Hepatitis B reactivation in a patient with chronic hepatitis C treated with direct-acting antivirals

Direct-acting antivirals (DAA), currently used as a treatment for hepatitis C virus (HCV), are not effective for the hepatitis B virus (HBV). Therefore, in co-infected patients (HCV/HBV) who are inactive carriers, DAA could cause the reactivation of HBV. This situation has been recently described in patients receiving treatment with DAA, although the real risk is unknown.^1–4

We present the case of a 52-year-old male patient referred to gastrointestinal medicine from nephrology for chronic HBV infection (HBsAg positive, anti-HBc positive, HBeAg negative, anti-HBe positive) and HCV genotype 4. Originally from Cameroon, he had been living in Spain for over 20 years. His only previous medical history was hypertension, with hypertensive retinopathy and mild renal failure.

Viral loads were determined, with HBV-DNA 112 IU/ml and HCV-RNA 965,000 IU/ml. A Fibroscan^® was performed to establish fibrosis stage, showing liver stiffness of 10.7 kPa.

The patient was started on therapy with ombitasvir, paritaprevir, ritonavir and ribavirin. His viral load was negative at week 4 of treatment; treatment duration was 8 weeks and he showed a sustained virological response (SVR) at 12 weeks after completion with normal AST and ALT. In week 8 of treatment, having been previously asymptomatic, the patient went to the hospital's Emergency Department with epigastric pain, with blood tests showing total bilirubin of 4.5 mg/dl with normal ALT. He was discharged as simply epigastric pain and he decided to stop taking the treatment. His symptoms did not subsequently return, so they could be attributed to the treatment.

At post-treatment follow-up in week 24, he had ALT of 295 IU/l with RNA-HCV <15 IU/ml. HBV-DNA was 53,678,800 IU/ml. He was started on treatment with entecavir (0.5 mg/day), with transaminase values back to normal after 12 weeks and HBV-DNA <15 IU/ml at 24 weeks.

Since treatment with DAA for HCV infection began, cases of HBV reactivation (increased HBV-DNA values in patients with HBsAg and/or anti-HBc positive) have been described in co-infected patients.¹ Although reactivation has not caused clinical repercussions in most patients, there are reports of liver failure and even the need for liver transplantation.^2,3 HCV is known to suppress the replication of HBV in co-infected patients.⁴

In the light of the evidence of reactivation in patients treated with the new DAA, in December 2016 the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) [Spanish Agency of Medicines and Medical Devices] recommended performing HBV serology before starting treatment with DAA in all patients who were candidates for the treatment, and in those already being treated.⁵ As early as April 2016, the Food and Drug Administration (FDA) had warned about the risk of reactivation of HBV in patients treated with DAA.

Although the current data are limited, they show that reactivation of HBV can occur with any DAA treatment. The reactivation usually occurs within the first 4–8 weeks after starting treatment with DAA, and is related to the rapid reduction of the HCV viral load characteristic of DAA. The recommendations are therefore to always rule out HBV infection before commencing treatment with DAA, and in cases where there is co-infection, monitor patients while on DAA treatment and after the treatment is completed.^6–8

The reactivation of HBV was not described as an adverse effect of DAA in clinical trials, as co-infected patients were excluded from the studies.

Recent studies assessing the actual risk of reactivation in patients treated with DAA show that reactivation occurs in more than 50% of patients who are HBsAg positive, while the risk is much lower in patients with isolated anti-HBc (less than 2%). In the majority of cases, the reactivation is not accompanied by an increase in transaminases, especially when the HBV-DNA is less than 20,000 IU/ml, which is most often the case. Although rare, cases like ours have been described with repercussions on blood parameters.^6,7,9 In our case, there was no HBV-DNA monitoring and the patient was not diagnosed until his transaminase levels had already risen and his HBV-DNA levels were very high, confirming that, although an uncommon occurrence, the risk of clinically significant reactivation is real.

There is no consensus on the optimal management of prophylaxis and treatment of HBV reactivation by DAA. Some authors suggest that not all patients with reactivation should be treated. If the data from the latest studies are confirmed, one possibility would be to closely monitor and treat if HBV-DNA values are higher than 20,000 IU/ml or transaminases are also increased. The recommendation of the European Association for the Study of the Liver (EASL) of 2017 is to perform HBV serology before treatment. They recommend treating HBsAg-positive or anti-HBC-positive patients with detectable HBV-DNA with nucleoside/nucleotide analogues and monitoring transaminase levels in patients who are anti-HBs and anti-HBc positive.¹⁰ If antiviral treatment is started, there is no consensus on how long it should last.

In conclusion, patients with HCV who are going to be treated with DAA should be screened for chronic HBV infection and, if positive, they should be closely monitored for possible HBV reactivation.