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Prophylactic lamivudine to improve the outcome of HBsAg-positive lymphoma patients during chemotherapy: A systematic review and meta-analysis

Clinics and Research in Hepatology and Gastroenterology

Summary

Hepatitis B viral (HBV) reactivation in lymphoma patients undergoing chemotherapy is associated with significant morbidity and mortality. Increasingly, lamivudine is being used to prevent hepatitis B reactivation. To assess the effects of prophylactic lamivudine on reactivation and mortality following chemotherapy in lymphoma patients who are hepatitis B surface antigen (HBsAg)-positive, we searched Medline/PubMed, Ovid MEDLINE, EMBASE, Web of Knowledge and the Cochrane Library for studies through November 2013. Statistical analysis was performed using REVMAN. Fourteen studies consisting of 636 patients were included in the analysis. The rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis due to HBV reactivation in patients with lamivudine prophylaxis was significantly lower than those with no prophylaxis. Risk ratios [RRs] were 0.25 (95% confidence intervals [CI] 0.13–0.51;P = 0.0001), 0.40 (95% CI 0.26–0.63;P < 0.0001), and 0.21 (95% CI 0.09–0.51;P = 0.0005) respectively. In addition, patients given prophylactic lamivudine had significant reductions in overall mortality and mortality attributable to HBV reactivation compared with control group. Risk ratios [RRs] were 0.45 (95% CI 0.29–0.70;P = 0.0004) and 0.41 (95% CI 0.20–0.84;P = 0.01) respectively. Chemotherapy disruption was not significantly different between the two groups. Risk ratios [RRs] were 0.34 (95% CI 0.09–1.26;P = 0.11). Prophylactic therapy with lamivudine for HBsAg-positive lymphoma patients who are undergoing chemotherapy may reduce the risk for HBV reactivation, hepatitis due to HBV reactivation, overall mortality and mortality attributable to HBV reactivation. Additionally, patients with preventive lamivudine had a trend towards the decreased incidence of chemotherapy disruption.

Introduction

Hepatitis B infection, caused by the hepatitis B virus (HBV), is one of the most common infectious diseases worldwide and is a major global health problem, affecting more than 350 million persons worldwide[1] and [2]. Infection with HBV can lead to chronic liver disease, cirrhosis, and liver cancer [3] . The incidence of HBV reactivation in HBsAg-positive patients undergoing chemotherapy is 10–50%[4], [5], [6], [7], [8], [9], and [10]. A growing number of published reports of HBV reactivation-related morbidity and mortality have made this population the focus of considerable investigation, including the role of prophylactic antiviral therapy[11], [12], [13], and [14].

Lamivudine, an oral nucleoside analogue, inhibits HBV replication and reduces viral load, leading to clinical, biochemical, serological and histological improvement in patients with chronic hepatitis B[15], [16], and [17]. Lamivudine also has an excellent long-term safety profile and is generally well tolerated [18] . Despite receiving lamivudine as a therapeutic measure at the time of HBV reactivation, HBsAg-positive patients who develop HBV reactivation during chemotherapy may still suffer fatal hepatic injury[19], [20], and [21]. Therefore, prophylaxis may be the key to effective management of HBV reactivation [19] . Administration of prophylactic or preemptive lamivudine or other nucleoside/nucleotide analogues before commencing chemotherapy seems to be a reasonable approach for preventing reactivation of HBV [20] . HBV reactivation has been described in chronic HBV carriers diagnosed with a variety of cancers who were treated with chemotherapy agents. However, the most commonly reported cases are patients with lymphoma[21], [22], [23], and [24]. In 2009, a meta-analysis including nine clinical studies evaluated the effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma patients. This preliminary meta-analysis showed that lamivudine prophylaxis is associated with a significant reduction in HBV reactivation and a trend in reducing HBV-related mortality [25] . However, the efficacy of prophylactic lamivudine in preventing hepatitis, hepatitis due to HBV reactivation, overall mortality and chemotherapy disruption is not reported. Furthermore, in recent years, several new trials comparing lamivudine prophylaxis with no prophylaxis for the outcome of HBsAg-positive lymphoma patients undergoing chemotherapy have been published[26], [27], [28], [29], and [30].

Therefore, we conducted this meta-analysis to study the impact of lamivudine prophylaxis on HBsAg-positive lymphoma patients undergoing chemotherapy. Our hypothesis was that lamivudine prophylaxis reduces the rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis attributable to HBV reactivation, overall and HBV reactivation-associated mortality and the rate of chemotherapy disruption.

Materials and methods

We searched the following databases until November2013: Medline/PubMed, Ovid MEDLINE, EMBASE, Web of Knowledge and the Cochrane Library. Search terms were selected to maximize both the search sensitivity and specificity. The search strategy of the databases involved selecting subject headings and keywords used either alone or in combination: “prophylaxis”, “preemptive”, “lamivudine”, “hepatitis B virus”, “HBV”, “reactivation”, “flare”, “HBsAg”, “chemotherapy”, “lymphoma”. Any emerging discrepancies were resolved by consensus between two independent reviewers or with the help of a third author (Huai-dong Hu) via referencing the original article. The scope of the search was restricted to “human” and “English”.

Inclusion and exclusion criteria

Inclusion criteria for the meta-analysis were:

  • randomized controlled trials (RCTs), or retrospective or prospective cohort studies with a control (concurrent or historical) group;
  • studies including a lamivudine prophylaxis group and a non-prophylaxis group;
  • all lymphoma patients in the two groups had undergone chemotherapy and were seropositive for HBsAg.

Patient populations were excluded if:

  • reactivation/flares were not related to HBV, or the HBV reactivation/flare was not a specific outcome of the study;
  • did not involve chemotherapy;
  • the study involved human immunodeficiency virus (HIV) co-infection;
  • case reports or series and studies that included patients who had hepatitis D virus, hepatitis C virus or other liver diseases;
  • did not have a lamivudine prophylaxis and non-prophylaxis group. Trials were also excluded if relevant data could not be extracted.

Efficacy measures

HBV reactivation was defined as new liver function disturbances in the presence of new anti-HBc IgM and/or signs of viral replication with a seroconversion from HBeAb-positive to HBeAg-positive [31] . Hepatitis was defined as at least a 3-fold increase in alanine aminotransferase (ALT) that exceeded the upper limit of normal (ULN; 40 U/L) or an absolute increase of ALT to more than 100 U/L[4] and [32]. Hepatitis attributed to HBV reactivation was defined as at least a 10-fold increase in serum HBV DNA levels or an absolute increase > 105copies/mL in the HBV DNA level [33] . Disruption of chemotherapy treatment was defined as either premature termination of chemotherapy or a delay of more than one week between cycles [33] .

Data extraction

Two reviewers (Hong Li and Hong-min Zhang) independently applied inclusion criteria, selected the studies and extracted data from eligible studies. From each article, the reviewers extracted:

  • the number of patients in respective studies;
  • details of the study design;
  • patient characteristics;
  • treatment regimen;
  • outcome measures performed as defined above. Disagreements were resolved with the assistance of an arbiter (Huai-dong Hu) when necessary.

Study quality

The methodological quality of each RCT was assessed using the Cochrane collaboration's tool for assessing risk of bias [34] , The risk of bias (RoB) tool was developed through an extensive process in order to improve on other tools used for quality assessment [34] . The RoB tool comprises seven domains:

  • details of randomization method;
  • allocation concealment;
  • blinding of participants and personnel;
  • blinding of outcome assessment;
  • incomplete outcome data;
  • selective outcome reporting;
  • other sources of bias.

We adopted the Newcastle–Ottawa assessment scale (NOS) to evaluate cohort studies. A quality score, up to a total score of 9, was calculated on the basis of 3 major components of cohort studies:

  • selection of study groups (0–4 points);
  • comparability of study groups (0–2 points);
  • outcome of study groups (0–3 points).

A score of seven and above was used to indicate high quality [35] . Two reviewers independently assigned study quality and disagreement was resolved by re-examining the relevant paper until consensus was achieved.

Statistical analysis

Meta-analysis was carried out with the use of Review Manager Software 5.0 (Cochrane Collaboration, Oxford, United Kingdom). Statistical heterogeneity between trials was evaluated by the chi-square (Chi2) andI-square (I2) tests andP < 0.10 was used to indicate significant heterogeneity. TheI2value was used to assess the impact of heterogeneity on the meta-analysis. In cases where significant heterogeneity existed, a random effect model was used for analysis. Otherwise, a fixed effect model was used. Results withPvalues 0.05 are regarded as “significant findings”. We used the relative risk (RR) of the main dichotomous outcomes as the measure of efficacy. An RR less than 1.00 indicates risk reduction in the intervention group (lamivudine prophylaxis) over the control group (no lamivudine prophylaxis). The 95% confidence interval (CI) for the combined RR was also provided.

Results

Search results

All of the 1067 records were identified in the primary literature search. Duplicates were removed, and abstracts from the remaining 623 publications were screened. There were 558 records left after excluding case reports, reviews, adolescent studies and studies irrelevant to the current analysis. Of the remaining 65 articles selected for further evaluation, 51 studies were further excluded for various reasons, including the lack of a control group and inadequate information. After the final exclusions, fourteen studies comprising a total of 636 patients met the eligibility criteria and were included in this meta-analysis ( Fig. 1 ). All of these studies were published between 2002 and 2013.

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Figure 1 Study flow diagram.

Characteristics and quality of studies

The fourteen studies were predominantly cohort studies. Of the fourteen studies, two were RCTs[36] and [37], two were prospective cohort studies[31] and [38]and ten were retrospective cohort studies[26], [27], [28], [29], [30], [33], [39], [40], [41], and [42]. The basic characteristics of each study are listed in Table 1 . Of the fourteen studies, three were from China[27], [33], and [36], three from Taiwan[28], [37], and [39], two from Turkey[26] and [38], one from Korea [40] , one from Asia including Korea, Taiwan, China, Singapore, Malaysia, Indonesia, Thailand [30] , one from Singapore [29] , one from Italy [41] , one from Israel [31] and one from Japan [42] . In each study case, the entire patient population was from the country of origin. The population size of the studies ranged from 7 [38] to 156 [33] . The median patient age ranged from 39 [38] to 57.5 [31] years old. The patients in the fourteen studies had tested positive for HBsAg. Across all fourteen studies, there were no significant differences among baseline study characteristics with regards to patients’ baseline ALT levels, baseline HBV DNA levels and baseline HBeAg status prior to chemotherapy between the prophylactic and the control group. Chemotherapeutic regimens were not significantly different in four studies[27], [28], [30], and [42], but rituximab was added to combination chemotherapy. Patients in the prophylactic group received lamivudine 100 mg once daily, except in four studies: one [31] in which they received 150 mg/day and the other three not mentioned. RCTs were evaluated with the help of the “assessing risk of bias” tool, and the risk of bias was low in two RCTs[36] and [37]( Table 1 ). Each cohort study was scored based on the Newcastle–Ottawa assessment scale (NOS) seen in Table 1 . These twelve cohort studies[26], [27], [28], [29], [30], [31], [33], [38], [39], [40], [41], and [42]that mostly scored 6–8 were of sufficient quality for inclusion in the meta-analysis.

Table 1 Characteristics of studies and quality assessment.

Study, year Location Multi/single Study type NOS score/risk of bias Lamivudine prophylaxis vs no lamivudine prophylaxis
          No. participants

n
NHL/HL

n/n
Median age (Range)

y
Men/women

n/n
ALT

IU/L (or n/N)
Chen et al., 2012 [27] China Single centre Retrospective cohort study 7 30 vs 20 30/0 vs 20/0 47 (21–76) vs 46.9 (22–76) 19/11 vs 11/9 Median (range): 47 (11–120) vs 31 (10–94)
Hsu et al., 2008 [37] Taiwan Multicentre RCT Low risk 26 vs 25 26/0 vs 25/0 50.5 (32–67) vs 41 (20–74) 12/14 vs 13/12 Total: ALT < 5ULN
Idilman et al., 2004 [38] Turkey Single centre Prospective cohort study 8 4 vs 3 3/1 vs 3/0 44 (41–54) vs 39 (37–44) 3/1 vs 1/2 Mean ± SD: 30.25 ± 8.18 vs 29 ± 14.18
Kim et al., 2013 [30] Asia Multicentre Retrospective cohort study 6 96 vs 22 96/0 vs 22/0 NR NR NR
Lau et al., 2003 [32] China Single centre RCT Low risk 15 vs 15 12/3 vs 12/3 50.6 (23–98) vs 51.2 (24–98) 8/7 vs 9/6 Total: ALT < 10ULN
Leaw et al., 2004 [39] Taiwan Single centre Retrospective cohort study 6 11 vs 53 NR NR NR NR
Lee et al., 2003 [40] Korea Single centre Retrospective cohort study 7 11 vs 20 11/0 vs 20/0 44 (29–68) vs 47.5 (18–70) 6/5 vs 13/7 < ULN (n/N): 3/11 vs 4/20
Li et al., 2006 [33] China Single centre Retrospective cohort study with historical control group 7 40 vs 116 36/4 vs 111/5 40 (16–74) vs 41 (12–75) 25/15 vs 72/44 Total: basically normal
Lim et al., 2007 [29] Singapore Single centre Retrospective cohort study 6 24 vs 21 24/0 vs 21/0 NR NR < ULN (n/N): 22/24 vs 18/21
Ozguroglu et al., 2004 [26] Turkey Single centre Retrospective cohort study 6 4 vs 8 4/0 vs 8/0 44 (35–49) vs 42.5 (14–72) 3/1 vs 3/5 Mean ± SD: 34 ± 13.37 vs 963.88 ± 820.33;

< ULN (n/N): 2/4 vs 0/8
Pei et al., 2010 [28] Taiwan Single centre Retrospective cohort study 7 5 vs 10 5/0 vs 10/0 49 (31–72) vs 54 (40–81) 2/3 vs 5/5 Mean ± SD: 32.6 ± 13.48 vs 28.1 ± 16.82

< ULN (n/N) 4/5 vs 8/10
Persico et al., 2002 [41] Italy Single centre Retrospective cohort study 7 3 vs 18 3/0 vs 18/0 Total: 45 (38–64) Total: 11/10 Mean ± SD (total): 22.27 ± 9.4
Shibolet et al., 2002 [31] Israel Single centre Prospective cohort study with historical control group 7 7 vs 4 Total: 10/1 55 (38–65) vs 57.5 (46–67) 5/2 vs 4/0 Mean ± SD: 66 ± 56.17 vs 35 ± 16.27

< ULN (n/N): 3/7 vs 4/4
Tsutsumi et al., 2009 [42] Japan Multicentre Retrospective cohort study 6 10 vs 15 10/0 vs 15/0 NR NR NR
Study, year Lamivudine prophylaxis vs no lamivudine prophylaxis Dose of lamivudine Lamivudine duration
  HBV DNA positive

n/N
HBeAg-positive

n/N
Chemotherapy Receipt of cortico-steroids

n/N
Receipt of anthracyclines

n/n
   
Chen et al., 2012 [27] 10/30 vs 0/20 NR Rituximab combined with anthracyclines-containing chemotherapy NR 30/30 vs 20/20 100 mg/d Start: 7 days before chem

End: at least 3 months after chem
Hsu et al., 2008 [37] > 10 copies/mL: 3/23 vs 9/16 2/26 vs 8/25 CHOP 26/26 vs 25/25 26/26 vs 25/25 100 mg/d Start: day 1 of chem

End: 2 months after chem
Idilman et al., 2004 [38] 0/4 vs 0/3 0/4 vs 0/3 CHOP; 2-CDA; ABVD 2/4 vs 3/3 3/4 vs 3/3 100 mg/d Start: day 1 of chem

End: 12 months after chem
Kim et al., 2013 [30] NR NR Rituximab combined with chemotherapy (CHOP, CVP) NR NR NR NR
Lau et al., 2003 [32] 3/15 vs 5/15 4/15 vs 4/15 CEOP; ABVD; CHOP; COPP; other 8/15 vs 5/15 9/15 vs 5/15 100 mg/d Start: 7 days before chem

End: 1.5 months after chem
Leaw et al., 2004 [39] NR NR CEOP was the most frequently used 11/11 vs 48/53 11/11 vs 53/53 100 mg/d Start: day 1 of chem

End: 1 months after chem
Lee et al., 2003 [40] 5/11 vs 6/20 7/11 vs 5/20 CHOP; EDAP; proMACE-ctaBOM 10/11 vs 19/20 10/11 vs 19/20 100 mg/d NR
Li et al., 2006 [33] NR 23/40 vs 47/116 NR 37/40 vs 107/116 35/40 vs 111/116 100 mg/d Start: 7 days before chem

End: 8–64 weeks (range) after chem

12 weeks (median)
Lim et al., 2007 [29] 13/24 vs 6/21 NR NR 24/24 vs 21/21 20/24 vs 16/21 100 mg/d End: 3–6 months (range) after chem
Ozguroglu et al., 2004 [26] 4/4 vs 8/8 1/4 vs 3/8 CHOP; COP; DHAP; BACOP 4/4 vs 8/8 4/4 vs 7/8 100 mg/d Start: before the initiation of chem.
Pei et al., 2010 [28] NR NR Rituximab combined with chemotherapy (CHOP or CHOP-like regimen and etoposide-methylprednisolone-cytarabine cisplatin, ProMACE-CytaBOM, etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin, and mesna-ifosfamide-novantrone-etoposide) NR NR NR End: 0–9months (range) after chem

2 months (median)
Persico et al., 2002 [41] 0/3 vs 0/18 0/3 vs 0/18 NR NR NR 100 mg/d Start: during chem

End: 2 months after chem
Shibolet et al., 2002 [31] NR 2/7 vs 1/4 CHOP; COP; chlorambucil; MACOP-B; MOPP; ABVD 6/7 vs 3/4 5/7 vs 3/4 150 mg/d Start: 1 to 60 days (range) before chem

15 days (mean)

End: 0.5 to 24 months (range) following initiation of chem

7 months (mean)
Tsutsumi et al., 2009 [42] NR NR Rituximab combined with chemotherapy NR NR NR NR

Comparison of HBV reactivation rate between the lamivudine prophylaxis and non-prophylaxis groups

Twelve of the fourteen included studies reported HBV reactivation, which included 222 patients in the lamivudine prophylaxis group, and 213 patients in the control group. The overall meta-analysis revealed that patients receiving prophylactic lamivudine had a statistically significant reduction in risk of HBV reactivation, after applying the random-effects model to account for the observed heterogeneity (RR = 0.25, 95% CI: 0.13–0.51,P = 0.0001; Fig. 2 A).

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Figure 2 (A) Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: HBV reactivation rate. (B) Sensitivity analysis of the study design on HBV reactivation rate.

Sensitivity analysis was performed by excluding the Pei et al. [28] study in which there was no significant difference of HBV reactivation rate between prophylaxis group and control group. The heterogeneity became small (P = 0.16,I2 = 30%). The HBV reactivation rate of lamivudine prophylaxis group was significantly reduced compared to control group with an overall pooled outcome value of 0.24 (95% CI: 0.16 to 0.36,P = 0.00001) ( Fig. 2 B). It appears that the outcome was relatively stable.

To investigate the various factors affecting the HBV reactivation rate, we applied subgroup analyses including the aspects of study design, multi/single centre, lymphoma types and rituximab use/non-use. Table 2 presents the results of subgroup analysis, where the HBV reactivation rate is mostly similar to the overall result. It is noteworthy that in the use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimens with rituximab (RCHOP) group, there was no significant reduction of the HBV reactivation rate in the prevention group, whereas the CHOP group had a significantly lower HBV reactivation rate in the prevention group.

Table 2 Subgroup analyses of the association between prophylactic lamivudine and the outcome of lymphoma patients with HBsAg-positive during chemotherapy.

Outcome Factor Level No of studies Effects model RR [95% CI] P value Heterogeneity

Q statistic (I2)
          Within subgroups Total Within subgroups Total Within subgroups Between subgroups Total
HBV reactivation Study design RCT 2 Random 0.18 [0.06, 0.50] 0.25 [0.13, 0.51] 0.001 0.0001 0.44 (0%) 0.46 (0%) 0.0005 (67%)
    Cohort 10   0.29 [0.13, 0.61]   0.001   0.001 (67%)    
  Multi/single centre Single centre 9 Random 0.19 [0.06, 0.62]   0.006   < 0.0001 (76%) 0.40 (0%)  
    Multicentre 3   0.36 [0.15, 0.83]   0.02   0.17 (44%)    
  Lymphoma NHL 8 Random 0.31 [0.15, 0.66]   0.002   0.0006 (72%) 0.21 (35.1%)  
    HL + NHL 4   0.11 [0.03, 0.46]   0.002   0.97 (0%)    
  Rituximab Use 4 Random 0.49 [0.23, 1.06]   0.07   0.01 (73%) 0.03 (79.3%)  
    Non-use 8   0.15 [0.07,0.31]   < 0.00001   1.00 (0%)    
Hepatitis Study design RCT 2 Random 0.27 [0.13, 0.56] 0.40 [0.26, 0.63] 0.0004 < 0.0001 0.83 (0%) 0.26 (20.2%) 0.06 (47%)
    Cohort 7   0.46 [0.27, 0.77]   0.003   0.07 (48%)    
  Multi/single centre Single centre 8 Random 0.44 [0.27, 0.70]   0.0006   0.08 (45%) 0.33 (0%)  
    Multicentre 1   0.26 [0.10, 0.67]   0.005   NA    
  Lymphoma NHL 5 Random 0.49 [0.28, 0.84]   0.01   0.08 (52%) 0.23 (29.9%)  
    HL + NHL 4   0.30 [0.17, 0.53]   < 0.0001   0.83 (0%)    
Hepatitis due to HBV reactivation Study design RCT 2 Random 0.13 [0.04, 0.47] 0.21 [0.09, 0.51] 0.002 0.0005 0.57 (0%) 0.48 (0%) 0.0003 (70%)
    Cohort 9   0.24 [0.09, 0.63]   0.004   0.0005 (71%)    
  Multi/single centre Single centre 10 Random 0.21 [0.08, 0.57]   0.002   0.0003 (71%) 0.74 (0%)  
    Multicentre 1   0.16 [0.04, 0.65]   0.010   NA    
  Lymphoma NHL 7 Random 0.26 [0.09, 0.72]   0.01   0.0002 (78%) 0.36 (0%)  
    HL + NHL 4   0.11 [0.03, 0.46]   0.002   0.97 (0%)    
Overall mortality Study design RCT 2 Fixed 1.19 [0.56, 2.55] 0.45 [0.29, 0.70] 0.65 0.0004 0.38 (0%) 0.005 (87.3%) 0.18 (29%)
    Cohort 7   0.30 [0.17,0.54]   < 0.0001   0.66 (0%)    
  Multi/single centre Single centre 8 Fixed 0.31 [0.17, 0.54]   < 0.0001   0.77 (0%) 0.002 (89.1%)  
    Multicentre 1   1.37 [0.62, 3.04]   0.43   NA    
  Lymphoma NHL 4 Random 0.52 [0.21, 1.27]   0.15   0.06 (60%) 0.83 (0%)  
    HL + NHL 5   0.45 [0.18, 1.10]   0.08   0.45 (0%)    
HBV-related mortality Study design RCT 2 Fixed 4.81 [0.24, 95.58] 0.41 [0.20, 0.84] 0.30 0.01 NA 0.08 (67.2%) 0.49 (0%)
    Cohort 9   0.31 [0.14, 0.68]   0.004   0.75 (0%)    
  Multi/single centre Single centre 9 Random 0.39 [0.13, 1.12]   0.08   0.68 (0%) 0.66 (0%)  
    Multicentre 2   0.80 [0.04, 18.23]   0.89   0.05 (74%)    
  Lymphoma NHL 7 Fixed 0.43 [0.21, 0.88]   0.02   0.37 (7%) 0.81 (0%)  
    HL + NHL 4   0.30 [0.02, 4.90]   0.40   NA    
  Rituximab Use 3 Fixed 0.28 [0.11, 0.71]   0.008   0.24 (30%) 0.28 (13.7%)  
    Non-use 8   0.61 [0.20, 1.86]   0.39   0.60 (0%)    
Disruption of chemotherapy Study design RCT 1 Random 0.79 [0.51, 1.24] 0.34 [0.09, 1.26] 0.31 0.11 NA 0.01 (84.8%) 0.005 (81%)
    Cohort 2   0.22 [0.09, 0.53]   0.0006   0.36 (0%)    

Comparison of the incidence of hepatitis, hepatitis due to HBV reactivation between lamivudine prophylaxis and non-prophylaxis groups

Nine of the fourteen included studies reported hepatitis. The incidence of hepatitis in patients with lamivudine prophylaxis was significantly lower than those with no prophylaxis (RR = 0.40, 95% CI: 0.26–0.63,P < 0.0001, Fig. 3 A). There was heterogeneity in the data (P = 0.06,I2 = 47%, Fig. 3 A) and the random-effects model was applied. If Lim 2007 [29] was omitted, then no statistically significant heterogeneity was identified (P = 0.28,I2 = 19%, Fig. 3 B). The overall risk estimates did not vary significantly (RR = 0.33, 95% CI: 0.23–0.47,P < 0.00001, Fig. 3 B), indicating that the outcome was relatively stable.

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Figure 3 (A) Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: the incidence of hepatitis. (B) Sensitivity analysis of the study design on the incidence of hepatitis. (C) Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: the incidence of hepatitis due to HBV reactivation. (D) Sensitivity analysis of the study design on the incidence of hepatitis due to HBV reactivation.

Eleven studies reported hepatitis due to HBV reactivation, in which the incidence of hepatitis attributable to HBV reactivation in patients with lamivudine prophylaxis was significantly lower than the incidence with no prophylaxis (RR = 0.21, 95% CI: 0.09–0.51,P = 0.0005, Fig. 3 C). There was significant heterogeneity in the data (P = 0.0003,I2 = 70%, Fig. 3 C) and the random-effects model was applied. If Pei [28] was omitted, then no statistical heterogeneity was identified (P = 0.98,I2 = 0%, Fig. 3 D). The overall risk estimates did not vary significantly (RR = 0.17, 95% CI: 0.09–0.29,P < 0.00001, Fig. 3 D). It appears that the outcome was not substantially influenced by the individual study.

To investigate the various factors affecting the incidence of hepatitis, we applied subgroup analyses including the aspects of study design, multi/single centre and lymphoma types. Table 2 presents the results of subgroup analysis, the pooled RRs were very similar to the overall RR. This result is similar to the incidence of hepatitis due to HBV reactivation.

Comparison of overall mortality, mortality attributable to HBV reactivation between lamivudine prophylaxis and non-prophylaxis groups.

Nine of eleven studies reported overall mortality, mortality attributable to HBV reactivation respectively. Patients with lamivudine prophylaxis had a statistically reduced rate in overall mortality and mortality attributable to HBV reactivation (RR = 0.45, 95% CI: 0.29–0.70,P = 0.0004, Fig. 4 A; RR = 0.41, 95% CI: 0.20–0.84,P = 0.01, Fig. 4 B). No statistically significant heterogeneity across studies was found (P = 0.18,I2 = 29%, Fig. 4 A;P = 0.49,I2 = 0%, Fig. 4 B) and the fixed effect model was used.

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Figure 4 (A) Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: overall mortality. (B) Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: mortality attributable to HBV reactivation.

To investigate the various factors affecting the overall mortality, we applied subgroup analyses including the aspects of study design, multi/single centre and lymphoma types. Table 2 presents the results of subgroup analysis and a majority of the pooled RRs were similar to the overall RR. For mortality attributable to HBV reactivation, we applied subgroup analyses to find the vast majority of the pooled RRs were similar to the overall RR. Notably, the use of RCHOP had significantly lower HBV-related mortality in the prevention group, whereas CHOP group did not have significantly lower HBV-related mortality in the prevention group ( Table 2 ).

Comparison of the incidence of chemotherapy disruption between the lamivudine prophylaxis and non-prophylaxis groups

Only three studies reported disruption of chemotherapy. There was a trend towards decreased incidence of chemotherapy disruption while on lamivudine prophylaxis. However, it did not reach statistical significance. The random-effects model calculated an RR = 0.34, 95% CI: 0.09-1.26,P = 0.11 ( Fig. 5 ).

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Figure 5 Forest plot of comparison: lamivudine prophylaxis vs no lamivudine prophylaxis, outcome: the incidence of chemotherapy disruption.

In the subgroup by study design, non-significant difference was found for RCT or cohort studies ( Table 2 ).

Discussion

Hepatitis B virus (HBV) reactivation is a well-recognized complication in HBsAg-positive cancer patients and reactivation risk differs according to the types of cancer and treatment modality. Lymphoma shows the highest incidence of HBV reactivation[6] and [43]and key elements of chemotherapy regimens for lymphoma, such as glucocorticoid and anthracycline, are known to influence HBV reactivation[44] and [45]. A 2-stage process contributes to the reactivation in HBV carriers with malignancy receiving chemotherapy [32] . First, enhancing the rate of viral replication as a result of the chemotherapy-induced immune myelosuppression may result in an increase in the number of infected hepatocytes to a number that is manifested as clinical hepatic disease[45] and [46]. HBV contains a glucocorticoid-responsive element, which is an enhancer of HBV [32] . Second, with the subsequent restoration of immune function due to the cessation of cytotoxic or immunosuppressive therapy, there is an immune-mediated destruction of the liver cells that contain the virus [47] , which is manifested clinically as various degrees of hepatitis, disruption of chemotherapy and an unfavorable prognosis (even death) in these patients[5], [23], [46], and [48].

Because hepatitis is related to HBV reactivation, the application of effective antiviral therapy to HBV (anti-HBV), such as lamivudine, has been attempted [32] . The toxicity profile of lamivudine is particularly favorable because it does not overlap with those of other antiviral agents, making this agent particularly suitable for a simultaneous use with chemotherapy [40] . Despite the use of these antiviral agent sat the time of clinical hepatitis, some HBsAg-positive patients still developed hepatic failure and died[49] and [50]. This is probably related to the late institution of the nucleoside analogues when the immune-mediated liver damage had already been established [51] . Hence, it is now generally accepted that nucleoside analogues should be administered preemptively before the onset of hepatitis due to HBV reactivation [51] .

The strategy of lamivudine prophylaxis was applied in several studies. However, several inconsistencies were found in the outcomes of HBV reactivation rates, reduction in the incidence of overall mortality, hepatitis and hepatitis due to HBV reactivation between the lamivudine prophylaxis group and the non-prophylaxis group in those studies[26], [27], [28], [30], [31], [36], [37], [38], [39], [40], [41], and [42]. Lee et al. reported that lymphoma patients with lamivudine prophylaxis had significantly less HBV reactivation and a lower overall mortality than those with no prophylaxis (9% vs 85% and 18% vs 60%) [40] . A study by Hsu et al. showed that in the lamivudine prophylaxis group, there were significantly fewer incidences of HBV reactivation and hepatitis than in the non-prophylaxis group (11.5% vs 56% and 15.4% vs 60%), with no significant difference in chemotherapy disruptions and overall mortality between the two groups [37] . Moreover, recently a retrospective cohort study suggested that the HBV reactivation rates and incidence of hepatitis due to HBV reactivation were not statistically different between the groups, even though an elevatory trend was seen with mortality attributable to HBV reactivation in the lamivudine prophylaxis group [28] .

However, previous systematic evaluation of the relationship between lamivudine prophylaxis and the outcome of HBsAg-positive patients with lymphoma undergoing chemotherapy is still limited [28] . First, previous studies did not assess and evaluate the quality of the available evidence, which is very important for clinical decision-making. Second, previous studies failed to assess the relationship between lamivudine prophylaxis and overall hepatitis, hepatitis due to HBV reactivation, overall mortality or chemotherapy disruption for lymphoma patients who test positive for HBsAg and are undergoing chemotherapy. Third, methodologically high quality controlled clinical trials were sparse for this preventive lamivudine intervention. Therefore, more research is necessary to determine whether lamivudine prophylaxis treatment improves the outcomes.

Thus, to address these issues, we conducted a study to investigate the relationship between prophylactic lamivudine and the outcome of lymphoma patients who are HBsAg-positive during chemotherapy, including the recent publications. The current meta-analysis demonstrates that prophylactic lamivudine is effective in reducing the rates of HBV reactivation, hepatitis and reactivation-related hepatitis occurrence, overall mortality and reactivation-related liver mortality in lymphoma patients who are HBsAg-positive during chemotherapy. Moreover, our results suggest that prophylactic lamivudine may be helpful in reducing the incidence of chemotherapy disruption. It is therefore important to deal with the clinical problem to get the maximum potential benefit from chemotherapy.

An important limitation to the use of lamivudine is the potential emergence of lamivudine-resistant HBV strains, so-called “YMDD mutations”, which can be associated with biochemical and clinical flares [52] . Some of the included studies examined this issue, in HBsAg-positive lymphoma patients during chemotherapy, the risk of developing resistance to lamivudine increased with the duration of lamivudine therapy up to 40% after 16 months [28] , others reported very low numbers of resistance[33] and [37]. This antiviral agent should therefore be cautiously administered, especially in those who require extended periods of chemotherapy [53] . Recently, newer nucleoside analogues, such as adefovir, entecavir, tenofovir, and telbivudine, have been approved for the treatment of chronic hepatitis B and have demonstrated sustained treatment efficacy. Some of these analogues have low rates of viral resistance [54] . A study of a small-case series, for example, demonstrated that entecavir was effective in preventing HBV reactivation in cancer patients [55] . Unfortunately, large prospective randomized trials on the prophylactic use of these antiviral agents in lymphoma patients undergoing chemotherapy have been largely lacking. Further studies are needed to clarify the role of antiviral agent prophylaxis in different cancer patients undergoing chemotherapy with HBV infection.

In addition, average annual cost of lamivudine is 117 (U$), entecavir 1266 (U$), adefovir 1246 (U$), tenofovir 763 (U$), telbivudine 4976 (U$) [56] . Furthermore, total expenditure on health and per capita health expenditure in developed countries is much higher than in under-developed countries. Simultaneously, the costs associated with cancer therapy, particularly oral therapies, continue to increase [57] . Therefore, considering the cost, lamivudine as a standard care in under-developed countries is a rational choice.

Ultimately, in our present study, we find that the use of RCHOP did not have significant reduction of the HBV reactivation rate in the prevention group, whereas the CHOP group had significantly lower HBV reactivation rate in the prevention group. But, surprisingly, the use of RCHOP had significantly lower HBV-related mortality in the prevention group, whereas CHOP group did not have significantly lower HBV-related mortality in the prevention group. It has been reported that the increasing use of rituximab may be associated with more frequent HBV reactivation and higher morbidity and mortality of HBV reactivation in HbsAg-positive lymphoma patients[27], [28], and [58]. However, several inconsistencies were found in another study. Xie et al. reported that an RCHOP regimen had no greater risk of HBV reactivation compared with a CHOP regimen when combined with a lamivudine antiviral treatment and RCHOP has an advantage over CHOP on the overall survival (OS) rate [59] . In rituximab-containing chemotherapy, the effectiveness of lamivudine prophylaxis and the role of rituximab need further study.

In conclusion, prophylactic therapy with lamivudine for HBsAg-positive lymphoma patients who are undergoing chemotherapy may reduce the risk for HBV reactivation, hepatitis, and hepatitis due to HBV reactivation, overall mortality and mortality attributable to HBV reactivation. Meanwhile, patients with lamivudine prophylaxis had a trend towards decreased the incidence of chemotherapy disruption. However, further study is needed to elucidate the exact role of lamivudine and other antiviral agents in prophylactic therapy and to determine the outcomes of this prophylaxis for patients undergoing chemotherapy containing rituximab.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments

This research was supported by the National Natural Science Foundation of China (81171560, 30930082, 81171561, 30972584), the National Science and Technology Major Project of China (2008ZX10002-006, 2012ZX1002007001, 2011ZX09302005, 2012ZX09303001-001, 2012ZX10002003), The National High Technology Research and Development Program of China (2011AA020111), the Key Project of Chongqing Science and Technology Commission (cstc2012gg-yyjsB10007), the Chongqing Natural Science Foundation (cstc2011jjA10025), the Medical Research Fund by Chongqing Municipal Health Bureau (2009-1-71).

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Footnotes

a Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, 76, Linjiang Road, 400010 Chongqing, China

b Institute for Viral Hepatitis of Chongqing Medical University, Chongqing, China

c Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China

d Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

lowast Corresponding author. Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, 76, Linjiang Road, 400010 Chongqing, China. Tel.: +86 23 63726663; fax: +86 23 63711527.

1 These authors contributed equally to this work.