Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China

Abstract

Chronic hepatitis B is a major health problem in China. The universal vaccination program since 1992 has changed the epidemiology of hepatitis B virus infection in China from highly to moderately endemic. The most prevalent hepatitis B virus strains in China are genotypes B and C, whereas those in western provinces are genotypes D and C/D hybrid. Chronic hepatitis B poses a heavy burden to the society in China. Different treatment strategies have been explored to improve patient outcomes in a cost-effective manner. However, antiviral drugs with a low genetic barrier to resistance are still extensively used because of the generally low income and limited resources in China. Individualized antiviral therapy is closely associated with translational medicine, which utilizes information from studies on genomics, immune biomarkers, and fibrosis. The results of these studies are crucial in further improving treatment outcomes.

Keywords

chronic hepatitis B / epidemiology / prevention / treatment

1 Introduction

Hepatitis B virus (HBV) is a major global pathogen. More than 240 million people have chronic liver infections, and approximately 600 000 people die every year because of the acute or chronic consequences of hepatitis B [1]. The long-term hepatic effect of HBV infection varies from minimal hepatic inflammation to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC), leading to high morbidity and mortality [2]. In China, chronic hepatitis B (CHB) infection as the leading cause of HCC [3] poses a heavy burden to the society and patients. Remarkable progress in disease management has been achieved with the implementation of universal infant immunization since 1992 and with the development of antiviral drugs in the past decade. The increasing demands for optimal treatment outcomes in specific individuals have placed utmost urgency on the development of translational medicine-based individualized therapy. This review summarizes the recent progress in the epidemiology, prevention, treatment options, and challenges for CHB in China.

2 Epidemiology and prevention of chronic hepatitis B

2.1 Vaccination program and prevalence changes

The national hepatitis sero-epidemiological survey in 1992 revealed that the prevalence of hepatitis B surface antigen (HBsAg) in individuals aged 1 to 59 years was 9.75% in China. This finding classified the mainland of China as a high-HBV-prevalence region. However, hepatitis B is preventable by immunization. Perinatal or early childhood transmission is the mainly cause of CHB in China. Therefore, universal hepatitis B vaccination is the best, cost-effective preventive strategy for hepatitis B control. Since 1992, the Ministry of Health has implemented a series of regulation policies on the management of hepatitis B vaccination. The routine three-dose active HBV immunization was recommended to all infants in 1992; in 2002, the government obliged all local authorities to provide free HBV vaccination to all infants and only required service fee for the vaccination procedure. Nevertheless, immunization coverage remains relatively low in rural areas and in the western part of China because of the uneven economic conditions across the country. The government implemented a completely free HBV vaccination program for all neonates in May 2005. The second national survey of HBV sero-epidemiology showed a decrease (to 7.18%) in the general prevalence rate of HBsAg in 2006 and a decrease (from 9.67% to 0.96%) in the prevalence rate of HBsAg in children below 5 years of age. This great achievement has changed the epidemiology of HBV infection in China from highly to moderately endemic [4]. However, the prevalence of HBsAg can be further decreased by maintaining free immunization of infants and targeting timely birth dose to reach all newborns in the coming years across China. In addition, expanded vaccination is necessary to prevent HBV infection in adolescents and adults who have missed the newborn vaccination or who are at high risk of HBV infection.

2.2 Geographical distribution of HBV genotypes

The most prevalent HBV strains in western countries are genotypes A and D, whereas those in China are genotypes B and C, which possibly lead to different levels of disease progression [5]. A total of 1096 chronic HBV carriers were analyzed from nine provinces in the mainland of China, with genotypes A, B, C, and D having prevalence rates of 1%, 41%, 53%, and 4%, respectively. Genotypes E, F, G, and H were not detected in China. In addition, a north-south division in the distribution of genotypes B and C exists. Genotype C is predominant in Northern China (77%), whereas genotype B is predominant in southern provinces (59%). Genotype D is principally found in Northwestern China[6]. In Tibet Autonomous Region and Gansu Province, two C/D hybrid patterns were first identified [7]. The presence of these hybrid patterns increased the genetic diversity of HBV. Different ethnic groups of five provinces were further studied; the HBV C/D recombinant is restricted to the Qinghai-Tibet Plateau in Western China and predominantly in Tibet where family-cluster HBV infection is common [8,9].

3 Heavy burdens and critical challenges in a resource-constrained area

The long-term and recurring effects of HBV infection are compounded by the frequency of delayed consultation. Patients with CHB need long-term treatment, which incurs a high cost for patients with advanced liver disease. Therefore, CHB poses a considerate economic burden on the Chinese healthcare system, the patients, and their families. Sustained suppression of serum HBV DNA to low or undetectable levels by antivirals helps prevent liver disease progression and minimize HCC risks [10]. Proper treatment is critical for preventing downstream liver disease, reducing mortality, and improving the quality of life. However, the generally low income in China has been the main barrier in providing proper treatment. In the past, most patients pay their own treatments for limited reimbursement. The Chinese healthcare system has recently shown some amended policies. Conventional and pegylated interferons (PEG-IFN) and nucleos(t)ide analogs (NAs) have been included into the new national reimbursement list, and the health insurance has covered the majority of patients in rural and urban areas. However, the reimbursement is still limited. The government funding to public providers still cannot sufficiently cover the direct and indirect disease costs. Therefore, most naïve CHB patients cannot initiate treatment following major international recommendations to use potent antiviral agents. The data of the China Registry of Hepatitis B (CR-HepB) showed that drugs with low antiviral potency or low genetic barrier are still widely used in China (Fig. 1). These drugs include lamivudine (LAM), adefovir (ADV), and other drugs without certain antiviral efficacy. The long-term use of these drugs increases the rate of resistance or poor response.

4 Treatment strategy

The existing problems in China have placed urgency in the development and assessment of treatment strategies based on specific national conditions. The Chinese Society of Hepatology and the Chinese Society of Infectious Disease published a new evidence-based guideline in 2010 for the management of CHB in China. The currently available antiviral agents for CHB treatment in China include standard IFNα (2a, 2b, 1b); PEG-IFNα(2a, 2b); and all five NAs, namely, the L-nucleoside analogs LAM and telbivudine (LDT), the deoxyguanosine analog entecavir (ETV), and the acyclic nucleoside phosphonates ADV and tenofovir disoproxil fumarate (TDF). TDF was only approved for HIV treatment in China until October 2013. These drugs have different long-term efficiency rates because of their particular potency and drug resistance patterns (Table 1). ETV, TDF, and PEG-IFN were recommended as first-line drugs in major international guidelines [11–13]. In the Chinese guideline, all NAs are recommended as first-line therapy, although high-potent and low-resistance agents are preferred. This compromise is mainly due to the highly heterogeneous economic situations across China, where ETV or TDF may not be reimbursable, not affordable, or not available. IFNs could be chosen for patients without decompensated liver cirrhosis who require finite duration because of their non-resistance and relatively high HBeAg and HBsAg seroconversion rates.

4.1 IFN-α based therapy and early stopping role

IFN-α has been used against HBV for over 30 years and has been approved without limitations in its pegylated form. IFN-α and PEG-IFN have dual actions: enhancing host immune system to defend against HBV and modest antiviral action. PEG-IFN has well-known advantages and disadvantages. On the one hand, PEG-IFN achieves an approximately 30% hepatitis B e antigen (HBeAg) seroconversion rate after a finite standard of care for 48 weeks. On the other hand, it is burdened with significant side effects and contraindications. Particularly, it should be used with major caution in patients with cirrhosis owing to its risk of potentially fatal hepatic failure. In addition, treatment with PEG-IFN should be limited to patients with a favorable baseline profile and to those who achieve early response. For instance, Janssen et al. identified genotype-specified stopping rules in HBeAg-positive CHB patients treated with PEG-IFN. For patients with genotypes A or D, no decline in HBsAg at week 12 predicts low response rates (negative predictive value: 97% to 100%); for patients with genotypes B or C, HBsAg>20 000 IU/ml at week 12 is associated with a low probability of subsequent HBeAg seroconversion (negative predictive value: 92% to 98%) [14]. For all patients irrespective of HBV genotype, HBsAg level > 20 000 IU/ml at week 24 may be used as a stopping rule (Fig. 2). Prolonged treatment or addition of NAs are always preferred for patients without early responses. However, this theoretical strategy has yet to be determined in an well-designed clinical trial. In China, the EXCEL study (NCT00734162) [15] was conducted to explore whether or not response-guided therapy can be used to optimize PEG-IFNα-2a treatment. In this study, 264 patients with HBeAg-positive CHB were enrolled to receive PEG-IFNα-2a treatment for 24 weeks. Early responders (defined as HBsAg<1500 IU/ml and HBV DNA<10⁵ copies/ml at week 24) received PEG-IFNα-2a for another 24 weeks. Non-early responders were randomized to receive PEG-IFNα-2a for another 24 weeks, prolonged treatment of PEG-IFNα-2a for another 72 weeks, or addition of ADV. Mean decline in quantitative HBsAg from baseline to 24 weeks after the treatment was higher in early responders than in non-early responders (−1.15, −0.67, −0.71, and −0.64 log₁₀ IU/ml, respectively), and the HBsAg loss rates were 4.5% (3/66), 0% (0/67), 1.5% (1/67), and 3.1% (2/64), respectively. No significant difference was observed among groups of non-early responders in any other efficacy endpoints. The results demonstrated that the early responders to PEG-IFNα-2a had a high rate of HBsAg loss. However, prolonged duration or addition of ADV may have no effect on the treatment efficacy for non-early responders. Therefore, new strategies must be discovered to further improve the efficacy for this subpopulation. In patients with HBeAg-negative CHB, baseline predictors of response to PEG-IFN are poorly defined compared with HBeAg-positive disease. Janssen et al. [16] conducted a multicenter, randomized, double-blind, controlled trial to explore whether or not early on-treatment predictors of sustained response enable on-treatment adjustment in patients with HBeAg-negative CHB treated with PEG-IFN. They found a combination of decline in serum HBV DNA (<2 log₁₀ copies/ml) and absence of HBsAg level decline from the baseline at week 12 can be established as a stopping rule, in which therapy could be discontinued without a loss of sustained responders.

HBsAg loss is rare among NAs-treated patients who maintain HBV DNA suppression. The OSST study (NCT00940485) [17] was conducted to compare the efficacy by switching to PEG-IFNα-2a or continuing ETV treatment in 200 patients who responded to ETV (HBV DNA<300 copies/ml and HBeAg<100 PEIU/ml). The on-treatment reductions in HBsAg and HBeAg were significantly greater with PEG-IFNα-2a than with ETV. A large proportion of the patients who switched to PEG-IFNα-2a achieved HBeAg seroconversion at week 48 compared with continued ETV (15.5% vs. 6.0%). Only patients in the PEG-IFNα-2a arm achieved HBsAg loss (9.3%). This result indicates that CHB patients may discontinue long-term NAs therapy by switching to a finite course of PEG-IFNα-2a. A response-guided approach of sequential antiviral therapy may identify patients with a high possibility of success. However, the treatment strategy has several limitations. Viral rebound as a reduction of efficacy occurred in 39 patients when switched to PEG-IFNα-2a. Post-treatment data for further follow-up are still needed to assess the durability of the response.

Overall, patients should be carefully selected for initial IFNs therapy or extended therapy by using predictors at baseline or according to the on-treatment response. Further studies are needed to clarify the individualized tailoring of PEG-IFN treatment [18].

4.2 NAs-based therapy

NAs, which inhibit the reverse transcription of hepatitis B polymerase, are an important class of drugs that changed the treatment paradigm and prognosis of CHB. Oral NAs therapy has advantages over IFN therapy because of its potent antiviral effects, good tolerance, minimal side effects, and convenience. The major shortcomings of this therapy are drug resistance, low HBsAg loss rate, and high virological relapse rate when treatment is discontinued or interrupted because of low adherence, necessitating long, and indefinite treatment.

4.3 Initial monotherapy

In international guidelines [11–13], potent HBV inhibitors, such as ETV and TDF, are recommended as first-line monotherapies. Both drugs achieved high rates of HBV DNA suppression and ALT normalization, which were associated with low rates of resistance development in NAs-naïve patients during long-term therapy. Long-term treatment of ETV shows good efficacy and a low resistance rate of only 1.2% after 6 years [19,20]. TDF monotherapy is effective in suppressing HBV DNA through 7 years with no evidence of TDF resistance [21]. In addition, the long-term suppression of HBV with TDF benefits the regression of advanced liver fibrosis and cirrhosis [22]. However, for financial and social reasons, the other three drugs are also listed as first-line therapy in the 2010 version of the Chinese guideline. LAM and ADV are inexpensive agents; however, both engender high rates of resistance with long-term monotherapy [23]. ADV is less efficacious, engendering high rates of resistance [24]. Patients with an HBV DNA level of more than 3 log₁₀ copies/ml at 6 months of LAM therapy have a 63.2% chance of developing YMDD variants within 29 months of follow-up [25]. However, LAM may remain an effective first-line therapy for HBeAg-positive patients with baseline HBV DNA<6.6 log₁₀ copies/ml [26]. LDT is a potent inhibitor of HBV replication; patients with high baseline HBV DNA levels and detectable HBV DNA after 24 weeks of therapy have a high incidence of resistance [27]. However, patients with low baseline HBV DNA combined with negative HBV DNA at week 24 obtain good therapeutic results with LDT [28]. Thus, selecting patients who may respond well without developing virological breakthrough is crucial.

4.4 Initial combination therapy

Combination therapy is the current standard of care for the treatment of human immunodeficiency virus infection. It is superior to sequential monotherapy in terms of efficacy and prevention of drug resistance. In the treatment of CHB with first-generation NAs, ADV and LAM, two controlled trials compared the efficacy and safety between combination theapy and monotherapy. These studies revealed minimal additive or synergistic antiviral effects of combination therapy over monotherapy; in addition, the decline in HBV DNA levels and HBeAg and HBsAg seroconversion rates was comparable between groups [29,30]. Among the approved NAs, ETV and TDF have potent antiviral activities with a non-overlapping pattern of resistance. Lok et al. [31] conducted a randomized, open-label, multicenter, phase IIIb superiority study to compare the efficacy and safety of ETV monotherapy with those of a combination of ETV and TDF. They found that the antiviral efficacy of ETV monotherapy is similar to that of ETV plus TDF combination therapy over 96 weeks of treatment. Thus, combination therapy cannot be recommended as first-line therapy for typical patients with CHB because of insufficient evidence regarding its efficiency [32].

4.5 Response-guided therapy

Starting treatment with high barrier to resistance is crucial to minimize the development of resistance, preserve future treatment options, and maximize the chances of long-term treatment success. However, the high daily costs of ETV and TDF limit their widespread use in China. Drugs (LAM, ADV, or LDT) with low cost and low genetic barrier to resistance are still used extensively. To better manage antiviral treatments that use drugs with low genetic barrier in the Asia-Pacific region, a panel of hepatologists proposed the “Roadmap concept” in 2007 [33]. This strategy suggests that patients with suboptimal response after 24 weeks of initial drug treatment switch to a potent agent or add a second agent without cross-resistance. However, this proposal is based on expert opinion and retrospective analysis. Therefore, Sun et al. [34] conducted the Efficacy Optimization of Response to Telbivudine (EFFORT) study (NCT00962533) to prospectively evaluate the efficacy and safety of the Roadmap strategy by adding ADV to LDT for suboptimal responders. A total of 606 HBeAg-positive CHB patients were enrolled in the study. The final two-year results showed that, compared to the Mono group, more patients in the Optimized group achieved HBV DNA<300 copies/ml (76.7% vs. 61.2%, P<0.001) with less genotypic resistance (2.7% vs. 25.8%, P<0.001) at week 104. For week 24 suboptimal responders, LDT plus ADV showed an additive antiviral potency, with 71.1% achieving virological response at week 104 and only 0.5% developing genotypic resistance, compared with 46.6% who achieved virological response and 37.8% who developed genotypic resistance with LDT monotherapy. Thus, optimization strategy successfully proved the benefits by adding ADV to patients of suboptimal virological responses with additive antiviral potency and low resistance. However, the long-term resistance rate of the optimization strategy is still needed to be investigated in the extension study. In addition, as around two-thirds of patients in the Optimized group were treated with combination therapy, cost effectiveness is another concern.

4.6 Rescue of patients with drug resistance

Despite the recent development in antiviral drugs, drug resistance has been a serious challenge in China because of the widespread use of drugs with low genetic barrier. Therefore, mandatory monitoring is necessary in case of viral resistance and breakthrough. In patients with LAM-resistant HBV infection, switching to or adding on an approach has been controversial for a long time, and no differences in the rates of response or virological breakthrough were evident after 12 months of treatment [35]. Combination therapy has shown superiority over ADV monotherapy in preventing ADV resistance after long-term treatment [36,37]. Despite the good efficacy of ADV in controlling HBV replication, a degree of cross-resistance still exists [38,39]. Thus, the combination of ADV and LAM is proven superior to ADV alone in preventing the subsequent development of multidrug-resistant HBV. In addition, with respect to the non-resistance and finite course of PEG-IFNα-2a-based therapy, a randomized control trial was conducted to compare the efficacy of PEG-IFNα-2a and ADV treatment for CHB patients with LAM resistance [40]. Although the HBeAg seroconversion rate at week 72 after 48 weeks of PEG-IFNα-2a treatment was higher than continuous ADV therapy (25.5% vs. 7.7%), the viral suppression rate (defined as HBV DNA<80 IU/ml) was suboptimal in both treatment arms at week 72 (10.6% vs. 22.5%). Thus, the efficacy of PEG-IFNα-2a in the rescue treatment of patients with LAM resistance is not as optimistic as expected. For patients with CHB with ADV-resistant, ETV-resistant, or TDF-resistant HBV mutations, few comparison studies of NAs therapy was conducted, as resistance to these agents is less or the time for these drugs being available are shorter. Nonetheless, the LAM-resistance studies support the use of combination therapy in patients with drug-resistant HBV. With the availability of new and potent NAs, particularly ETV and TDF, studies have recommended switching to high potent drugs without cross resistance [41,42]. However, the efficacy of switching to an agent with cross resistance is not optimistic and thus should be avoided. Among the LAM-resistant patients who switched to ETV, 15% developed ETV resistance after 96 weeks of treatment [43]. The rescue therapy of multidrug-resistant CHB with the combination of ETV and TDF showed high efficacy and safety in a specific subset of difficult-to-treat patients with resistant HBV strains, leading to rapid HBV DNA suppression and avoidance of unnecessary changes [44].

5 Compliance of patients

Although medications and therapies are effective in suppressing HBV infection, the virus cannot be eradicated in infected hepatocytes. Thus, long-term antiviral therapy is needed in the majority of patients. During the long-term treatment period, the adherence among patients who receive NAs is important for management of CHB. Lok et al. [45] analyzed the persistence rates and the adherence rates to NAs therapy based on the data of 11 100 patients with CHB. The results showed that the one-year persistence rate is 81% in this study, which is higher than those of hypertensive medications and statins. One possibility may be that the patients perceived that hepatitis B is a serious illness than hypertension or hypercholesterolemia. However, younger and newly diagnosed patients had a low adherence rate. It is probably that young patients are generally less concerned about their health than old patients; moreover, these patients mostly consider themselves invincible. The low adherence among new patients might be due to the inadequate understanding of their illness or insufficient reinforcement of medication adherence by physicians. In China, detailed patient education always cannot be guaranteed because of the relatively limited medical resources. Therefore, specialty practices should be provided for hepatitis B in China for better patient education and counseling on medication adherence.

6 Future perspective

Despite many treatment strategies being applied, the treatment results are still far from satisfactory. Thus, individualized therapy of CHB was proposed to explore different treatment strategies based on the characteristics of individual patients. In China, the focus of research is on exploring HBV-related biomarkers from studies on genomics, virology, immunology, and fibrosis to further improve the efficacy of antiviral therapy.

6.1 Genome wide association study (GWAS)

GWAS is an examination of many common genetic variants in different individuals to detect any associations between single nucleotide polymorphisms and diseases. In the genetic study of HBV infection, susceptibility to virus and HBV-related HCC has been extensively researched. By contrast, little is known about the association between treatment responses and genome polymorphism. Most recently, 1161 Chinese patients were included from optimization-based clinical trials to explore relationships between treatment responses and genome polymorphism. All blood samples were scanned by Human OmniExpress Exome chip, which can detect a variation of more than 70 million in each sample while adding more than 200 000 custom exon mutation sites, thereby ensuring the high quality of data and content. Currently, 1145 effective results (average call rate>99.9%) were obtained. Patients with different response gene polymorphisms were found with different treatment responses after initial analysis, suggesting the important implications for patients to optimize or adjust treatment strategy. Refined analysis and validation studies are ongoing to further investigate the mechanism.

6.2 High-throughput DNA sequencing

Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication [46]. The application of quasispecies theory to HBV populations has boosted our understanding of interactions within mutant spectra. Cloning and subsequent Sanger dideoxy sequencing have been widely used in the analysis of HBV quasispecies heterogeneity [47]. However, this procedure is time consuming and costly, and only limited clones were obtained within a patient sample. Ultra-deep sequencing technologies have changed the situation dramatically. They allow for massively parallel picoliter-scale amplification and detection of individual DNA molecules. Hundreds and thousands of clones can be obtained within a single sample. We obtained response-guided samples from an HBV patient cohort who underwent therapy by using the ultra-deep sequencing technology for in-depth microevolution analysis of the evolving dynamics of their quasispecies pools detected by ultra-deep sequencing. The genetic analysis revealed that the virological responses of patients to chemotherapy are determined by the composition of the critical drug-resistant mutants at the early stage of treatment. The detailed genetic mechanism allows us to propose a conceptual roadmap for future studies of antiviral therapy.

6.3 Immune biomarkers

The treatment goal of anti-HBV therapy is to reconstruct HBV-specific immune function and achieve the seroconversion of HBeAg and HBsAg. The exploration of host-based predictors of efficient and immunologic strategies is indispensable because of the important functions of the host immune system in the antiviral process. Ma et al. [48] proposed that the serum concentration of interleukin-21 (IL-21), a newly discovered cytokine with wide and efficient immune functions, can be used as an independent predictor of HBeAg seroconversion for patients who received LDT treatment for 12 weeks. Li et al. [49] found that circulating chemokine (C-XC motif) receptor 5 (CXCR5)⁺CD4⁺ T cells have important functions in facilitating HBeAg seroconversion in patients with chronic HBV infection by producing IL-21. These results indicate that IL-21 is a plausible biomarker that might contribute to the individualization of antiviral therapy for HBeAg-positive CHB or to the development of immunotherapies for CHB.

6.4 Assessment of liver fibrosis

Alanine aminotransferase (ALT)>2 times the upper limit of laboratory normal was taken as the indicator of significant hepatitis among non-cirrhotic patients who may warrant antiviral therapy. However, recent data have increasingly recognized that patients with normal or mildly elevated serum ALT are not guaranteed to be free from liver damage. Antiviral therapy should be recommended if significant hepatic necroinflammation or fibrosis is detected on liver biopsy irrespective of the ALT levels. Thus, assessment of liver fibrosis is important in selecting patients for treatment. Liver biopsy is the gold standard of liver fibrosis assessment; however, this procedure is limited by its invasiveness and potential sampling error. Numerous methods for the non-invasive assessment of liver fibrosis have been investigated in the past decade. Transient elastography (TE) is a rapid, non-invasive, and reproducible method that uses shear wave technology to measure liver stiffness. A high liver stiffness reflects severe liver fibrosis. The use of transient elastography has been extensively validated by numerous investigators in CHB [50]. However, when serum ALT is elevated, TE tends to over-estimate the severity of liver fibrosis, so fibrosis score should be evaluated according to ALT-stratified cutoffs. Recently, bilirubin normalization has been considered important in improving the performance of TE for compensated hepatitis B cirrhosis detection [52]. Furthermore, TE has been confirmed to be valuable for the high-risk prediction of esophageal varices in patients with hepatitis B-related cirrhosis [53]. Accordingly, TE is a reliable tool for detecting severe fibrosis and cirrhosis in patients with CHB. However, validation studies are still needed to identify the other clinical applications of this tool.

7 Conclusions

Remarkable progress in CHB management has been achieved with the development of new antiviral drugs in the past decade. The introduction of hepatitis B vaccination programs has changed the epidemiology of hepatitis B virus infection in China from highly to moderately endemic. The adoption of good clinical practice and proper conduction of well-designed clinical trials on conventional and pegylated IFNs and NAs has generated important clinical evidence. However, financial burden and drug resistance remain to be the challenges in China. Many treatment issues that are still unsatisfactory or unclear need further investigation. Further studies are needed to clarify how to establish individualized treatment strategy by using the multi-sided predictors in the management of patients in clinical practice.

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