The authors wrote this article on behalf of the Interferon Beta-1a Hepatitis C Study Group.
Potential conflict of interest: Nothing to report.
The standard of care for chronic hepatitis C virus (HCV) infection, pegylated interferon (IFN) alpha plus ribavirin, results in a sustained virologic response (SVR) in approximately 50%-60% of patients. IFN beta is a potential alternative to IFN alpha. The aim of this study was to investigate the efficiency and durability of IFN beta and its combination with ribavirin in the naïve setting of chronic hepatitis C in Asian patients. In the initial randomized, double-blind phase, patients with chronic hepatitis C (n = 257) received 12 weeks of treatment with IFN beta-1a, 44 μg subcutaneously 3 times weekly, or a placebo. In the subsequent open-label phase, placebo nonresponders received 24 weeks of treatment with IFN beta-1a plus ribavirin, whereas patients receiving IFN beta-1a monotherapy received an additional 12 weeks of therapy. The primary outcome variable was SVR, which was defined as negative HCV RNA after weeks 24 and 48. A total of 34 of 128 patients (26.6%) receiving IFN beta-1a achieved an SVR versus 0 of 129 patients (0%) receiving the placebo (P < 0.001). In the IFN beta-1a/ribavirin group, 73 of 127 patients (57.5%) achieved an SVR [P < 0.001 versus IFN beta-1a; the adjusted odds ratio was 4.54 (95% confidence interval: 2.53, 8.13)]. In HCV genotype 1 patients, 37 of 80 patients (46.3%) treated with IFN beta-1a/ribavirin achieved an SVR versus 19 of 85 patients (22.4%) treated with IFN beta-1a (P = 0.001). Conclusion: IFN beta-1a produced a clear antiviral effect in Asian patients with chronic HCV infection. The addition of ribavirin to IFN beta-1a significantly increased the proportion of patients who achieved an SVR versus IFN beta-1a monotherapy. (HEPATOLOGY 2007.)
Interferon (IFN) alpha has been the mainstay of hepatitis C virus (HCV) therapy in the West since the early 1990s,1 although in Asia IFN-based therapy has become standard care only in the last 4-5 years. The addition of ribavirin during IFN alpha therapy increases the proportion of patients achieving a sustained virologic response (SVR) from 13%-19% to 38%-43%;2, 3 the substitution of IFN alpha with a pegylated formulation further increases the SVR to 54%-63%.4–7 Nevertheless, a clinically significant proportion of patients with HCV are not cleared of their infection with this treatment.5 In addition, many patients are unable to complete the treatment or require dose reductions because of tolerability issues.
IFN beta, an alternative type I IFN that binds to the same cell surface receptor as IFN alpha, may trigger distinct biological responses and elicit distinct patterns of gene expression within the same target cell.8–11 Extensive and successful use of IFN beta-1a therapy in patients with multiple sclerosis has demonstrated a good safety profile for this agent; a long-term treatment with 44 μg (equivalent to 12 million international units) 3 times weekly (tiw) through subcutaneous (sc) injection is generally well tolerated.12 In hepatitis C, the efficacy of IFN beta has been investigated in several small studies in a variety of patient populations using a range of dosing regimens, from twice daily to tiw through intravenous, sc, or intramuscular delivery.13–20 In a phase 2 multinational study of patients unresponsive to IFN alpha treatment, it was noted that the SVR rate in Asian patients receiving IFN beta-1a as either 44 μg sc tiw or 88 μg sc tiw was markedly higher than that observed in the rest of the study population. This could not be explained by the virus genotype.21
This study sought to confirm the effectiveness of IFN beta-1a in treatment-naive Asian patients. Additionally, it was anticipated that a combination treatment with ribavirin and IFN beta-1a would increase the proportion of sustained virus responders without additional safety concerns. The primary objective of this study was to compare the effects of IFN beta-1a and placebo treatments on SVR in Asian patients with chronic hepatitis C who had not received previous IFN therapy for their infection. The main secondary objective was to assess the effects of IFN beta-1a monotherapy compared with IFN beta-1a plus ribavirin on SVR.
ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; HCV, hepatitis C virus; IFN, interferon; sc, subcutaneous; SD, standard deviation; SVR, sustained virologic response; tiw, 3 times weekly.
Patients and Methods
This was a 12-week, randomized, double-blind, placebo-controlled phase III study followed by an open-label, 12-week extension period with crossover to 24 weeks of active treatment for nonresponders in the placebo group and 24 weeks of follow-up after active treatment for all patients (protocol number 23744).
Asian patients 18-65 years old with chronic hepatitis C infection demonstrated by positive HCV RNA and a liver biopsy (within 1 year) were recruited for this study. All patients had elevated serum alanine aminotransferase (ALT) levels (1.5-10 times the upper limit of normal). The inclusion criteria also included the following: a white blood cell count greater than or equal to 3.0 × 109/L, a neutrophil count greater than or equal to 1.5 × 109/L, a platelet count greater than or equal to 100 × 109/L; hemoglobin levels greater than or equal to 120 (women) or 130 g/L (men), a creatinine level less than or equal to the upper limit of normal; and a bilirubin level less than or equal to 27.4 μmol/L. Female participants were to be neither pregnant nor breastfeeding. All participants were required to undertake effective contraception measures. The exclusion criteria included the following: clinical evidence of decompensated liver cirrhosis (including Child's grade B cirrhosis and complications of liver cirrhosis); a history of hepatic failure, cancer, or immune-mediated disease; hepatitis B; chronic renal impairment; any cause of liver disease other than chronic hepatitis C; a disease that could interfere with safety, compliance, or evaluation of the condition under study; an unstable psychiatric disorder; previous systemic treatment for hepatitis C with an IFN or ribavirin; and participation in any other investigational study within the previous 3 months.
Ethical approval was obtained from the relevant ethics committee for each study center. All patients gave written informed consent. Research centers were situated in China, Hong Kong, and Singapore.
Randomization and Blinding
Patients were randomized (1:1) to either an IFN beta-1a monotherapy or a placebo treatment and stratified according to the following: the baseline serum HCV RNA (<2 × 106 copies/mL or ≥2 × 106 copies/mL), the HCV genotype (type 1 or nontype 1), and the center.
During the double-blind treatment period, patients received IFN beta-1a, 44 μg sc tiw (Rebif, Merck Serono SA, Geneva, Switzerland), or a matching placebo (Fig. 1). At week 12, blood samples for HCV RNA assessment were taken, and the blinding of the treatment groups was removed. Patients in the IFN beta-1a group continued open-label treatment for a further 12 weeks until week 24. They were followed up to 24 weeks after the end of the treatment. Patients in the placebo group who were nonresponders at 12 weeks (i.e., there was detectable HCV RNA in their serum sample) crossed over to receive 24 weeks of treatment with IFN beta-1a, 44 μg sc tiw, in combination with oral ribavirin daily (IFN beta-1a/ribavirin). There was a 3-week to 4-week treatment-free gap between the double-blind and open-label treatment periods in this group. The treatment started at week 16 to allow time for HCV RNA testing. Ribavirin was administered according to body weight: 1000 mg/day for patients weighing 75 kg or less and 1200 mg/day for patients weighing more than 75 kg. Patients receiving IFN beta-1a plus ribavirin for 24 weeks were followed up for a further 24 weeks. Patients in the placebo group who responded to the placebo treatment were followed up at 24 and 48 weeks.
Prestudy screening assessments included the following: the HCV genotype, human immunodeficiency virus antibodies, hepatitis B antibodies (surface antigen and immunoglobulin M hepatitis B core antibody), a chest X-ray, and an electrocardiogram. HCV RNA assessments were made before the study (within 35 days of study day 1), on study day 1, at week 12, at week 16, after 24 weeks of treatment with IFN beta-1a or IFN beta-1a/ribavirin, and 24 weeks after the end of active treatment. Physical examinations, body weight, vital signs, hematology, biochemistry, and urinalysis were assessed regularly throughout the study. Adverse events, other medications, and procedures were assessed continuously and at 4, 12, and 24 weeks after the active treatment. A liver biopsy was performed as the baseline and end of the treatment. Liver cirrhosis (stage 6; probable or definite) was defined on the basis of the Ishak-modified staging system22 by a central histopathologist who was unaware of the treatment allocation.
All assays were performed in a central laboratory. HCV genotyping was carried out with INNO-LiPA HCV II (Innogentics, Ghent, Belgium). An HCV RNA qualitative assay was performed with a Cobas Amplicor HCV v2.0 assay (Roche Diagnostics, Branchburg, NJ) with a lower limit of detection of less than 6600 copies/mL. AN HCV RNA quantitative assay of the viral load was carried out with a Versant HCV RNA 3.0 quantitative assay (Bayer Corp., Tarrytown, NY).
The primary outcome variable was the proportion of patients who achieved an SVR in the IFN beta-1a monotherapy group compared with those in the placebo group; SVR was defined as an absence of detectable serum HCV RNA at the end of both the treatment period (week 24) and the observation period (week 48). Week 12 HCV RNA in the placebo group was used for comparison with the SVR of the IFN beta-1a monotherapy group. Secondary efficacy variables included the following: a change in the viral load (HCV RNA) from the baseline to weeks 12, 24, and 48; SVR in the combination treatment group; the proportion of patients with ALT normalization at weeks 12 and 24; the proportion of patients with sustained ALT normalization (i.e., at the end of both week 24 and week 48); the proportion of patients with both SVR and sustained ALT normalization at week 48; and the proportion of patients with complete virus clearance (absence of detectable serum HCV RNA) at weeks 12, 24, and 48.
The hypotheses tested in this study were 2-sided, with a significance level of 0.05. Three separate analyses were performed: preliminary, primary, and final. The preliminary analysis compared the IFN beta-1a group with the placebo group at week 12; the primary analysis reported all data for the IFN beta-1a group at week 48 and for the placebo responder patients at week 12 and up to week 16. The final analysis compared the IFN beta-1a group with the IFN beta-1a/ribavirin group at the end of the follow-up period. All analyses were carried out with SAS v8.2 (SAS Institute Inc., Cary, NC).
The full analysis set of patients comprised all those that entered the active treatment phase of the study, received at least 1 dose of study medication, and had at least 1 efficacy or safety value measured on treatment. The safety set comprised all patients who received at least 1 dose of study medication. For the handling of missing SVR data, a conservative approach of “no response” was imputed. For other variables, no imputation was used.
The comparison of IFN beta-1a plus ribavirin versus IFN beta-1a monotherapy was performed descriptively with point and interval estimates of the proportions of patients with an SVR. The interval estimates were the 95% confidence intervals (CI) for the proportions of patients with an SVR within each treatment group based on the exact method using the F-distribution.
The change from the baseline in the viral load (HCV RNA) was calculated at weeks 12, 24, 36, and 48. Summaries of the viral load (HCV RNA) and changes from the baseline were performed on the basis of the log (base 10) values. Unless otherwise specified, the odds ratios were adjusted according to the main analysis.
Safety analyses were performed on patients in the safety set. Abnormalities were classified according to the National Cancer Institute Common Toxicity Criteria with the patient's worst grade by study period. Adverse events were classified with the MedDRA coding dictionary.
Patient Demographics and Disposition
All patients recruited into the study were Asian. The treatment was administered between September 2002 and August 2005. At the baseline, both treatment groups were balanced in terms of age, sex, viral load, level of ALT, and liver cirrhosis. Overall, 65% of the patients were infected with HCV genotype 1, and 65% of the patients had a high pretreatment viral load (≥2 × 106 copies/mL; Table 1).
Table 1. Demographics and Baseline Characteristics for the Full Analysis Set
IFN Beta-1a (n = 128)
Placebo (n = 129)
IFN Beta-1a/Ribavirin (n = 127)
Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; HCV, hepatitis C virus; IFN, interferon; SD, standard deviation.
A total of 257 patients were randomized: 128 to IFN beta-1a and 129 to a placebo. Of the patients on the placebo, 127 subsequently initiated the treatment with IFN beta-1a/ribavirin (Fig. 2). Of the 255 patients receiving IFN beta-1a, 25 (9.8%) withdrew before week 48, and 230 (90.2%) completed the study. The full analysis set comprised 255 patients.
IFN Beta-1a Versus the Placebo.
At week 12, 34/128 patients (26.6%; 95% CI: 19.1, 35.1) receiving IFN beta-1a monotherapy experienced an SVR versus 0/129 placebo patients (0%; P < 0.001; primary efficacy variable). Additionally, at 12 weeks, a significantly higher proportion of patients in the IFN beta-1a group (n = 126) in comparison with the placebo group (n = 129) achieved at least a 2-log reduction in the viral load or complete virus clearance, complete virus clearance, or ALT normalization (P < 0.001 for all comparisons of IFN beta-1a versus the placebo; Fig. 3).
IFN Beta-1a/Ribavirin Versus IFN Beta-1a.
When placebo nonresponders were initiated on IFN beta-1a/ribavirin, 73/127 patients (57.5%; 95% CI: 48.4, 66.2) experienced an SVR at week 48.There was a statistically significant difference between patients on IFN beta-1a monotherapy and IFN beta-1a/ribavirin for the proportion who achieved an SVR (P < 0.001); the adjusted odds ratio (adjusted for screening the HCV RNA level and HCV genotype stratification level) was 4.54 (95% CI: 2.534, 8.131). In addition, when the odds ratio for the SVR between IFN beta-1a and IFN beta-1a/ribavirin was adjusted for screening the HCV RNA stratification level, HCV genotype stratification level, ALT level, and presence or absence of liver cirrhosis, at the baseline, it was 5.506 (95% CI: 2.955, 10.257).
After 12 weeks of treatment, complete virus clearance was achieved in 105/127 (82.7%) of the IFN beta-1a/ribavirin group and 95/128 (74.2%) of the IFN beta-1a monotherapy group [P = 0.079; the adjusted odds ratio was 1.8 (95% CI 0.933, 3.486)]. For complete virus clearance at 24 weeks (the end of the treatment), there was a significant difference between the IFN beta-1a/ribavirin group [99/127 (78.0%)] and the IFN beta-1a monotherapy group [71/128 (55.5%); P < 0.001; the adjusted odds ratio was 2.94 (95% CI 1.685, 5.132); Fig. 4].
Analyzing the SVR results according to the HCV genotype at the baseline revealed that of the 165 patients who were infected with HCV genotype 1, 37/80 (46.3%) patients in the IFN beta-1a/ribavirin group achieved an SVR versus 19/85 (22.4%) in the IFN beta-1a monotherapy group (P = 0.001; Table 2). Regardless of the HCV genotype, more patients achieved an SVR if their viral load at the baseline was low rather than high. Of patients who had HCV genotype 1 and had a high viral load at the baseline, an SVR was observed in 5/60 (8.3%) patients and18/55 (32.7%) patients treated with IFN beta-1a monotherapy and IFN beta-1a/ribavirin, respectively. For HCV genotype 1 patients with a low viral load at the baseline, the proportion of patients responding was greater, but the difference between the 2 groups was similar [14/25 (56.0%) for IFN beta-1a monotherapy versus 19/25 (76.0%) for IFN beta-1a/ribavirin].
Table 2. Summary of the Percentage of Patients with SVR at Week 48 as a Function of the HCV Genotype and Baseline Viral Load for the Full Analysis Set
Baseline HCV RNA of patients who achieved SVR, n (%)
At week 48, significantly more patients receiving IFN beta-1a/ribarivin [67/127 (52.8%)] achieved sustained ALT normalization than patients receiving IFN beta-1a monotherapy [32/128 (25.0%); P < 0.001; the adjusted odds ratio was 3.55 (95% CI: 2.050, 6.148)]. Furthermore, significantly more patients receiving IFN beta-1a/ribarivin achieved an SVR and sustained normalization of ALT [60/127 (47.2%)] than patients in the IFN beta-1a monotherapy group [21/128 (16.4%); P < 0.001] with an adjusted odds ratio of 5.24 (95% CI: 2.809, 9.770).
Although a meaningful comparison between the placebo and IFN beta-1a monotherapy groups is limited because of the different treatment durations (24 weeks versus 12 weeks for IFN beta-1a and the placebo, respectively), IFN beta-1a was associated with a higher rate of adverse events than the placebo (96.1% and 44.2%; Table 3). The rate of compliance in the 2 treatment groups was high: 98.8% for IFN beta-1a monotherapy and 97.9% for IFN beta-1a/ribavirin.
Table 3. Summary of Patients with Adverse Events (n [%]) During the Period of Treatment by the Body System and Preferred Term in Which the Overall Incidence of the Event is Greater than 3% in the Safety Set
Among patients in the safety set, the adverse events reported most frequently were fever, headache, injection-site rash, and fatigue (Table 3). The majority of adverse events were mild to moderate in severity. Adverse events considered possibly or probably related to the study medication occurred in 91.0% of patients and were experienced by a similar number of patients in both treatment groups (IFN beta-1a monotherapy and IFN beta-1a/ribavirin). Sixteen patients (6.3%) had adverse events that were considered to be severe, 12 of whom were in the IFN beta-1a monotherapy group (9.4%). The most commonly reported severe events were granulocytopenia [IFN beta-1a/ribavirin group, n = 4 (3.1%); IFN beta-1a monotherapy group, n = 1 (0.8%)], fever [IFN beta-1a monotherapy group, n = 4 (3.1%); IFN beta-1a/ribavirin group, n = 0], and injection-site reaction [IFN beta-1a monotherapy group, n = 3 (2.3%); IFN beta-1a/ribavirin group, n = 0].
Adverse events leading to treatment discontinuation were as follows: severe leucopenia and severe granulocytopenia (experienced by 1 patient in the placebo group); injection-site reaction; fever and arthralgia; and thrombocytopenia (each experienced by 1 patient in the IFN beta-1a group). Seven (5.5%) patients in the IFN beta-1a/ribavirin group had their ribavirin dose adjusted because of anemia or a hemoglobin decrease.
There were no serious adverse events and no deaths during the study period. Two patients experienced 1 serious adverse event each outside the period of treatment. One patient was diagnosed with B-cell lymphoma before treatment initiation, the second patient attempted suicide approximately 10 weeks after her last dose of study medication. There was no relevant medical history, concomitant medication, or adverse event of depression recorded. The investigator considered it unlikely that this event was related to the study medication.
In this population of Asian patients with chronic HCV infection, these results clearly confirm the antiviral effect of IFN beta-1a observed previously in the subgroup analysis from a phase II study.21 Furthermore, the addition of ribavirin to IFN beta-1a significantly increased the proportion of patients who achieved an SVR in comparison with IFN beta-1a monotherapy. The impact of adding ribavirin on the SVR observed here is similar to that reported previously with IFN alpha-2b.2, 3
The characteristics of the patients recruited in this study and their type of disease were generally comparable with those described previously in studies of standard or pegylated IFN alpha-2b with respect to age, sex, and the proportion of patients with a high viral load, HCV genotype 1, and liver cirrhosis.2, 3, 5–7, 23 All patients in this study, however, were Asian.
The SVR in 57.5% of the patients observed in this study 6 months after a 24-week treatment with IFN beta-1a/ribavirin is similar to that reported previously 6 months after a 48-week treatment with pegylated IFN alpha plus ribavirin.5, 7, 23, 24 An SVR was achieved in a greater proportion of patients in this study than in the study by Cheng et al.21 The patients in the latter study, however, were previous nonresponders to IFN alpha. Thus, the lower response rate corresponds to the use of IFN beta-1a for retreatment as opposed to its use in treatment-naive patients.
The effects of the genotype and viral load at the baseline on SVR were consistent with those reported for pegylated IFN alpha plus ribavirin.5–7, 24 In the subgroup of patients in this study who had HCV genotype 1 and a low viral load, an SVR was observed in 76% of the patients. This compares favorably with the SVR observed in this subgroup of patients following 48 weeks of treatment with pegylated IFN alpha-2a plus ribavirin, which was 56-65%.5, 6 In addition, a recent study reported SVR in 19% and 48% of patients with treatment-naive HCV genotype 1 hepatitis C infection following 24 and 48 weeks of treatment with pegylated IFN alpha plus ribavirin, respectively.25 Thus, there appears to be a substantial advantage for 24 weeks of treatment with ribavirin combined with IFN beta-1a over 24 weeks of combination with pegylated IFN alpha.
More patients receiving combination therapy (52.8%) achieved sustained normalization of ALT compared with those receiving monotherapy (25.0%), with a similar difference in the number of patients who achieved both an SVR and sustained ALT normalization.
The incidence of adverse events was marginally greater in the IFN beta-1a monotherapy group than in the ribavirin combination group, except for anemia, which was observed only in patients treated with IFN beta-1a/ribavirin. The adverse events profile observed in this study is consistent with studies of IFN beta-1a, 44 μg sc tiw, and postmarketing experience (more than 300,000 patient years of exposure) in multiple sclerosis.
The most notable changes over time in routine laboratory tests were a decrease in hemoglobin, although the mean value remained within the normal range (more marked in the IFN beta-1a/ribavirin group), and a decrease in the mean values of platelets (more marked in the IFN beta-1a group). Anemia and thrombocytopenia have been associated with both ribavirin and IFN treatment.23
During treatment with pegylated IFN alpha-2a, the incidence of severe and serious adverse events is increased with 48 weeks of treatment versus 24 weeks,5 highlighting further the benefit of a shorter treatment duration with IFN. Findings from this study suggest that IFN beta-1a may be associated with hematological effects less severe than those reported previously for pegylated IFN alpha-2a. In this study, mean hemoglobin concentrations remained within the normal range. Up to 15% of patients treated with pegylated IFN alpha-2a plus ribavirin, however, have been reported to have hemoglobin decreases to well below the lower limit of normal.5, 7
Standard and pegylated IFN alpha-2b has been associated with neutrophil count decreases to below 500/mL.5, 6, 23 This was reported in 3%-5% of patients in 1 study5 and resulted in dose reductions in 8%-18% of patients in another.7 Conversely, in this study, only 2 patients had neutrophil counts below 500/mL during the treatment with IFN beta-1a (both in the IFN beta-1a/ribavirin group). One patient required treatment interruption, but the other needed no dose reduction. No severe case of thrombocytopenia (platelet counts below 2 × 1010) occurred in this study, and the findings were comparable with those reported previously with pegylated IFN alpha-2b.5–7 In previous studies, dose reductions or treatment discontinuations of pegylated IFN alpha that were often required to manage hematologic adverse events have been associated with a reduction in therapeutic efficacy.3, 7, 26
Previous studies have demonstrated a good safety profile of IFN beta-1a in various regimens, including the daily administration of 88 μg for up to 48 weeks in combination with ribavirin.21, 27 Here, no serious adverse events were reported during the treatment period, and the discontinuation rate due to an adverse event was only 2.3% (3 patients in the monotherapy group). The good tolerability of this treatment is confirmed by the high compliance rates observed in both treatment groups. Indeed, the results observed in this study agree favorably with other data on the safety of IFN beta treatment (alone and in combination with ribavirin) in patients with chronic HCV hepatitis and support the use of IFN beta-1a as a safe and alternative option in this Asian study population.28–30 The good safety profile and clinical efficacy should make IFN beta-1a an option for the first-line treatment of chronic hepatitis C in Asian patients. Patients who cannot tolerate peginterferon-alfa treatment or those who fail peginterferon-alfa treatment because of a requirement of dose reduction for the side effects can be considered for retreatment by IFN beta-1a combination therapy.
In conclusion, the positive virologic response seen in this study strongly supports the use of IFN beta-1a (44 μg sc tiw) as an alternative to the existing IFN alpha–based therapies for Asian patients with chronic hepatitis C infection. The addition of ribavirin to IFN beta-1a for the treatment of chronic hepatitis C in Asian patients markedly increased the proportion of patients who achieved an SVR in comparison with IFN beta alone, with no effect on the tolerability of the IFN beta-1a treatment. Although no direct head-to-head study between IFN beta-1a and pegylated IFN alpha has been performed to date, these results suggest that IFN beta-1a may have distinct advantages. For example, a shorter 24-week treatment regimen for IFN beta-1a/ribavirin in HCV genotype 1 patients may offset the advantage of the once-a-week administration for the pegylated IFN alpha regimen as the latter has to be administered over a 48-week period. The available data also suggest that IFN beta-1a plus ribavirin therapy offers similar efficacy and a superior safety profile in comparison with pegylated IFN alpha–based therapy. Furthermore, the favorable safety profile of IFN beta-1a combined with the shorter treatment regimen is likely to contribute to good treatment compliance, as observed in this study, and therefore offers the opportunity for a good treatment response. IFN beta-1a combined with ribavirin may therefore offer an exciting new treatment option in comparison with current combination therapies.
This study was supported by Merck Serono SA. We acknowledge the assistance of David Burton in the preparation of this article. We also acknowledge the other members of the Interferon Beta-1a Hepatitis C Study Group: Duan D. Luo, Wuhan Xiehe Hospital, China; Huan Y. Chen, Harbin Medical University 1st Affiliated Hospital, China; Dao Z. Xu, Beijing Ditan Hospital, China; Xia Q. Zhou, Shanghai Ruijin Hospital, China; Jun Q. Niu, Jilin University 1st Hospital, China; De M. Tan, Xiangya Hospital, Central South University, China; Li M. Zhu, Tianjin Infectious Disease Hospital, China; Jia Z. Xu, 81st Hospital P.L.A., China; Ya G. Chen, First Affiliated Hospital, Medical School, Zhejiang University, China; Zheng W. Liu, First Hospital of Xi'an Jiaotong University, China; Xue F. Bai, Fourth Military Medical University, Tangdu Hospital, China; Pei Liu, Second Hospital Affiliated to China Medical University, China; and Lai Wei, Peking University People's Hospital, China.