HBV Reactivation during Direct-Acting Antiviral Therapy in Hepatitis B and C Coinfected Patients Undergoing Haemodialysis

Abstract

Background

There have been increasing reports of HBV reactivation in HBV and HCV coinfected patients with direct-acting antiviral (DAA) treatment. The potential risk of HBV reactivation in patients undergoing haemodialysis has also been noted. There is a lack of data pertaining to the reactivation risk during DAA treatment in those coinfected patients with end-stage renal disease who are undergoing haemodialysis.

Methods

HBV–HCV-coinfected patients were screened from 178 persons at two blood purification centres in China and received sofosbuvir (200 mg) combined with daclatasvir (60 mg) daily. The risk and pattern of HBV reactivation during DAA treatment was retrospectively analysed.

Results

HBV reactivation occurred in 45.5% (5/11) of the HBV–HCV-coinfected patients undergoing haemodialysis during DAA treatment, which was much higher than the reported rates in the general population of coinfected patients. Five patients with HBV reactivation were all positive for hepatitis B surface antigen (HBsAg) before DAA treatment. Three patients (27.3%) had mild hepatitis fares due to HBV reactivation, but no patients had severe hepatitis or hepatic failure. Compared with the four patients who were HBsAg- at the baseline, the risk of HBV reactivation in HBsAg+ patients was greater (71.4% versus 0; c²=5.238; P=0.061), although the difference was not statistically significant.

Conclusions

A significant proportion of HBV–HCV-coinfected patients undergoing haemodialysis developed HBV reactivation after DAA therapy. The risk of HBV reactivation was greater in HBsAg+ patients than in those patients who were HBsAg- but anti-HBc+ or HBV DNA+.

Introduction

Coinfection with both HBV and HCV is common worldwide due to the shared routes of transmission [1]; the coinfection rate has been estimated to be as high as 7–15% [2,3]. In general, HBV–HCV coinfection is likely to be HCV-dominant, with high HCV RNA loads and low HBV DNA loads. However, with the new information regarding the risk of HBV reactivation in anti-HCV treatment, monitoring and treatment for HBV has been an option for patients with reactivation [4].

The efficacy of interferon (IFN)-based treatment for HCV-monoinfected and HBV–HCV-coinfected patients has been established [5,6], but HBV reactivation has been reported in HCV-coinfected patients treated with IFN [7,8]. Yalcin et al. [9] reported a case with the reactivation of HBV and a severe hepatitis fare during combination therapy with IFN and ribavirin [9]. Viganò et al. [8] reported 14% (3/21) of HBV–HCV-coinfected patients had their serum HBV DNA loads increase >1 log₁₀ copies/ml during IFN and ribavirin treatment [8]. Recently, the treatment of chronic HCV has been revolutionized by the advent of direct-acting antivirals (DAAs) [10]. Compared with IFN-based therapy, DAA treatment is associated with rarer side effects and higher sustained virological response, and it is also recommended for HBV–HCV coinfection [11,12]. However, it has recently been noted that HBV reactivation occurs in coinfected patients during DAA treatment. Following a series of case reports, the US Food and Drug Administration has identified 24 cases of HBV reactivation in coinfected patients treated with DAAs from November 2013 to July 2016 [13–15]. Chen et al. [16] reviewed 909 HBV–HCV-coinfected patients and indicated that the HBV reactivation rate was 12.2% in hepatitis B surface antigen (HBsAg)+ patients treated with pan-oral DAAs. Compared with IFN-based therapy, DAA treatment resulted in HBV reactivation occurring earlier and becoming more clinically significant, and a similar situation was observed in those HBsAg- and anti-HBc+ patients with chronic hepatitis C infection [16].

Recently, HBV reactivation has also required careful attention in patients with immune dysfunction, those patients undergoing conditioning therapy for stem-cell transplantation, doxorubicin-based chemotherapy or high-dose prednisone treatment are all at moderate to high risk of HBV reactivation [4]. Haemodialysis treatment is related to immune dysfunction of patients with chronic kidney disease. Li Cavoli et al. [17] reported a case undergoing haemodialysis treatment who had HBV reactivation. Wahle et al. [2] observed HBV reactivation in 6/10 haemodialysis cases with HBV–HCV coinfection during IFN treatment. Theoretically, those HBV–HCV-coinfected patients undergoing chronic haemodialysis treatment have more risk factors for HBV reactivation and should be at higher risk for it during DAA treatment, but there is a lack of data pertaining to the reactivation risk in this special population.

In January 2016, an epidemic nosocomial outbreak of HCV infection occurred in two blood purification centres of China, and most patients received DAA agents during the process of public health control. Hence, we retrospectively analysed the risk of HBV reactivation during sofosbuvir combined with daclatasvir treatment in HBV–HCV-coinfected patients with end-stage renal disease who were undergoing haemodialysis to facilitate a better understanding of the potential risk of HBV reactivation during DAA treatment in HCV–HBV-coinfected patients undergoing haemodialysis.

Methods

Patients and data collection

An epidemic nosocomial outbreak of HCV infection in patients undergoing haemodialysis occurred in two blood purification centres in Zhen'an County, Shaanxi Province, China. All the patients undergoing haemodialysis in these centres and their close household contacts, as well as the medical staff, were screened for HCV infection. The local government and hospital administration provided DAA treatment for most patients with HCV infection due to intolerances to IFN and ribavirin treatment. Several patients were found to have HBV coinfection before treatment. To analyse the risk of HBV reactivation during DAA treatment in these coinfected patients undergoing haemodialysis, the current retrospective study was conducted. The study protocol was approved by the ethics committee of the First Affiliated Hospital of Xi'an Jiaotong University. The study inclusion criteria were as follows: patients older than 18 years old; patients with chronic kidney disease requiring haemodialysis (estimated glomerular filtration rate <15 ml/min/173 cm²); patients with HCV infections; patients receiving DAA treatment; patients positive for HBsAg, anti-HBc or HBV DNA for more than 6 months. The primary exclusion criterion was the administration of anti-HBV agents during DAA therapy. As shown in Figure 1, 11 patients were screened out of 178 persons, and they received a half dose of sofosbuvir (200 mg daily) after haemodialysis and a full dose of daclatasvir (60 mg daily) for 24 weeks. The protocol dose of sofosbuvir 200 mg daily was achieved by splitting the 400-mg tablet into two portions, with each portion ingested on consecutive days. The patients with HBV reactivation received entecavir (0.5 mg daily) at the end of DAA treatment.

Figure 1

Flow chart of the patients enrolled in the study

The patient characteristics were collected from electronic databases and hand copies of medical records. FibroScan was used to determine the fibrosis stage at baseline. The blood samples were collected before haemodialysis to obtain baseline laboratory values of liver function (alanine transaminase [ALT], aspartate aminotransferase, total bilirubin [TBil]), renal function (serum creatinine, blood urea nitrogen), HBV markers (HBsAg, anti-HBs, hepatitis B e antigen [HBeAg], anti-HBe and anti-HBc) and HCV RNA load, and measured every 4 weeks during DAA treatments. HBV DNA load was measured at the baseline and the termination of the treatment.

Definition of HBV reactivation

HBV reactivation was defined as one of the following: for patients who were HBsAg+ and HBV DNA+, there was an abrupt increase in HBV replication, defined as >1 log₁₀ IU/ml increase in HBV DNA levels; for patients who were HBsAg+ and HBV DNA-, the HBV DNA load became detectable; for patients who were negative for HBsAg but positive for anti-HBc or HBV DNA, HBsAg and the HBV DNA load became detectable or the HBV DNA had a more than 1 log₁₀ IU/ml increase [16,18,19].

Laboratory testing

HCV RNA was estimated by quantitative real-time PCR assay using the COBAS^® Ampliprep/Cobas^® TaqMan^® HCV test, with a lower limit of 15 IU/ml. The HCV genotypes were determined using a genotyping kit (Triplex International Biosciences [China] Co., Ltd, Xiamen, China) and confirmed via sequence analysis targeting NS5B and C1/E. HBV DNA load was measured by a real-time PCR-based Roche COBAS® AmpliPrep/ COBAS® TaqMan® HBV test (lower limit of the dynamic range: 12-1.7x10⁸ IU/ml; Roche Molecular Systems, Branchburg, NJ, USA). HBV serum markers (HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc) were tested by enzyme-linked immunosorbent assay (ELISA; Kehua Co., Shanghai, China). Liver function and renal function tests were performed with an automated bioanalyzer (Olympus AU5400, Tokyo, Japan). The FibroScan fibrosis stage cutoff was 9.5 kPa (<9.5 kPa, F0-F2; >9.5 kPa, F3-F4).

Statistical analysis

Data were analysed statistically with SPSS 13.0 (SPSS, Inc., Chicago, IL, USA). Descriptive analysis was conducted (that is, calculations of medians, averages, proportions or rates). Fisher's exact test was used for the comparison of rates. The significance level was set at P<0.05.

Results

Population characteristics

As shown in Methods, 11 patients who were HBsAg+, anti-HBc+ or HBV DNA+ were enrolled out of the 33 identified HCV-coinfected patients with end-stage renal disease requiring haemodialysis (Figure 1). The demographics and baseline characteristics of the 11 enrolled subjects are summarized in Table 1. None of them had histories of alcohol consumption, drug use or herb intake. Based on ultrasonography and liver stiffness measurements, 3 of the 11 subjects had hepatic cirrhosis. Before receiving DAA agents, two patients had anti-HBV treatment (α-2b IFN) for approximately 4 months and discontinued due to adverse events. At the baseline, 5 of the 11 patients had elevated ALT levels (above 40 U/l), and among those patients, 1 had an ALT level more than 5x upper limit of normal (ULN; 696.5 U/l) and 1 had an ALT >2xULN (133.1 U/l). Before DAA treatment, 11 patients had a definite history of HBV infection, 7 (63.6%) were HBsAg+, 2 were HBeAg+. Among the 11 patients, 6 (54.6%) had undetectable HBV DNA loads, and 5 (45.5%) had positive HBV DNA levels. Of the latter five, two patients had HBV DNA loads greater than 100 IU/ml (453.0 IU/ml and 5,880.0 IU/ml, respectively).

Table 1

The demographics and baseline characteristics of the study subjects

Variable (n=11)	Value
Age, years^a	61 (25–73)
Male gender, n (%)	9 (81.82)
BMI, kg/m^2a	22.04 (19.15–26.04)
HD duration, months^a	20 (8–48)
History of alcohol consumption, n (%)	0 (0)
Previous anti-HBV therapy, n (%)	2 (18.18)
HCV genotype
1b, n (%)	3 (27.27)
2a, n (%)	8 (72.73)
LSM, Kpa^a	8 (2.6–14.7)
ALT, U/l^a	44.41 (20.00–636.52)
TBil, mmol/l^a	9.53 (3.00–25.23)
eGFR, ml/min/1.73 m^2a	8 (5–14)
eGFR <10 ml/min/1.73 m², n (%)	6 (54.55)
HCV RNA load, log₁₀ IU/ml^a	7.11 (5.44–7.55)
HBsAg+, n (%)	7 (63.64)
HBeAg+, n (%)	2 (18.18)
Anti-HBc+, n (%)	7 (63.64)
HBV DNA load, log₁₀ IU/ml
Negative, n (%)	6 (54.55)
Detectable–2, n (%)	3 (27.27)
2–4, n (%)	2 (18.18)

The values are expressed as the median (range). ALT, alanine transaminase; anti-HBc, hepatitis B core antibody; BMI, body mass index; eGFR, estimated glomerular filtration rate; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HD, haemodialysis; LSM, liver stiffness measurement; TBil, total bilirubin.

HBV Reactivation during DAA Treatment

HBV reactivation occurred in 45.5% (5/11) of the HBV–HCV-coinfected patients undergoing haemodialysis during DAA treatment, which was much higher than the reported rate (approximately 12%) in coinfected patients not undergoing haemodialysis [16].

As shown in Figure 2, seven subjects were positive for HBsAg before receiving sofosbuvir and daclatasvir, and two of those seven HBsAg+ patients were HBV DNA+ at baseline and had increased HBV DNA levels during DAA treatment (1.03 and 1.94 log₁₀ IU/ml, respectively). Five patients were HBsAg+ and HBV DNA-before DAA treatment, and three of those five patients had increased HBV DNA levels during treatment, and two were always HBsAg+ and HBV DNA- during the whole process of DAA treatment. Four patients were negative for HBsAg at the baseline, and all of them were persistently HBsAg-, with none experiencing elevated HBV DNA levels during DAA treatment. The HBV reactivation rate of the patients who were HBsAg+ at the baseline was 71.4% (5/7), in contrast to the four patients who were HBsAg- at the baseline, of whom none experienced HBV reactivation during DAA treatment. However, this difference was not statistically significant (71.4% versus 0; χ²=5.238; P=0.061).

Figure 2

HBV reactivation during DAA treatment in 11 HBV–HCV-coinfected patients undergoing haemodialysis

Dynamic changes of HBV DNA load, ALT and TBil levels in the process of HBV reactivation

As showed before, 5 of the 11 patients experienced HBV reactivation, all of whom were HBsAg+ at the baseline and had significant increases in HBV DNA load after DAA treatment (Figure 3A). Compared with the levels of HBV DNA before DAA treatment, HBV DNA load increased by a mean of 5.04 ±3.41 log₁₀ IU/ml (range: 1.03 log₁₀ IU/ml to more than 8.23 log₁₀ IU/ml) after the treatment.

Compared with the baseline, DAA treatments resulted in a quick decrease in the HCV RNA load in all the patients; HCV RNA was undetectable at weeks 4, 8 and 12 in 7 (63.6%), 10 (90.9%) and 11 (100.0%) patients, respectively. With the HCV RNA load inhibition, the levels of ALT and TBil declined to normal rapidly. To exclude the effect of HCV infection on ALT and TBil levels as much as possible, Figure 3B and 3C show the dynamic changes of ALT and TBil levels after HCV RNA became undetectable. During DAA treatment, three patients with HBV reactivation had mildly elevated ALT levels (45.9 U/l, 54.0 U/l and 63.7 U/l, respectively) and one had an elevated TBil level (29.8 mmol/l), and most patients without HBV reactivation had normal levels of ALT and TBil throughout the whole course of DAA treatment.

Figure 3

Dynamic changes in HBV DNA load, ALT and TBil levels in the process of HBV reactivation

During the DAA treatment, 27.3% (3/11) of patients had ALT fares. Although none of the 11 patients had severe hepatitis, hepatic failure or icteric hepatitis due to HBV reactivation, 3 out of the 5 (60%) patients with HBV reactivation had mild hepatitis, whereas none of the 6 patients without HBV reactivation developed hepatitis. In this study, one patient died due to a pulmonary infection; he had an undetectable HCV RNA load after 4 weeks of DAA treatment and normal ALT and TBil levels throughout the treatment.

Discussion

No published reports have evaluated the risk of HBV reactivation during DAA treatment in HBV and HCV coinfected patients with end-stage renal disease who are undergoing haemodialysis. In 2016, an epidemic nosocomial outbreak of HCV infection occurred in two blood purification centres of China, and due to intolerances to IFN and ribavirin treatment, most patients involved in this incident received sofosbuvir (200 mg daily) and daclatasvir (60 mg daily) during the process of public health control. To assess the risk of HBV reactivation in this special population, this current study analysed the risk and mode of HBV reactivation and considered hepatitis fare due to HBV reactivation in these coinfected patients undergoing haemodialysis.

Previous studies reported that the rate of HBV reactivation during DAA therapy in the general chronic HBV and HCV coinfected patient population ranged from 0% to 30% [19–24]. Chen et al. [16] reviewed 28 reported studies up to 21 September 2016 and indicated that the reactivation rate was 12.2% in the patients with HBV and HCV coinfection. Our results showed the HBV reactivation rate during DAA treatment was 45.5% (5/11) in HBV–HCV-coinfected patients undergoing haemodialysis, which was much higher than the reported rates in the general coinfected population of patients. The haemodialysis treatment may be another HBV reactivation risk factor for coinfected patients. HBV reactivation has been observed in patients with haemodialysis treatment [2,17]. In addition, via a mechanism related to both uraemic toxins and the haemodialysis treatment process, patients with chronic kidney disease show immune system dysfunction. In this study, these patients had more risk factors, including receiving DAA therapy, having end-stage renal disease and undergoing haemodialysis, which may lead to an increase in their susceptibility to HBV reactivation. Therefore, it is crucial for this special population to be screened for evidence of HBV infection and monitored closely during DAA therapy.

The risk of HBV reactivation depends upon the initial HBV serostatus. In this study, the five patients with HBV reactivation were all positive for HBsAg before DAA treatment. The HBV reactivation rate of HBsAg+ patients was 71.4% (5/7). Doi et al. [25] reported 2 patients out of 4 patients (50%) positive for HBsAg and 3 out of 143 (2.1%) negative for HBsAg at baseline presented HBV reactivation under DAA treatment. In the current study, our data showed much higher risk of HBV reactivation in those HBsAg+ and HBV–HCV-coinfected patients undergoing haemodialysis, while the reactivation rate of HBsAg- patients was 0 (0/4), indicating that HBsAg+ patients undergoing haemodialysis were at higher risk of HBV reactivation during DAA treatment. However, it does not imply that it is risk-free for the patients who are HBsAg- but anti-HBc+ or HBV DNA+. In this study, the number of patients with anti-HBc+ alone or HBV DNA+ alone was small (only four patients), and the HBV DNA levels were extremely low (<20 IU/ml but detectable) in the three subjects with HBsAg- and HBV DNA+; consequently, it was not unexpected that no HBV reactivation was observed in the four patients who were only anti-HBc+ or only HBV DNA+. In practice, the risk of reactivation is low but not always zero. Previous studies have shown HBV reactivation rates ranging from 0 to 6.1% in patients who were anti-HBc+ alone, which was lower than the rate in HBsAg+ patients [3,19,21–23]. HBV reactivation can occur in patients with varying HBV serostatuses, whereas compared to the patients who were only anti-HBc+ or only HBV DNA+, the reactivation risk was much higher in those HBsAg+ patients undergoing haemodialysis (71.4% versus 0), and more attention should be paid to these HBsAg+ patients during DAA therapy.

Despite HBV reactivation after DAA treatments, patients did not develop clinically evident hepatitis. Consistent with the results of previous studies (reported rates of hepatitis fare ranged from 0 to 30%) [15,16,23], 27.3% (3/11) of the coinfected patients undergoing haemodialysis had mild hepatitis due to HBV reactivation, and the peak ALTs of the three patients were all at low levels (ranged from 45.9 U/l to 63.7 U/l). Considering that these patients had impaired immune systems, affecting both acquired and innate immunity [26,27], it was possible that the risk of HBV reactivation was significant but no hepatic failure, icteric hepatitis or death due to HBV reactivation occurred in those HBV and HCV coinfected patients undergoing haemodialysis treatment. Two patients had elevated ALT levels (696.5 U/l and 133.1 U/l) before DAA treatment, which was associated with HCV infection. During DAA treatment, ALT normalization was synchronous with HCV RNA load decline, the levels of ALT recovered to normal and HCV RNA load became undetected before 12th week of treatment in all patients. To exclude the effect factors of ALT fare due to HBV reactivation, in this study, the histories of alcohol consumption, drug use and herb intake of these patients was checked repeatedly, and ALT levels were observed after HCV RNA became undetectable during DAA treatment. Our results showed that the severity of hepatitis was mild in these coinfected patients undergoing haemodialysis; however, hepatitis due to HBV reactivation may still develop into severe or fulminant hepatitis [28], and therefore, ALT levels should be monitored closely during DAA treatment in HBV–HCV-coinfected patients.

In this study, HCV infection was due to an epidemic nosocomial outbreak, to dismiss the possibility that HBV infection was due to the outbreak, we retrospectively analysed virological data before the outbreak. Among the 11 patients, 9 were negative for HBeAg, only 2 were positive for HBeAg and HBsAg, which indicated that the HBV serostatus in most patients were different from the conventional new HBV infection mode. Moreover, high levels of HCV RNA load were detected after the outbreak, while the levels of HBV DNA load at baseline (after the outbreak but before DAA treatment) were approximately consistent with the HBV DNA levels before the outbreak in the 11 patients. In addition, normative haemodialysis treatment was administrated in the two blood purification centres after the outbreak, and no HBV or HCV new infection was detected. Consequently, it was almost impossible that HBV infection was due to the outbreak.

It was revealed by this study that the risk of HBV reactivation during DAA treatment is significant in patients undergoing haemodialysis. However, there were some limitations to this study. The HBV DNA loads of the patients were not monitored closely during DAA treatment, and the time point of reactivation was not determined.

In conclusion, a significant proportion of HBV–HCV-coinfected patients undergoing haemodialysis treatment developed HBV reactivation after DAA therapy. The risk of HBV reactivation was more significant in the HBsAg+ patients compared with those patients who were HBsAg- but anti-HBc+ or HBV DNA+. Therefore, it is crucial to screen HBsAg+ patients undergoing dialysis for evidence of HBV infection.

Footnotes

Acknowledgment

We thank the National Natural Science Foundation of China (No. 81570528 and No.8177031729).

The authors declare no other funding or conflicts of interest relating to the publication of this manuscript.

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