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Yu Zhang, Jian-Hua Zhou, Xiao-Ling Yin, Feng-Yu Wang, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China Author contributions: Zhang Y designed the research, collected and analyzed the data and wrote the manuscript; Zhou JH designed the research and revised the manuscript; Yin XL and Wang FY participated in the data collection. Supported by National Natural Science Foundation of China, No. 30772360 Correspondence to: Jian-Hua Zhou, Professor, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. jhzhou@tjh.tjmu.edu.cn Telephone: +86-27-83663256 Fax: +86-27-83663256 Received: October 13, 2009 Revised: December 31, 2009 Accepted: January 7, 2010 Published online: February 14, 2010
Abstract AIM: To evaluate the efficacy of antiviral or corticosteroid treatment on hepatitis B virus-associated glomerulonephritis (HBV-GN).
METHODS: Six and five trials were used respectively to evaluate the efficacy of either antiviral or corticosteroid treatment on HBV-GN. Pediatric patients were pooled separately to assess their response to the above treatment modalities. The primary and secondary outcomes were remission of proteinuria and clearance of Hepatitis B e-antigen (HBeAg), respectively. A fixed or random effect model was established to collect the data.
RESULTS: The remission rate of proteinuria (RR = 1.69, 95% CI: 1.08-2.65) and the clearance rate of HBeAg (RR = 6.44, 95% CI: 3.11-13.35) were significantly higher in antiviral treatment group than in control group. The proteinuria remission was significantly associated with HBeAg clearance (P = 0.002). However, the difference in proteinuria remission rate was not statistically significant between corticosteroid treatment group and control group (RR = 1.45, 95% CI: 0.68-3.11). Antiviral therapy could significantly promote the HBeAg clearance in pediatric patients, but neither antiviral nor corticosteroid therapy could significantly decrease proteinuria in pediatric patients compared to controls.
CONCLUSION: Antiviral but not corticosteroid treatment can decrease proteinuria and promote HBeAg clearance in HBV-GN patients.
© 2010 Baishideng. All rights reserved.
Key words: Hepatitis B virus-associated glomerulonephritis; Drug therapy; Meta-analysis
Peer reviewer: Eva Herrmann, Professor, Department of Internal Medicine, Biomathematics Saarland University, Faculty of Medicine, Kirrberger Str., 66421 Homburg/Saar, Germany
Zhang Y, Zhou JH, Yin XL, Wang FY. Treatment of hepatitis B virus-associated glomerulonephritis: A meta-analysis. World J Gastroenterol 2010; 16(6): 770-777 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i6/770.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i6.770
INTRODUCTION Hepatitis B virus-associated glomerulonephritis (HBV-GN) remains one of the most common secondary glomerular diseases in Chinese children, although its incidence seems to decrease nowadays after the popularization of HBV vaccination[1,2]. Most HBV-GN patients present with nephrotic syndrome and some show mild to moderate proteinuria with hematuria[3]. Although spontaneous remission has been reported in many pediatric patients[3], some still develop progressive renal failure[4-6]. Therefore, it is very important to attenuate proteinuria and slow down renal disease progression in HBV-GN patients. HBV-GN is treated with either antiviral drugs including interferon, lamivudine, and entecavir or with corticosteroids and even immunosuppressive agents like mycophenolate mofetil, leflunomide[7,8]. It has been shown that antiviral therapy can promote the clearance of HBV and improve the coexisting renal disease[3], but the efficacy of interferon on HBV-GN has not been confirmed[9,10]. Moreover, interferon therapy is not as successful for HBV-GN in children as for HBV-GN in adults[3]. Thus, the efficacy of antiviral therapy on HBV-GN remains to have been established, especially in pediatric patients. Corticosteroids are also used in treatment of some patients with nephrotic syndrome. However, it is argued that corticosteroid and immunosuppressive agents are unfavorable for HBV-GN since they inhibit the immune system and activate latent HBV, leading to active replication of HBV and deterioration of renal lesions[3,11]. So the efficacy of these treatment modalities on HBV-GN is still uncertain. Up to date, we are not sure if patients with HBV-GN can be treated with antiviral drugs alone and if nephrotic patients can be treated with corticosteroids. Unfortunately, the data available in studies on HBV-GN treatment are limited and often provide inconsistent results, which can be explained by many factors like variable sample size, racial differences, disease variation as well as interference of other treatment. These inconsistencies can be solved by meta-analysis. In a meta-analysis[12] of antiviral therapy for HBV-GN published in 2006, 2 of the 6 trials included were non-controlled studies, other treatments like corticosteroids and pediatric patients were not analyzed. Thus, we performed a meta-analysis including just controlled trials to evaluate the effects of antiviral drugs and corticosteroids on HBV-GN both in adults and in children.
MATERIALS AND METHODS Literature search All eligible articles in English and Chinese published prior to November 2008 were searched from PubMed, EMBASE, Cochrane Library and CNKI. The terms, including hepatitis B virus (or hepatitis B), nephropathy, nephrotic syndrome and therapy, interferon, lamivudine, corticosteroid, prednisolone, etc., were crossed. Furthermore, bibliographies of retrieved articles, proceedings of major recent meetings on nephrology and hepatology and related dissertations in English or Chinese were manually searched.
Criteria for inclusion Controlled clinical trials, cohort studies, and case-control studies were searched for this systematic review. The diagnosis of HBV-GN was established based on renal pathology. The primary and secondary outcomes were remission of proteinuria and clearance of Hepatitis B e-antigen (HBeAg), respectively. Only dissertations, conference papers and full-text papers published in peer-reviewed journals concerning the treatment of HBV-GN were included in the study. The decision was made based on the quality of studies rather than on their results.
Criteria for exclusion Publications were excluded if they were non-controlled studies or on treatment of HBV-GN with Chinese herbal drugs. For serial reports of the same patients, only those who provided the most comprehensive information were included.
Definition of treatment effect The assessed outcomes included clinical and virologic responses. Clinical responses were divided into complete remission and partial remission, which were respectively defined as disappearance of proteinuria (< 0.3 g/d) and reduction in urine protein excretion. Virologic response was defined as clearance of HBeAg from serum.
Data extraction and quality assessment Two reviewers independently selected the studies, and extracted data and outcomes according to the inclusion criteria. In case of disagreement between the two reviewers, a third reviewer was introduced to discuss with the two reviewers and extracted the data when all the three reviewers reached a consensus.
Statistical analysis Meta-analysis was performed using fixed-effect or random-effect methods, depending on the absence or presence of significant heterogeneity. Statistical heterogeneity between trials was evaluated by the Cochran c2 test and significance was considered when P < 0.10. In the absence of statistically significant heterogeneity, the Mantel-Haenszel method in the fixed-effect model was used for meta-analysis. Otherwise, the DerSimonian and Laird method[13] in the random-effect model was selected. The relative risk (RR) with 95% confidence interval (CI) was used to assess the treatment efficacy. The combined result was an average RR and 95% CI weighted according to the standard error of the RR of the trial. P < 0.05 was considered statistically significant. We used funnel plots to assess the publication bias, and tested for funnel plot asymmetry using Egger’s test[14] and Begg’s test[15]. All analyses were performed with STATA version 9.0 (Stata Corp, College Station, Tx) and Review Manager version 4.2 (RevMan, Cochrane Collaboration, Oxford, England).
RESULTS Description of included trials in the meta-analysis Of the 998 studies we identified in the search, 55 and 943 articles were published in English and Chinese, respectively. After a review of the titles and abstracts or full texts, 989 articles were excluded and 9 articles[16-24] (8 in English and 1 in Chinese) were included based on the pre-specified criteria. One of them was randomized controlled trial (RCT)[16], others were cohort studies. Among the 9 articles, 5 (55.6%) were from China, corresponding to the high incidence of HBV-GN in China and the low incidence in Europe and North American. The characteristics of 9 clinical trials included are shown in Table 1, and the details of intervention methods like dose and duration of drugs, main outcomes, and follow-up time in each study are provided in Tables 2 and 3.
Therapeutic evaluation: Antiviral therapy The efficacy of antiviral therapy on HBV-GN was assessed using 6 trials[16-21], including 1 RCT[16] and 5 cohort studies[17-21]. The total number of patients was 159 (72 in treatment group with 5 dropped out, 87 in control group with 3 dropped out). Among the 159 patients, 133 presented with nephrotic syndrome and 134 with membranous nephropathy. The mean follow-up time was five months to ten years, significantly different between trials.
Clinical response in antiviral treatment group and control group: The c2 test of heterogeneity was highly significant (P = 0.0001). Accordingly, a random-effect model was used. The remission rate of proteinuria was significantly higher in antiviral treatment group (91.0%) than in control group (56.0%) with a combined RR of 1.69 (95% CI: 1.08-2.65, Figure 1A). The result of sensitivity analysis remained unchanged even if lamivudine treatment studies were excluded (RR = 1.50, 95% CI: 0.99-2.26, Figure 1B), indicating that the result is stable. Furthermore, three trials[16,17,21] on pediatric patients were analyzed. The c2 test of heterogeneity was also highly significant (P = 0.007), so a random-effect model was selected. As shown in Figure 1C, the remission rate of proteinuria in pediatric patients was slightly higher in treatment group (86.7%) than in control group (61.1%) with a combined RR of 1.40 (95% CI: 0.80-2.47), but the difference was not statistically significant (P = 0.24).
Virologic response in antiviral treatment group and control group: The c2 test of heterogeneity was not significant (P = 0.13), therefore a fixed-effect model was selected. The clearance rate of HBeAg was significantly higher in antiviral treatment group (59.7%) than in control group (8.33%) with a RR of 6.44 (95% CI: 3.11-13.35, Figure 2A). In addition, 3 trials[16,17,21] on pediatric patients were separately analyzed for virologic response. The c2 test of heterogeneity was significant (P = 0.05), therefore a random-effect model was used. The clearance rate of HBeAg was significantly higher in antiviral treatment group (73.3%) than in control group (7.4%) with a RR of 10.71 (95% CI: 3.74-30.63, Figure 2B).
Consistency analysis of clinical and virologic responses: Kappa analysis showed that proteinuria remission was significantly related with HBeAg clearance after antiviral therapy (kappa = 0.285, P = 0.002)
Effect of antiviral therapy on protection of renal function The renal function of patients was observed in 5 of the 6 trials during the follow-up (Table 2). Renal insufficiency was found in only 3 of 47 (6.38%) patients in the antiviral treatment group and in 11 of 64 (17.2%) patients in the control group, respectively.
Therapeutic evaluation: Corticosteroid treatment The efficacy of corticosteroid treatment on HBV-GN was assessed in 5 out of 9 articles[20-24]. Two of them were included in meta-analysis of antiviral therapy efficacy. Of the 23 patients in Panomsak’s study[20], 7, 6 and 10 were treated with antiviral drugs, prednisolone and symptomatic treatment, respectively. Of the 28 patients in Yang’s study[21], 6, 8 and 14 were treated with antiviral drugs, prednisolone and symptomatic treatment, respectively. All the 5 trials were cohort studies. The clinical response at the end of follow-up is shown in Figure 3A. Of the 76 patients analyzed, 37 were in corticosteroid treatment group with 3 dropped out, 39 were in control group with 3 dropped out. Among them, 52 presented with nephrotic syndrome and 56 with membranous nephropathy. The c2 test of heterogeneity was highly significant (P = 0.001), so a random-effect model was used. The combined RR was 1.45 with a 95% CI of 0.68-3.11 (P = 0.34), indicating that there is no significant difference in proteinuria remission rate between corticosteroid treatment group and control group. However, this result should be carefully interpreted since a limited number of clinical trials can affect the conclusion of meta-analysis. Besides, it was difficult to assess the protective effect of corticosteroid treatment on renal function since only 2 of 5 clinical trials described the renal function during the followed-up. Moreover, 3 trials[21,23,24] on pediatric patients were separately pooled to analyze the efficacy of corticosteroid treatment. The c2 test of heterogeneity was not significant (P = 0.61), so a fixed-effect model was used. The combined RR was 0.91 with a 95% CI of 0.65-1.27 (P = 0.58), indicating that the difference in the remission rate of proteinuria was also not significant between corticosteroid treatment group and control group (Figure 3B).
Publication bias Publication bias may exist when no significant findings remain unpublished, thus artificially inflating the apparent magnitude of an effect. Egger and Begg tests showed that the risk of having missed trials was acceptably low, since the P values for the clinical and virologic responses to antiviral therapy and the clinical response to corticosteroid treatment were greater than 0.05. The funnel plots of study results against precision are shown in Figure 4.
Adverse events Since adverse events were reported inconsistently in across studies and the relevant information in these studies was incomplete, we did not evaluate their incidence and severity of adverse events of these drugs. Some adverse events such as influenza-like illness, anemia, leucopenia, etc, were reported in patients treated with IFN. Almost all patients showed good tolerance to long-term administration of lamivudine, although some patients complained of headache, dizziness, local myalgia, paresthesia, etc.
DISCUSSION Most HBV-GN patients presented with nephrotic syndrome, many of them, especially pediatric patients showed a spontaneous remission trend, so whether the patients should be treated with antiviral drugs or with immunosuppressive agents remains to be elucidated. Antiviral therapy has been recommended in many studies for HBV-GN since it can effectively inhibit HBV replication and attenuate proteinuria[9,25-33]. Our results demonstrated that antiviral therapy could significantly improve the remission rate of proteinuria, the clearance rate of HBeAg, and renal progression. Moreover, Kappa analysis showed that proteinuria remission is significantly related with HBeAg clearance after antiviral therapy. Only 5 patients were dropped out in antiviral treatment group due to economical reasons. Almost all patients were tolerable to antiviral drugs. Our results are consistent with Fabrizi’s study[12]. Since each trial used different kinds, dosages and treatment courses of antiviral drugs, the meta-analysis proved the efficacy of antiviral treatment but did not necessarily mean that an exact treatment protocol should be recommended. The meta-analysis of pediatric patients showed that antiviral therapy could significantly increase the clearance rate of HBeAg, but not remarkably improve proteinuria, which is not consistent with our above findings possibly due the limited sample size. Large-scale randomized controlled trials on pediatric patients are needed to clarify if antiviral therapy can induce remission of proteinuria. Corticosteroid is the first-line drug for idiopathic nephrotic syndrome, but it may activate potent HBV infection leading to deterioration of liver and renal lesion[22,34-36]. Our meta-analysis showed that corticosteroid treatment could not significantly improve proteinuria. The effect of corticosteroids on proteinuria remission was not better than nonspecific symptomatic treatment, but its potent risk could not be neglected. Therefore, based on the results of this meta-analysis, corticosteroid should not be recommended for HBV-GN patients solely, especially for those with a high viral load and abnormal liver functions. Theoretically, corticosteroid in combination with antiviral drugs is certainly superior over corticosteroid alone, but no trials are available. So corticosteroid may only be used cautiously on the basis of antiviral therapy with viral load closely monitored. As with all meta-analyses, our study had certain limitations of publication bias[37]. The number of high-quality clinical trials and enrolled patients was limited in this study. Moreover, the time of treatment was not long enough to evaluate its effects on chronic HBV-GN. In conclusion, the efficacy and safety of antiviral therapy (including IFN and lamivudine) on HBV-GN are good. Antiviral therapy is effective on remission of proteinuria, and HBeAg clearance, delaying renal function deterioration. However, corticosteroids cannot ameliorate HBV-GN.
COMMENTS Background Hepatitis B virus-associated glomerulonephritis (HBV-GN) is one of the common secondary glomerular diseases in China. Although spontaneous remission can occur in many pediatric patients, some still develop progressive renal failure. Therefore, it is very important to attenuate proteinuria and delay renal disease progression. Research frontiers So far HBV-GN has been treated like hepatitis B with antiviral drugs including interferon, lamivudine, entecavir or like primary nephrotic syndrome with corticosteroids and even immunosuppressive agents such as mycophenolate mofetil, leflunomide, etc. However, it is still uncertain up to now about the efficacy of these treatment modalities. Innovations and breakthroughs The data available in previous studies on HBV-GN treatment are limited and often provide inconsistent results. So far only one meta-analysis of antiviral therapy for HBV-GN was published in 2006, but 2 of the 6 trials included were non-controlled studies. The meta-analysis including controlled studies is the first to evaluate the effects of antiviral drugs and corticosteroids on HBV-GN. Moreover, pediatric patients were separately assessed. Applications The results of this study suggest that antiviral but not corticosteroid treatment can decrease proteinuria and promote Hepatitis B e-antigen clearance in HBV-associated glomerulonephritis patients. It may help doctors to optimally treat HBV-GN patients. Terminology Hepatitis B virus-associated glomerulonephritis is an immune-mediated secondary glomerular disease characterized by deposits of hepatitis B viral antigens, immunoglobulins and C3 in the glomerular capillary wall and mesangium. Nephrotic syndrome, proteinuria and/or hematuria are the most common renal manifestations. Peer review The present manuscript describes a meta-analysis for the evaluation of clinical and virologic responses to antiviral and corticosteroid treatment of hepatitis B-associated nephritis. Overall, the methods are appropriate and the results are believable.
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S- Editor Tian L L- Editor Wang XL E- Editor Lin YP
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