Dual therapy with nucleos(t)ide analogues in the prevention of hepatitis B virus recurrence after liver transplantation: Two case reports

Abstract

BACKGROUND

Infection by the hepatitis B virus (HBV) represents a significant global socio-sanitary burden. While liver transplantation (LT) is an important therapeutic option, treatments that prevent HBV reinfection are necessary. The combination of anti-hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NA) is the standard post-transplant treatment; however, there are limitations in using HBIG, particularly its cost. We present two illustrative clinical cases as examples of post-transplant management using dual NA therapy, unaccompanied by HBIG.

CASE SUMMARY

The first case involves a 42-year-old man with HBV-related cirrhosis, who, in the context of a diagnosis of hepatocellular carcinoma and hepatopulmonary syndrome, underwent LT without viremia at the time of transplantation. A lack of availability of HBIG led to the combined use of two NAs, entecavir, and tenofovir alafenamide—resulting in the negativization of hepatitis B surface antigen (HBsAg) and maintenance of a negative viral load in the post-transplant period. In the second case, a 63-year-old woman presented with acute hepatic failure due to HBV with viremia during transplantation. Combined therapy with entecavir and tenofovir alafenamide, again due to the unavailability of HBIG, ultimately led to the negativization of HBsAg and viral load.

CONCLUSION

These cases suggest the efficacy of dual NA therapy in post-transplant HBV management, emphasizing the need to reconsider traditional treatment approaches.

Key Words: Antiviral drug; Liver transplant; Hepatitis B virus; Viral recurrence; Nucleoside analog; Case report

Core Tip: This manuscript explores post-liver transplant strategies for hepatitis B virus (HBV). Two cases showed the success of dual nucleoside/nucleotide analog (NA) therapy (entecavir and tenofovir alafenamide) without hepatitis B immunoglobulin (HBIG) in prevention of HBV recurrence. These cases emphasize the efficacy of dual NA therapy as a viable alternative in managing post-transplant HBV infection, especially when HBIG is unavailable. This challenges the standard protocol and proposes reconsidering post-transplant management when specific treatments are limited.

INTRODUCTION

Hepatitis B virus (HBV) infection represents a significant global burden in terms of morbidity and mortality. In 2019, roughly 296 million individuals were affected by chronic HBV infection, with approximately 1.5 million new infections each year. HBV is responsible for nearly 820000 annual deaths, primarily due to complications such as liver cirrhosis and hepatocellular carcinoma (HCC)[1]. Liver transplantation (LT) is considered the treatment of choice for HCC, liver failure, and end-stage liver disease related to HBV infection[2].

Until approximately two decades ago, LT in patients with chronic HBV infection was relatively contraindicated due to the high risk of viral replication associated with immunosuppressant use, potentially leading to graft infection. In the 1990s, the introduction of hepatitis B immunoglobulin (HBIG) significantly reduced the risk of graft infection, thereby improving liver transplant outcomes in patients with chronic HBV infection[3]. Preventing the recurrence of HBV infection in the graft is crucial for graft viability and patient survival. Current post-liver transplant protocols typically involve oral nucleoside/nucleotide analogs (NAs), HBIG, vaccines, or a combination of these modalities[4,5]. The European Association for the Study of the Liver guidelines strongly support the combination of a potent NA with HBIG to prevent HBV recurrence post-transplant, allowing for flexible HBIG discontinuation in low-risk patients while maintaining potent NA monotherapy[6].

Significant remaining challenges associated with intravenous HBIG infusions are the high cost, the necessity of hospitalization, and the frequent occurrence of adverse events[7], which complicates the long-term maintenance of this treatment. There are currently no clear guidelines on the exclusive use of NAs without transient HBIG use post-transplant. Moreover, there is no evidence of the simultaneous use of two different NAs for post-transplant prophylaxis without prior HBIG administration. In this context, we present two clinical cases of patients who underwent LT due to HBV infection and received treatment with dual NA therapy in the post-transplant period. These cases provide an opportunity to discuss the efficacy and feasibility of this alternative therapeutic strategy.

CASE PRESENTATION

Chief complaints

Case 1: A 42-year-old man, during routine follow-ups for liver cirrhosis secondary to chronic HBV and autoimmune hepatitis, was found to have a liver lesion with suspicions of malignancy.

Case 2: A 63-year-old woman presented with progressive swelling in the lower extremities and increased abdominal circumference.

History of present illness

Case 1: The patient had been incidentally and asymptomatically diagnosed with HBV-related liver cirrhosis six years previously during a cholecystectomy. At diagnosis, he was classified as Child-Pugh class B with a model for end-stage liver disease-sodium score of 16 points. He began subsequent antiviral treatment with entecavir, showing a favorable response. Four years ago, serological studies revealed an immunoglobulin G count of 5000 mg/dL (normal upper limit 1390 mg/dL), antinuclear antibody at 1:80, and anti-smooth muscle antibody at 1:1280, leading to a diagnosis of autoimmune hepatitis confirmed by liver biopsy. The patient showed a poor response to standard corticosteroid therapy for autoimmune hepatitis, necessitating the initiation of tacrolimus, which resulted in adverse reactions. Subsequently, he was switched to cyclosporine, with an adequate response. During follow-up, he was diagnosed with hepatopulmonary syndrome and cirrhotic cardiomyopathy, which indicated a liver transplant. He is currently on entecavir, prednisone, omeprazole, and carvedilol.

Case 2: The patient has a medical history of hypertension, asthma, and HBV infection, diagnosed 30 years ago. The patient had a recent hospitalization for hyperacute liver failure secondary to HBV reactivation, with negative King’s College and Clichy criteria. Current medications include tenofovir 300 mg, furosemide, losartan, rifaximin, polyethylene glycol, and esomeprazole. Five days after discharge, the patient presented with progressive swelling in the lower extremities and increased abdominal circumference. Additionally, she reported sleep-wake inversion and decreased urinary frequency but denied symptoms suggestive of gastrointestinal bleeding, fever, vomiting, or cardiorespiratory symptoms. During the most recent hospitalization, she experienced a deterioration in consciousness, raising suspicion of encephalopathy. On the third day of hospitalization, she developed upper gastrointestinal variceal bleeding.

Personal and family history

Case 1: The patient has no other relevant personal or family history.

Case 2: No history of drug use or alcohol consumption. The patient has no other relevant personal or family history.

Physical examination

Case 1: On physical examination, the patient has jaundice and no signs of hepatic encephalopathy or ascites.

Case 2: On presentation, the patient had vital signs within normal ranges, was well-hydrated, well-perfused, and oriented to time and place. Notable findings included bilateral edema and petechiae in the lower extremities, jaundice of the skin and sclerae, ascites, bilateral asterixis, hyperactive deep tendon reflexes, hepatojugular reflux, decreased breath sounds at both lung bases, no hepatosplenomegaly, and bilateral extensor plantar reflex.

Laboratory examinations

Case 1: The patient presented with elevated transaminases and positive hepatitis B surface antigen (HBsAg). Hepatitis B e antigen (HBeAg) and HBV viral load were negative, confirmed 13 days before LT. The laboratory results highlighted total bilirubin of 22 mg/dL, international normalized ratio (INR) of 1.77, alkaline phosphatase of 147 U/L, glutamyl transferase (GGT) of 135 U/L, aspartate aminotransferase (AST) of 130 U/L, alanine aminotransferase (ALT) of 67 U/L, creatinine of 2.66 mg/dL, blood urea nitrogen (BUN) of 54 mg/dL, C-reactive protein (CRP) of 53 mg/L, hemoglobin of 10.5 g/dL, leukocytes of 9000/μL, and platelets of 120000/μL.

Case 2: Admission laboratory results highlighted total bilirubin of 22 mg/dL, INR of 1.77, alkaline phosphatase of 147 U/L, GGT of 135 U/L, AST of 130 U/L, ALT of 67 U/L, creatinine of 2.66 mg/dL (baseline 1.06 mg/dL), BUN of 54 mg/dL (baseline 29 mg/dL), CRP of 53 mg/L, hemoglobin of 10.5 g/dL, leukocytes of 9000/μL, and platelets of 120000/μL.

Imaging examinations

Case 1: A 2 cm focal lesion with LIRADS 3 was detected during regular screening. Mild splenomegaly was also observed.

Further diagnostic workup was performed. The LIRADS 3 lesion was biopsied and identified as HCC. Additionally, pre-transplant routine studies showed a positive bubble test on the echocardiogram associated with hypoxemia, with a pO2 of 60 mmHg. The explanted liver biopsy revealed chronic hepatitis, steatohepatitis, cirrhosis, and HCC in three foci.

Case 2: A Doppler ultrasound of the portal vein showed signs of early liver damage, diffuse gallbladder wall thickening, pulsatile morphology of the portal and hepatic veins, and a patent hepatic artery with an increased average resistance index of 0.9. The study also shows moderate ascites, a spleen size of 10.9 cm, and no signs of portal vein thrombosis.

Abdominal and pelvic computed tomography without contrast showed a diffusely decreased liver size without renal abnormalities. No focal lesions were identified in this study.

FINAL DIAGNOSIS

Case 1: The final diagnosis was HCC and hepatopulmonary syndrome in a patient with a history of HBV-related liver cirrhosis and autoimmune hepatitis.

Case 2: Hyperacute liver failure due to hepatitis B.

TREATMENT

Case 1: Radiofrequency ablation of the HCC was performed. The patient was placed on the liver transplant waiting list, and immunosuppression was discontinued. A liver transplant was subsequently performed. The immediate postoperative period was complicated by impaired gas exchange due to hepatopulmonary syndrome, making extubation difficult. Due to the unavailability of HBIG, a combination of two NAs (entecavir 1 mg and tenofovir alafenamide 25 mg daily) was initiated.

Case 2: Depletive therapy was administered for symptomatic relief, and acute renal failure was initially managed as hepatorenal syndrome with terlipressin and albumin. Rifaximin was prescribed for the management and prophylaxis of hepatic encephalopathy. During endoscopy, a hemostatic agent was applied to the lesions, and multiple transfusions were performed due to upper gastrointestinal bleeding. Given the hyperacute liver failure, a decision for an orthotopic LT was taken. Post-operatively, entecavir, tenofovir, and methylprednisolone were restarted, and immunosuppressive therapy with tacrolimus and mycophenolate was initiated. The explant liver biopsy revealed acute hepatitis with multifocal confluent necrosis and ductular proliferation. There was marked canalicular cholestasis, mild steatosis (10%), and no significant fibrosis. Immunohistochemical tests confirmed HBV infection.

OUTCOME AND FOLLOW-UP

Case 1: Weekly follow-ups showed negative HBsAg and HBV viral load before discharge, with these results persisting up to 4 weeks post-transplant (Table 1). The patient continued regular follow-ups with negative HBsAg for two years. Considering the minimal risk of recurrence after two years and the current shortage of NAs therapy in Chile, we decided to discontinue the dual therapy for HBV and continue treatment with tenofovir alafenamide 25 mg monotherapy.

Table 1 Evolution of hepatitis B surface antigen before and after liver transplantation for both patients.

HBsAg	Case 1	Case 2
Before LT	+	+
1st week after LT	+	+
2nd week after LT	-	+
8th week after LT	-	+
24th week after LT	-	+
36th week after LT	-	-

LT: Liver transplant.

Case 2: The patient had a favorable post-transplant course, with early extubation, hemodynamic stability, and good oral intake tolerance. The patient continued regular follow-ups in gastroenterology after the transplant, with persistent positive HBsAg; however, viral load was at or below the detection limit. After eight months, the patient achieved HBsAg seronegativity with a negative viral load (Table 2), leading to the decision to continue monotherapy with entecavir. The reason for continuing with monotherapy, as in the previous clinical case, was the shortage of NAs therapy in Chile.

Table 2 Hepatitis B virus serological markers before liver transplantation for both patients.

Preoperative exams	Case 1	Case 2
HBsAg	+	+
Anti-HBs	UR	-
HBeAg	UR	-
Anti-HBe	UR	UR
Anti-HBc	UR	+
Viral load	-	+

UR: Unrequested.

DISCUSSION

In summary, we present two cases of LT in patients with HBV infection, managed in the early post-transplant period with dual NA therapy, resulting in clinically favorable outcomes. In the first case, the patient had HBV-related cirrhosis with no viremia at the time of transplantation. In the second case, the patient experienced HBV-related acute liver failure, had viremia during transplantation, and eventually showed late HBsAg seronegativity.

Patients at higher risk for HBV recurrence post-LT typically have high viral loads during transplantation, positive HBeAg, a history of resistance to oral HBV drugs, coinfection with HIV, and the presence of HCC[8,9]. Graft reinfection by HBV often leads to adverse outcomes such as cirrhosis, fibrosing cholestatic hepatitis, and fulminant hepatitis, resulting in graft loss within a short period[10,11].

Recent studies, highlighted in a meta-analysis, emphasize the greater effectiveness of HBIG combined with NA in preventing HBV recurrence post-LT compared to HBIG or NA alone[12]. However, these conclusions are primarily from studies involving older drugs like lamivudine, which is associated with lower efficacy and higher resistance compared to current NAs. Therefore, further investigation of high-potency NAs with a high genetic barrier is essential.

Regarding post-LT monotherapy with entecavir, a study by Fung et al[13] showed a cumulative relapse rate of 13.7% in the three years after initial HBsAg clearance, occurring mainly in the first year[13]. A more recent cohort from the same group shows that long-term monotherapy with entecavir, without the use of HBIG at any point, effectively prevents HBV reactivation post-LT for chronic hepatitis B, with a sustained HBsAg clearance rate of 92% at eight years was reported, with undetectable HBV DNA in 100% of cases, and nine-year survival of 85%[14]. This evidence supports the use of NAs as monotherapy without HBIG.

Conversely—drawing lessons from the development of treatments for HIV infection—it is reasonable to postulate that a combination of NAs without cross-resistance would be necessary to maintain long-term suppression of HBV replication[15]. Several lines of clinical evidence support the use of dual NA therapy. Firstly, it has already been tested in patients with chronic hepatitis B. For example, Zoulim et al[16] reported on patients with chronic hepatitis B who had previously experienced NA treatment failure. The authors found that combined entercavir/tenofovir disoproxil fumarate (ETV/TDF) therapy was effective, achieving virological suppression in most patients (85%) over 96 weeks without emergent resistance to either agent[16]. Similarly, Wang et al[17] demonstrated that in patients with chronic hepatitis B with partial virological response to entecavir, that combined therapy with TDF and entecavir significantly increased viral response at 48 weeks compared to TDF monotherapy (88.8% vs 71.4%)[17]. However, other studies have reported that in patients with adefovir-resistant HBV and multiple drug failure, TDF monotherapy provided a virological response similar to combined TDF and ETV therapy[18].

Secondly, in the context of post-transplant prophylaxis, Khemichian et al[19] reported on a cohort of 26 patients transplanted for HBV who had negative HBsAg with therapeutic anti-HBs titers for at least 1-year post-LT. In this population, discontinuation of HBIG and a switch to dual NAs therapy were associated with favorable outcomes[19]. All patients had undetectable HBV DNA, and 92.3% remained HBsAg negative during follow-up (mean of 31.9 months).

We used dual NA therapy (tenofovir alafenamide and entecavir) without HBIG in our clinical cases. To our knowledge, dual therapy with tenofovir alafenamide and entecavir exclusively (i.e., without concomitant use of HBIG or other therapies) for preventing HBV recurrence post-LT has not been studied. Additionally, it is crucial to consider that tenofovir alafenamide may be a safer alternative to TDF, especially for patients at risk of renal or bone diseases[20,21].

Finally, the persistence/recurrence of HBsAg post-LT was not associated with HBV DNA levels at the time of transplantation. Still, it was associated with HBsAg concentration during transplantation and was notably higher in HBsAg-positive cases. This underscores the potential importance of determining HBsAg concentration during transplantation to estimate the subsequent risk of HBV recurrence post-LT. Additionally, it raises questions about the long-term implications of HBsAg positivity with HBV DNA negativity.

CONCLUSION

The presentation of these cases allows for a deeper discussion on the need to reconsider the post-transplant management paradigm for patients with HBV. While the combined use of HBIG and antivirals is considered the gold standard for preventing HBV recurrence post-transplant, the limitations, primarily economic, suggest the possibility of omitting the use of HBIG in specific scenarios. In this sense, the early and combined use of high-potency NAs emerges as an adequate therapeutic alternative that remains to be tested in multicenter randomized clinical trials.