, 2016
Article in press: August 23, 2016
Published online: October 7, 2016
To determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients.
One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems).
Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%.
HCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.
Core tip: The high cost of the newly introduced direct acting antivirals precludes universal replacement of the suboptimal interferon-based therapy for chronic hepatitis C. Therefore, a series of host- and virus-related factors are used as prognostic markers of treatment response. In Asian patients, a newly described viral factor is represented by amino acid substitutions in the hepatitis C virus core protein at positions 70 and 91. The present study confirms that core substitutions are also found in Caucasian patients and, together with age and IL28B genotype, can be used as predictors of the outcome of interferon-based therapy.
- Citation: Sultana C, Oprişan G, Teleman MD, Dinu S, HepGen 88/2012 Project Team, Oprea C, Voiculescu M, Ruta S. Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C. World J Gastroenterol 2016; 22(37): 8406-8413
- URL: https://www.wjgnet.com/1007-9327/full/v22/i37/8406.htm
- DOI: https://dx.doi.org/10.3748/wjg.v22.i37.8406
Hepatitis C might become the first curable chronic disease due the remarkable efficacy of the newly introduced direct acting antiviral drugs (DAAs). Interferon-free regimens, based on combinations of DAAs with pan-genotypic activity, allow for shorter courses of treatment without severe side effects[1]. Nevertheless, the high cost of DAAs continues to preclude universal replacement of the classic treatment consisting of PEGylated-interferon and ribavirin (PEGIFN/RBV). This therapeutic combination is effective in approximately 50% of hepatitis C virus (HCV) chronically infected patients, with the response rate strongly dependent on the infecting genotype[2] and correlated with a series of other viral and host factors, e.g., baseline/on-treatment viral load, liver fibrosis, host IL28B polymorphisms[3-6].
Across the 9.6 kb genome of HCV, several regions (specifically HVR1, IFN sensitivity-determining region and an IFN/ribavirin resistance-determining region in NS5A[7,8]) have been extensively analyzed in relation to treatment outcome, whereas the more conserved core gene has been mostly used for HCV genotyping and classification. Nevertheless, the core region has been reported to antagonize the antiviral response induced by IFN by interacting with the IFN-activating and signaling pathways[9,10]. Substitutions in certain less conserved sites of the core region can give rise to viral quasispecies resistant to interferon treatment[11]. Several reports, mainly from Japan, have indicated that amino acid substitutions in positions 70 and 91 of the core protein are associated with the outcome of interferon-based therapy[12,13].
Because most of the studies related to these core mutations have been conducted in Asian populations, the aim of the present study is to determine whether HCV core substitutions are present and play a significant role in the outcome of interferon-based treatment in Caucasian patients, as well to inform better selection and prioritization of those patients who can still benefit from this affordable therapy.
An observational study was conducted on 108 HCV chronically infected Caucasian patients treated for the first time with a combination of PEGylated IFN-a2a (180 μg per week) or PEGylated IFN-a2b (1.5 μg/kg per week) plus ribavirin (1000 or 1200 mg, dependent on body weight) in two tertiary care facilities in Bucharest, Romania. All patients met the following inclusion criteria: 18-65 years of age, detectable HCV viremia, and previously untreated. The exclusion criteria were: HBV or HIV co-infections’ malignancies; coexistent liver disease of other etiology; organ recipients, clinically significant pulmonary, renal, cardiovascular or hematological diseases; current pregnancy and lactation. Each patient provided informed consent and the Bioethics Committee of the Institute of Virology approved the study.
HCV-RNA was performed at baseline, weeks 4 and 12 of treatment and 24 wk after treatment completion using COBAS AmpliPrep/COBAS TaqMan Quantitative Test, version 2.0 (Roche Diagnostics GmbH, Germany) with a linear range of HCV-RNA quantification between 15 and 100000000 IU/mL. Rapid virologic response (RVR) was defined as undetectable HCV-RNA at week 4 of treatment. Early virological response (EVR) was defined as undetectable HCV-RNA at week 12 of treatment, and sustained virological response (SVR) was defined as undetectable HCV-RNA 6 mo after treatment completion.
Viral RNA was extracted from 140 μL serum using a commercial kit (QIAamp Mini Viral Kit, Qiagen). Reverse transcription was performed as described previously[14] and the cDNA was used in a semi-nested PCR yielding a 422 bp amplicon spanning the HCV core region[14,15]. The amplicons were sequenced (BigDye Terminator v3.1 and 3130 Genetic Analyzer, Applied Biosystems) and the resulting sequences were edited with BioEdit version 7.0.5.3[16] and used for genotyping (NCBI BLAST) and to assess the presence of substitutions at positions 70 and 91 in the core protein.
Genetic polymorphism in the IL28B gene (rs12979860) was investigated using Custom TaqMan 5’ allelic discrimination assay (Assays-by-DesignSM Service for SNP Genotyping Assays, Applied Biosystems, United States) and running a real time PCR on an ABI 7300 instrument with primers and fluorescent probes predesigned by the manufacturer and interpreted using SDS software from Applied Biosystems Inc., United States.
Liver fibrosis was assessed using a noninvasive method - transient elastography (FibroScan™) - that discriminated between mild/moderate fibrosis (F1 + F2) and advanced fibrosis (F3 + F4) by assigning a value of liver stiffness lower or higher than 9.5 kPa[17].
Statistical analysis performed with IBM SPSS Statistics version 20. Univariate analysis was performed for both categorical and continuous variables; P values were calculated using the independent samples Mann-Whitney U test for continuous variables and Pearson χ2 or Fisher’s exact test for categorical variables. Variables with statistical significance (P < 0.05) in the univariate analysis were introduced into a multivariate logistic regression model.
Patients’ characteristics are summarized in Table 1. The median baseline HCV-RNA was 6.1 log10IU/mL. Of the 108 patients, 44.4% had a baseline HCV viral load lower than 600000 IU/mL (5.8 log10IU/mL) and 37.9% had mild or moderate fibrosis. All patients were infected with HCV genotype 1b. Only 38.9% (42 patients) achieved SVR, and modest percentages had prompt responses during therapy: 13% had RVR and 39.8% had EVR.
| Characteristics | Total | IL28B CC | IL28B non-CC | P value |
| n = 108 | n = 19 | n = 89 | ||
| Age (yr), median | 53.5 (22.0-68.3) | 48.2 (22.1-66.4) | 53.8 (22.1-68.3) | 0.137 |
| Female | 64 (59.3) | 8 (42.1) | 56 (62.9) | 0.094 |
| Residence urban | 78 (72.2) | 17 (87.5) | 61 (68.5) | 0.090 |
| Baseline ALT (mg/dL), median | 76.5 (16-890) | 103 (16-890) | 74 (17-256) | 0.031 |
| Baseline HCV-RNA (log10IU/mL), median | 6.1 (4.15-7.3) | 6.2 (4.15-7.2) | 6.1 (4.15-7.3) | 0.333 |
| Mild/moderate fibrosis | 38 (58.5) | 9 (69.23) | 29 (55.8) | 0.470 |
| Absence of core mutations - DW | 13 (12.0) | 6 (31.6) | 7 (7.9) | 0.011 |
| RVR (%) | 14 (13.0) | 7 (36.8) | 7 (7.9) | 0.003 |
| EVR (%) | 43 (39.8) | 16 (84.2) | 27 (30.3) | < 0.001 |
| SVR (%) | 42 (38.9) | 17 (89.5) | 25 (28.1) | < 0.001 |
The favorable IL28B CC genotype was detected in only 17.6% of the patients, and had no significant correlation with patients’ demographic characteristics (age, gender, urban residence; Table 1).
Patients with IL28B genotype CC had the highest therapeutic success rates than those with TT or CT genotypes for the following outcomes: RVR (36.8% vs 7.9%, OR = 6.8, P = 0.003); EVR (84.2% vs 30.3%, OR = 12.2, P < 0.001), and SVR (89.5% vs 28.1%, OR = 21.8, P < 0.001).
According to the sequencing results, only 12% of the patients were infected with double wild-type (DW) strains - defined as presence of arginine (R) and leucine (L) at core position 70 and 91, respectively - while the rest had glutamine/histidine at position 70 (R70Q/H), or/and methionine at position 91 (L91M). Of the patients, R70Q/H substitution was present in viral isolates infecting 7.4%, and L91M was observed in 37%, while patients displaying both mutations represented 43.5% of the study population.
The presence of any substitutions at positions 70 and 91 of the core protein was associated with lower rates of RVR, EVR, and SVR (Table 2). Patients infected with DW-type strains obtained SVR more frequently than patients with R70Q/H substitution (76.9% vs 37.5%, OR = 5.6, P = 0.032), or L91M substitution (76.9% vs 25.0%; OR = 12, P = 0.032). Furthermore, looking simultaneously at both mutation sites, patients infected with HCV DW-type strains obtained SVR significantly more frequently than patients with substitution at any 70 or 91 positions (76.9% vs 33.7%, P = 0.032; OR = 6.6, P = 0.005).
| Characteristics | Patients withDW-type infectionn = 13 | Patients with R70Q/H and/or L91Msubstitutions n =95 | Patients withL91M substitutionn = 40 | Patients with R70Q/H substitution n = 8 | P value1 |
| Age (yr) | 51.5 | 53.6 | 53.3 | 50 | a = 0.607 |
| median | (29.1-66.54) | (22.1-68.3) | (24.4-67.3) | (33.8-58.8) | b = 0.694 |
| c = 0.860 | |||||
| Gender | 7 (53.8) | 57 (60) | 22 (55) | 5 (62.5) | a = 0.767 |
| Female (%) | b = 1.000 | ||||
| c = 1.000 | |||||
| Residence | 11 (84.6) | 67 (70.5) | 33 (82.5) | 5 (62.5) | a = 0.509 |
| Urban (%) | b = 1.000 | ||||
| c = 0.325 | |||||
| Baseline ALT (mg/dL) | 94 | 76 | 78 | 67 | a = 0.592 |
| median | (3-235) | (16-890) | (17-890) | (54-197) | b = 0.849 |
| c = 1.000 | |||||
| Baseline HCV-RNA (log10IU/mL), median | 6.25 | 6.05 | 6.05 | 6.3 | a = 0.966 |
| (4.15-6.9) | (4.15-7.3) | (4.1-7.3) | (5.2-7.1) | b = 1.000 | |
| c = 0.414 | |||||
| Mild/moderate fibrosis (F1 + F2, %) | 4 (57.1) | 34 (58.6) | 14 (58.3) | 4 (57.14) | a = 0.881 |
| b = 0.925 | |||||
| c = 0.283 | |||||
| IL28B CC (%) | 6 (46.2) | 13 (13.7) | 8 (20.0) | 1 (12.5) | a = 0.011 |
| b = 0.080 | |||||
| c = 0.174 | |||||
| RVR (%) | 6 (46.2) | 8 (8.4) | 4 (10.0) | 0 (0.0) | a = 0.002 |
| b = 0.009 | |||||
| c = 0.005 | |||||
| EVR (%) | 10 (76.9) | 33 (34.7) | 15 (37.5) | 3 (37.5) | a = 0.005 |
| b = 0.024 | |||||
| c = 0.164 | |||||
| SVR (%) | 10 (76.9) | 32 (33.7) | 15 (37.5) | 2 (25.0) | a = 0.005 |
| b = 0.024 | |||||
| c = 0.032 |
No significant differences related to demographic characteristics or virological parameters (HCV viremia, ALT, liver fibrosis) were detected between the patients infected with DW-type strains and those with R70Q/H and L91M substitutions (Table 2).
In the univariate analysis, young age, urban residence, IL28B CC genotype, absence of core mutations and achievement of RVR and EVR were significantly correlated with the rate of therapeutic success, defined as SVR (Table 3).
| Variable | SVR n = 42 | No SVR n = 66 | P value |
| Age (yr), median | 48.1 (22.1-68.3) | 54.7 (22.1-67.3) | < 0.001 |
| Female gender | 22 (52.4) | 42 (63.6) | 0.246 |
| Urban residence (%) | 37 (88.1) | 41 (62.1) | 0.004 |
| Baseline ALT (mg/dL), median | 79 (16-890) | 75 (17-231) | 0.688 |
| Baseline HCV-RNA, median | 6.2 (4.15-7.3) | 6.2 (4.8; 7.3) | 0.167 |
| Mild/moderate fibrosis | 18 (75.0) | 20 (48.8) | 0.107 |
| IL28B type CC (%) | 17 (40.5) | 2 (3.0) | < 0.001 |
| Absence of core mutations - DW | 10 (23.8) | 3 (4.5) | 0.005 |
| Presence of any core mutation, (%) | 32 (76.2) | 63 (95.5) | 0.005 |
| Viral mutation in core 91 only (%) | 15 (60.0) | 25 (84.3) | 0.024 |
| Viral mutation in core 70 only (%) | 2 (16.7) | 6 (66.7) | 0.032 |
| RVR (%) | 13 (31.0) | 1 (1.5) | < 0.001 |
| EVR (%) | 37 (88.1) | 6 (9.1) | < 0.001 |
Direct logistic regression was performed to assess the impact of different viral and host factors on the likelihood of achieving SVR, and the overall model contained all predictors with statistically significance in the univariate analysis. In the multivariate analysis, young age (less than 50 years old), absence of any type of core mutations, and presence of IL28B CC genotype were independently associated with achieving SVR (Table 4).
| Variable | Adjusted OR | 95%CI | P value |
| Age (< 50 yr) | 0.976 | 0.967-0.986 | < 0.001 |
| Absence of core mutations | 4.710 | 1.10-21.30 | 0.04 |
| IL28B polymorphism | 19.200 | 4.05-91.40 | < 0.001 |
This multivariate model correctly classified 75.9% of cases with a positive predictive value of 80.7%.
We report that the absence of substitutions in core positions 70 and 91 is a good predictor for achieving SVR after PEG-IFN/RBV treatment in Caucasian patients; together with IL28B polymorphisms and age, this absence can be used to stratify HCV-infected patients according to the likelihood of response to a currently suboptimal, but affordable, interferon-based therapy.
The success rate of IFN-based therapy was rather low in the present cohort, despite the fact that several baseline predictors suggested a promising patient profile (relatively young age (median: 53.5 years), low baseline HCV viral load in half of the cases, and minimal fibrosis in more than one-third of the cases). Nevertheless, the on-treatment viral kinetic response was modest, with a minority of patients achieving undetectable viral replication after 4 wk of therapy. An analysis of IL28B polymorphism rs12979860, the most important predictor of SVR in patients without RVR[18], revealed that non-CC IL28B genotypes were predominant (82.4%). These variants are associated with endogenous activation of the innate immune responses, higher baseline expression levels of IFN-stimulated genes, and a constant activation of the IFN signaling pathway that renders patients unresponsive to IFN treatment[18,19]. The exclusive presence of subtype 1b and the low prevalence of the favorable CC genotype can explain, at least in part, the low rate of virological response, but a series of others factors must be taken into consideration: questionable or inconsistent patient adherence to treatment, presence of adverse events that could determine temporary treatment interruptions (none were acknowledged by the study patients), and preexisting mutations in other genomic regions that could render the virus less susceptible to the prescribed drugs. In this study, core protein substitutions at positions 70 and 91 were present in viral isolates infecting 88% of the patients and linked with a significantly decreased probability of achieving SVR.
There has been increased evidence that substitutions at position 70 in the core protein are found regularly in Asian HCV 1b infected patients, with the mutant clone R70Q detectable even in newly infected people and no distinguishing characteristics for the mutant strain in terms of viral fitness or demographic distribution[20]. Studies investigating HCV core mutations in Caucasian patients are scarce, but two studies of very limited numbers of patients have suggested an association between R70 and an increased response to therapy[21, 22].
In our study, we detected high rates of core protein substitutions at positions 70 and 91 in 108 Caucasian patients infected with HCV subtype 1b; these substitutions had no significant association with viral load, but were significantly associated with a low therapeutic success rate. Our results are in accordance with previous reports that indicated an absence of substitutions at positions 70 and 91 in core protein as a significant predictor for the success of IFN-based therapy[12,21,22]. These results have also been confirmed in vitro; Funaoka et al[23] evaluated the effect of interferon-alpha on HCV core mutants (R70Q/H and L91M) in terms of viral replication and response to treatment and found a significantly higher degree of IFN resistance compared to the wild-type virus, associated with decreased expression of the IFN-stimulated genes. The proposed hypothesis for the interferon resistance of core mutants was related to the inhibition of the interferon signaling pathway, potentially involving SOCS3 (suppressor of cytokine signaling). These proteins are stimulated by various cytokines including IL6, which was upregulated in cells transfected with a core mutant. This mechanism can be observed in vivo as well, as chronically HCV infected patients have increased levels of inflammatory cytokines, including IL-6 and TNF-alpha[24].
Another interesting mechanism that might explain the role of core substitutions in interferon resistance is their potential influence on the expression of minicore proteins- isotypes of the normal core protein, that lack an N-terminal segment[25]. Two important minicore proteins terminate in the vicinity of amino acids 70 and 91; consequently, any structural changes in these amino acids can alter the expression of minicore proteins and implicitly the HCV functioning and IFN sensitivity[11].
To our knowledge, this is one of the first studies conducted on Caucasian patients that extend and confirm the results obtained in Asian populations related to the impact of amino acid substitution in the HCV core region on treatment response. Although our study does not involve a very large number of patients, further sampling is unlikely, as the clinical facilities investigated in this study treat subjects from all over the country. Performing mathematical modeling of the cost-effectiveness of sequencing for HCV core mutations would be beneficial. Although the cost of this test may be rather high, it is significantly lower than the prohibitive cost of DAAs. Several recent studies have attempted to provide an estimate on the cost-effectiveness of interferon-free regimens (assuming a price of $100000 and a success rate of 90%). Their results support a delay in treatment for patients with mild degrees of fibrosis[26-28]. As such, the potentially beneficial role of core sequencing in selecting patients from this subclass who are responsive to interferon-based therapy may outweigh the potential price limitation. This is particularly true for at this time, when there is a constant need for ethical, evidence-based criteria for the prioritization of interferon-free treatment in countries that cannot yet afford the universal introduction of the new highly active antivirals. In addition, there have been reports that HCV core substitutions can also predict the primary outcomes of therapy using first generation protease inhibitors[29] and that the IL28B genotype is furthermore predictive of the response to triple therapy in patients infected with HCV genotype 1[30]. Consequently, future studies will be needed to extend our results to patients treated with the novel categories of antivirals recently introduced for the treatment of HCV chronic infection.
Moreover, recent studies have also indicated that HCV core substitutions are involved in the progression of chronic hepatitis C to hepatocellular carcinoma (HCC)[31]. The R70Q variant has been associated with an increased malignancy risk[32-34], while the implication of core 91 substitution was dubitable[11]. A very recent study using deep-sequencing reported that the presence of baseline HCV strains harboring more than 42% non-R70 quasispecies or more than 98.5% non-L91 mutants was associated with an increased HCC risk[35]. As long as the residual risk for HCC development in compensated cirrhotic patients with SVR after IFN treatment remains quite high (3.4% at 5 years and 23.7% at 20 years[36]), the impact of core mutations on the transforming capacity of HCV core protein is worth studying.
In conclusion, this study reports absence of core genomic mutations associated with IL28B CC polymorphism as prognostic markers for a favorable outcome in HCV chronically infected Caucasian patients treated with interferon-based regimens. Core genomic mutations can be used to tailor treatment and distinguish between those patients who can respond to the affordable bi-therapy and those who must be urgently treated with DAAs to prevent evolution towards end-stage liver disease or HCC.
HepGen 88/2012 Project Team: Cantacuzino National Institute for Research and Development in Microbiology and Immunology: Maria Condei; Monica Straut; Codruta Usein; Mihaela Oprea; “Victor Babeş” Clinic of Infectious and Tropical Diseases, Bucharest; Prof. Petre Iacob Calistru; Alma Kosa; Gratiela Tardei; Claudia Leulescu; Angelica Nour; George Gherlan; Gh. Voiculescu; Simona Cazacu; Fundeni Clinical Institute: Mihai Voiculescu, Elena Rusu; Monica Ecobici; Laurentiu Micu; Diana Zilisteanu; Camelia Achim; Andreea Radasan; Mirela Miu; Emilia Grigore; Georgia Micu; Laura Panaiteanu; Paula Dragoescu; "St. Nicolau" Institute of Virology, Carmen Diaconu; Aura Temereanca; Claudia Dita; Petruta Mihaila; Personal Genetics: Georgeta Cardos; Bogdanka Militescu; Petruta Gurban; Antonie Edu; Gabriela Bucur; Cristina Ionescu; Pompilia Apostol; Vladimir Celmare; Sonia Spandole; Eugen Radu.
Interferon-free regimens, based on combinations of direct acting antivirals (DAAs) with pan-genotypic activity, have a remarkable efficacy and might transform hepatitis C into a curable chronic disease. Nevertheless, the high cost of DAAs still precludes the universal replacement of the classic PEGylated-interferon and ribavirin therapy (PEG-IFN/RBV) that is dependent on a series of host and viral factors. In Asian patients, a newly described viral factor influencing the outcome of bi-therapy treatment is represented by amino acid substitutions in hepatitis C virus (HCV) core protein positions 70 and 91.
There is very scarce information on the presence and significance of HCV core substitutions in Caucasian populations. Nevertheless, a number of studies have indicated that amino acid substitutions in the core protein play an important role in the very early dynamics of viral replication during bi-therapy and triple therapy of chronic hepatitis C as well as in the evolution toward hepatocellular carcinoma.
This is one of the first studies confirming that HCV core substitutions are not specific to the Asian population, being also found in Caucasian patients. Moreover, it demonstrates that absence of core genomic mutations, together with young age and IL28B CC genotype, is a prognostic marker for favorable outcome in chronic HCV-infected Caucasian patients treated with PEG-IFN/RBV.
The research hotspot is the identification of a new viral factor that can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be urgently treated with DAAs to prevent the evolution towards end-stage liver disease. This is an important practical instrument in countries with developing economies that cannot afford universal introduction of DAA because it can facilitate the prioritization of patients who will benefit from less expensive therapeutic regimens. Further application of these results can be derived from the recently reported role of core substitution in the progression of HCV infection to hepatocellular carcinoma. As long as a residual risk for HCC development persists even in patients successfully treated with interferon or with IFN-free regimens, the impact of core mutations on the transforming capacity of the HCV core protein is worth studying.
HCV core gene is a conserved part of the viral genome that is mostly used for HCV genotyping and classification. Nevertheless, the core region can antagonize the antiviral response induced by IFN, interacting with the IFN-activating and signaling pathways. Substitutions in less conserved sites (positions 70 and 91 in the core region) can contribute to resistance to interferon treatment.
The manuscript is very well written and clearly states its aims and conclusions. It looks overall good with some limitations of low number of patients and low SVR. Questions were raised concerning the cost of core mutations testing. A paragraph responding to the study limitations and the necessity of core sequencing cost effectiveness evaluation was added by the authors in the revised version.
Manuscript source: Invited manuscript
Specialty type: Gastroenterology and hepatology
Country of origin: Romania
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P- Reviewer: de Franca PHC, Elsharkawy A S- Editor: Yu J L- Editor: A E- Editor: Wang CH
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