Entecavir is Safe and Effective in Long Term for the Treatment of Hepatitis B in Immunocompromised Children

Abstract

Objective

Hepatitis B infection is common in patients with cancer, and prompt treatment is necessary; otherwise, it can result in life-threatening complications. The objective of this study was to assess the long-term safety and efficacy of entecavir in immunocompromised children with hepatitis B.

Methods

This single-center prospective study was conducted on children with different malignancies referred to our department with evidence of hepatitis B infection. Only those children were included in the study who had HBsAg positive and alanine aminotransferase (ALT) more than 2 times the upper limit of normal and whose hepatitis B virus (HBV) DNA was more than 20,000IU/ml. These children were put on entecavir and prospectively observed upto 192 weeks. Primary efficacy end point was the proportion of patients who achieved undetectable HBV DNA at 48 weeks of treatment. Other efficacy end points were the proportion of patients with HBeAg seroconversion, undetectable HBV DNA, and ALT normalization at weeks 48 and 96 weeks.

Results

A total of 41 children met the inclusion criteria, of which 5 children died because of malignancy and 5 were lost to follow-up. Mean log DNA was 7.67 at the start which after starting entecavir reduced to 4.1, 2.8, 1.19, 1.09, and 0.84 at 12, 24, 48, 72, and 96 weeks, respectively (P value < 0.0001). Mean ALT decreased from 332.5 which reduced to 190, 115, 63, and 46 at 4, 12, 24, and 48 weeks, respectively (P < 0.0001). 67.7% achieved the primary outcome and had undetectable DNA at 48 weeks which increased to 26 (83.9%) at 96 weeks. At 48 weeks, 80.6% patients achieved ALT normalization. Thirty percent developed HBeAg seroconversion. Two patients developed virological breakthrough, one at 96 weeks and another at 192 weeks. No significant adverse effects were observed.

Conclusion

Entecavir is safe and effective in long term for the treatment of hepatitis B in immunocompromised children.

Hepatitis B virus (HBV) infection is a major public health problem throughout the world with more than 2 billion infected individuals.¹ India is an intermediate to high endemicity zone for HBV with prevalence ranging from 2 to 10%.² Hepatitis B in children is usually acquired through perinatal transmission or during early childhood, resulting in chronic infection in 90% if infection occurs in infancy, 30% if infection occurs during first 5 years of life, and <5% when infection occurs in adults.³ Chronic hepatitis B (CHB) in children usually has a benign course, but still around 3–5% and 0.01–0.03% of children develop long-term complications like cirrhosis or hepatocellular carcinoma (HCC), respectively, before adulthood.^{4, 5, 6, 7} Besides, there is 9–24% lifetime risk of CHB-related HCC.⁴ Patients with cancer have higher prevalence of hepatitis B infection and also have increased risk of development of reactivation of hepatitis B.^{8, 9, 10} In children with cancer, particularly hematological malignancies, there is higher prevalence of both occult and overt HBV infection.^{11, 12, 13, 14} In children, who are receiving immunosuppressant drugs, hepatitis B infection can present as asymptomatic transaminitis, acute hepatitis, acute fulminant hepatitis Hepatitis B virus reactivation (HBVR) which can be life threatening.¹⁵ Besides, it can cause delay and/or interruption in chemotherapy (CT), which may result in progression/relapse of underlying malignancy.¹⁵ Hence, there is a need to start potent antiviral drug as soon as HBV infection is diagnosed in such patients so as to prevent hepatitis-related complications and also to restart CT quickly. In children, there is paucity of literature regarding HBVR, and there are no guidelines about HBVR in children.

In children (2–16 years), interferon, lamivudine, and recently entecavir have been approved for treatment of hepatitis B.¹⁶ Lamivudine is safe in children, but long-term efficacy is much lesser and resistance was higher than entecavir.^{17, 18} Tenofovir is effective but has safety concerns and is not yet approved for children.^{19, 20, 21} There is only one large randomized controlled study in children from 2 to 16 years which documents the efficacy and safety of entecavir.²² But there are very few small studies in immunocompromised adults, which show efficacy of entecavir in such patients and none in children. We started this study in immunocompromised children (1–16 years) with HBV infection, with the aim of documenting efficacy and safety of entecavir in them.

Material And Methods

This single-center prospective study was carried out at the Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, from October 2012 to July 2015. This study was approved by a local ethical committee. Children (less than 16 years) with different malignancies and evidence of hepatitis B infection were referred to our department from the Department of Medical Oncology and Hemato-oncology. After taking an informed consent from parents and/or guardians, all the records of patients were analyzed and the details were entered in a proforma. Only those children were included in the study who had HBsAg positive and alanine aminotransferase (ALT) more than 2 times the upper limit of normal and whose HBV DNA was more than 20,000IU/ml. All these children were put on entecavir. Entecavir was given at a dosage of 0.015 mg/kg once daily upto maximum of 0.5 mg/day.²³. These patients were then followed up closely to look for the response to the entecavir and adverse drug effects (if any). After taking detailed history and physical examination, baseline investigations including complete blood count, kidney function test, liver function test, uric acid, pH, electrolytes, coagulogram, lactic acid, and USG abdomen were performed. Besides hepatitis serology for A, B, C, D, E, and HIV, all hepatitis B viral markers were screened including HBsAg, HBeAg, Anti-HBe, IgM anticore, total anticore, and HBV DNA level (performed by polymerase chain reaction; Roche COBAS TaqMan HPS assay; Roche Diagnostics); the lower limit of detection was 50 IU/ml. The primary end point was the proportion of patients who achieved undetectable HBV DNA at week 48 of treatment. Other efficacy end points were the proportion of patients with HBsAg seroconversion and ALT normalization at weeks 48 and 96 weeks. Any adverse event reported by the patients was recorded. Patients were followed upto 192 weeks to look for safety and virological or biochemical rebound.

Statistical Analysis

Data were collected and managed by using statistical software programs (SPSS version 20.0, SPSS Inc.). Mean log DNA and ALT were compared at different stages of treatment using repeated measures analysis of variance. A P value < 0.05 was considered significant.

Results

Fifty children with different malignancies with evidence of hepatitis B were referred from the Department of Medical Oncology and Hemato-Oncology. Only 41 children met the inclusion criteria. Of 41, 32 (78%) were in the age group of 1–12 years and 9 (22%) were in the age group of 12–16 years. Mean age was 9.63 years with the youngest being 1 year and the oldest being 16 years. Majority of the children (87.8%) were suffering from hematological malignancies like acute lymphoid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and multiple myeloma (Table 1). Twenty-six (63.4%) patients were males, and fifteen (36.6%) were females. Twenty-seven (65.9%) were HBeAg positive, and 14 (34.1%) were HBeAg negative. Majority (78.05%) of the patients had asymptomatic transaminitis, and only 21.9% patients had symptoms like fatigue, jaundice, nausea, vomiting, and anorexia. In 10 patients (24.4%), CT was stopped or delayed as the symptoms/transaminitis was observed during CT. In rest of the patients (75.6%), HBV was diagnosed after CT or in between the cycles. Of 10 patients in whom CT was stopped or delayed, 2 patients died because of the underlying malignancy in comparison to 3 deaths in whom CT was not affected (P = 0.58). On follow-up, 5 children died because of malignancy and 5 were lost to follow-up. Mean log DNA was 7.67 at the start which after starting entecavir reduced to 4.1, 2.8, 1.19, 1.09, and 0.84 at 12, 24, 48, 72, and 96 weeks, respectively (P value < 0.0001) as shown in Figure 1. Mean ALT decreased from 332.5 which reduced to 190, 115, 63, and 46 at 4, 12, 24, and 48 weeks, respectively (P < 0.0001)[Table 3]. Of 31 patients who completed the study, 21 patients (67.7%) achieved the primary outcome and had undetectable DNA at 48 weeks which increased to 26 (83.9%) at 96 weeks and 28 (90.32) at 192 weeks. At 48 weeks, 25 (80.6%) patients achieved ALT normalization which increased to 29 (93.5%) at 96 weeks (Table 2). Of 20 HBeAg-positive patients who completed the study, 6 (30%) developed HBeAg seroconversion at 48 weeks which increased to 10 (50%) at 96 weeks and 13 (65%) at 192 weeks. At 48 weeks, 8 patients (25.8%) also lost HBsAg but only 3 of them achieved seroconversion at 96 weeks (9.6%) which increased to 5 at 192 weeks (16.1%; Figure 2). Two patients developed virological breakthrough, one at 96 weeks and another at 192 weeks. One patient developed hepatitis C virus coinfection at 3 years. Five patients reported minor side effects like nausea, vomiting, and anorexia. No serious adverse event was reported by any of the patients, and drug was not stopped because of any adverse drug reaction (ADR).

Table 1.

Underlying Malignancies in Children With Hepatitis B.

Malignancy	Number	Percent
Acute lymphocytic leukemia	29	70.7
Acute myelocytic leukemia	2	4.9
Aplastic anemia	1	2.4
Ewing Sarcoma	1	2.4
Non-Hodgkin's lymphoma	4	9.8
Retinoblastoma	1	2.4
Sarcoma	1	2.4
Wilms' tumor	2	4.9
Total	41	100.0

Figure 1.

Graph showing significant drop in mean log₁₀ HBV DNA at 3, 6, 12, 18, and 24 months. HBV, hepatitis B virus.

Table 3.

Mean Change in HBV DNA and ALT after Start of Entecavir at 48 and 96 Weeks.

Parameter	At 48 weeks	At 96 weeks
Mean change in ALT from BL (P value)	−269 (P < 0.0001)	−286 (P < 0.0001)
Mean change in HBV DNA from BL in log10IU/ml (P value)	−6.48 (P < 0.0001)	−6.83 (P < 0.0001)

HBV, hepatitis B virus; ALT, alanine aminotransferase, BL=Baseline.

Table 2.

Efficacy Outcomes at Week 48 and 96 (Overall Cohort, N = 41).

Efficacy end point	Week 48	Week 96
Undetectable HBV DNA N (%)	21 (67.7%)	26 (83.87%)
ALT normalization N(%)	25 (80.6%)	29 (93.5%)

HBV, hepatitis B virus; ALT, alanine aminotransferase.

Figure 2.

Stagewise outcome at 48, 96, and 192 weeks of entecavir therapy. ALT, alanine aminotransferase.

Discussion

The prevalence of both overt and occult HBV infection in patients with cancer including both children and adults is higher than that in general population as seen in multiple studies.^{8, 9, 10, 11, 12, 13} In children, hematological malignancies are more common than solid malignancies as is seen in our study also. These patients need polychemotherapy resulting in extreme immunosuppression and usually require multiple blood transfusions and platelet transfusions which may predispose them to acquire hepatitis B because of the presence of occult hepatitis B in donors.^{14, 24} The best way to prevent hepatitis B in children is effective vaccination, but in our study, only 3 patients (7.3%) were vaccinated for hepatitis B before CT. Vaccination against HBV in patients with cancer before CT is not practiced uniformly among medical oncologists. The reason may be that the studies on active or passive immune prophylaxis against HBV in cancer patients receiving CT have shown varied efficacy.^{25, 26, 27} In some studies, escalated regimen in the form of accelerated, multiple, double-dose hepatitis B vaccine has shown better efficacy than conventional vaccine in cancer patients receiving CT.^{26, 27}

In our study, baseline screening for HBsAg was performed only in 17 patients (41.4%), and none of the patients was screened for total Anti-HBc. Problem of not screening for HBV markers in all patients with malignancy exists in other parts of the world.^{28, 29} Reasons may be unawareness and unwillingness of the clinicians and other health-care personnel dealing with patients with cancer and controversial literature about the cost-effectiveness of screening.³⁰ All latest hepatitis B guidelines including AASLD 2018,³¹ EASL 2017,³² and INASL 2018³³ now suggest routine screening of HBsAg and anti-HBc in patients opting for CT. We observed that entecavir was very effective in decreasing HBV DNA in almost all patients, resulting in biochemical recovery of these patients. Liver disease did not progress in any patient after starting entecavir, and CT could be restarted quickly, and there was no hepatitis B–related mortality. After 48 weeks of entecavir therapy, HBV DNA was undetectable in 67.7% of patients which increased to 83.9% after 96 weeks. This is almost similar to what has been observed in previous studies in immunocompetent adults. But in the pediatric study by Jonas et al.,¹⁷ HBV was undetectable in 49.2% at 48 weeks, which is lower than our study. The reason may be that baseline HBV DNA was lower in our study (7.67 vs 8.14). In adult and pediatric studies, it has been seen that the baseline HBV DNA is one of the predictors of virological response.^{34, 35} If we compare the children where baseline HBV DNA was less than 8 log₁₀ IU/ml in the same study, the virological response rate was higher (83%) than in our study.¹⁷ This could be explained by higher baseline ALT in our study (332.5 vs 107.1), which has also been shown a predictor of virological response to NUC (nucleotide/nucleoside analog) therapy in adult studies.³⁵ At 48 weeks, ALT normalization was seen in 80.6% where as in study by Jonas et al., ALT normalization was 67.5%.¹⁷ This difference in our patients may be due to rapid spontaneous immunological recovery after stopping CT. Baseline ALT was higher in our study because many patients might have HBVR and concomitant drug-induced liver injury because of chemotherapeutic agents. Of 20 HBeAg-positive patients who completed the study, 6 (30%) developed HBeAg seroconversion at 48 weeks. This is almost similar to what was observed by Jonas et al.¹⁷ (24.2%) in immunocompetent children. Virological breakthrough was observed in 2 patients after 192 weeks of follow-up (6.4%), but resistance testing was not performed. In pediatric study by Jonas et al.¹⁷, virological breakthrough was observed in 2.5% at 1 year and 11.6% at 2 years.

We observed that entecavir was very safe with few side effects and no serious ADR. No patient needed to stop the entecavir because of side effects. Similar observations have been made in both pediatric and adult studies.

There are many drawbacks in our study. The major drawback is the small number of patients. Another drawback is that our group of patients is heterogenous containing both HBeAg-positive and HBeAg-negative CHB. So we need to reproduce the aforementioned findings in the larger multicenter placebo-controlled randomized trials.

We conclude that in immunocompromised children with hepatitis B, entecavir is as effective and safe as in immunocompetent children and adults and should be the first-line antiviral drug to be used in such patients. However, the priority should be to prevent HBV infection in all malignancy patients rather than to treat them and that is possible by regular hepatitis B screening before going for CT as per the guidelines and by effective vaccination.

Conflicts of interest

The authors have none to declare.