Entecavir

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

An approximately 59-year-old man developed mitochondrial myopathy during treatment with entecavir for hepatitis B e antigen (HBeAg) chronic hepatitis B (CHB).

The man, who had more than 20 years of CHB history, was diagnosed with HBeAg positive CHB, at 54 years of the age in April 2011. Subsequently, he started receiving entecavir 0.5 mg/day [route not stated]. Following 24 weeks of treatment, HBV DNA less than 500 copies/mL and normal ALT were noted. His treatment continued with regular follow-up visits. In May 2016, at approximately 59 years of the age, he developed fatigue and poor appetite, for which he visited the local hospital many times for medical care. He developed the onset of dysosmia in December 2018 and subsequently, in March 2019, recurrent cough, expectoration with white sputum and with mild difficulty breathing following upper respiratory tract infection. His symptoms were mostly tolerable with no additional treatment. In August 2019, he completely lost his sense of smell and subsequently, visited the hospital for the treatment. His examination revealed that the nasal septum was bent to the right and there was no nasal mucosal oedema, nasal polyps or space-occupying lesions. His fatigue and poor appetite were aggravated at that time and in the past year his body weight was decreased by 3kg. Until July 2020, continuous decreased in weight was observed (decreased by approximately 5kg). Subsequently, colonic polyps were observed in examination which were clamped with forceps. In December 2019, he was hospitalized because of aggravated cough and expectoration with white sputum accompanied by dyspnoea. His laboratory examination revealed the following: arterial blood gas analysis: pH 7.38, arterial oxygen partial pressure (PaO2) 61.8mm Hg and arterial carbon dioxide partial pressure (PaCO2) 65.7mm Hg. Further, elevated serum muscle zymogram: creatine kinase-myocardial band (CK-MB), LDH and hydroxybutyrate dehydrogenase were noted. Lung functions were observed as follows: forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) 67%, FEV1 1.60L (51% of the predicted value), FVC 2.38L (61% of the predicted value) and a negative bronchial dilation test, indicating a possible restrictive pulmonary ventilation disorder. Chest CT revealed mild consolidation in the right lower lung. Subsequently, he was diagnosed with chronic obstructive pulmonary disease and type II respiratory failure. He started receiving theophylline and salbutamol with poor efficacy. Piperacillin, sulbactam combined with levofloxacin were added. Thereafter, his cough ​and expectoration were improved for short period. However, these symptoms continued to recur following discontinuation of treatment and no improvement in his dyspnoea was noted. On 14 January 2020, he visited the hospital and arterial blood gas analysis were observed as follows: pH 7.35, PaO ₂ 66mm Hg, PaCO ₂ 65mm Hg, oxygen saturation (SO ₂) 92.1%, lactate 4.3 mmol/L and after deep breathing: pH 7.40, PaO ₂ 107mm Hg, PaCO ₂ 50mm Hg, SO ₂ 98.3% and lactate 6.5 mmol/L. After the 6 minute walking test: pH 7.29, PaO ₂ 74mm Hg, PaCO ₂ 56mm Hg, SO2 93.7%, lactate 11.5 mmol/L. The serum muscle zymogram revealed elevated CK-MB and LDH. Later, the lung function test was repeated which revealed FEV1/FVC 85.85%, FEV1 1.82 L (58% of the predicted value), FVC 2.12L (55% of the predicted value), residual volume/predicted value 149%. In view of his examination results, shortness of breath caused by polymyositis or heart disease was excluded. His PaO ₂ was improved after deep breathing. Considering that there was no obstructive ventilation function disturbance, the decrease in FVC might be related to neuromuscular myopathy. Subsequent examination after neurology consultation indicated no abnormalities. In view of the increase in blood lactate after exercise, electromyography and muscle biopsy were suggested to determine whether nerve conduction and muscle mitochondrial lesions were present. But, because of the impact of the corona virus disease 2019 pandemic, the examinations were scheduled for the future. The preliminary diagnosis was hypoxaemia and possible mitochondrial myopathy following neurology consultation. He was treated with thiamine [vitamin B1], vitamin B complex and methycobal for nerve nourishment and with aerosol inhalation administered with budesonide. His entecavir was continued for hepatitis B. with this treatment, symptoms were not improved and even showed occasional worsening. In May 2020, he was entered a coma and his blood gas values of pO ₂ 20–30mm Hg and pCO ₂ 83mm Hg were noted. Subsequently, he underwent a tracheotomy and ventilator-assisted ventilation at the local hospital. Thereafter, his condition was stabilised and on July 2, blood gas analysis revealed pH of 7.38, PaO ₂ of 57.9mm Hg, PaCO ₂ of 48.1mm Hg and lactate of 3.5mmol/L, which indicates improvement. For a definitive diagnosis, he visited another hospital. Electromyography revealed the upper and lower limb nerves and parasternal muscles showed normal conduction. Pathological report for the quadriceps femoris biopsy suggested myogenic changes, slight differences in the sizes of muscle fibres, mild atrophy in scattered muscle fibres, light cytochrome c oxidase staining in a few muscle fibres and suspicious ragged red fibres on trichrome staining. On July 11, he was diagnosed with mitochondrial myopathy.

Subsequently, the man's entecavir was stopped for 1 month, considering that mitochondrial myopathy is associated with entecavir. Thereafter, his dyspnoea was improved, 1 month following entecavir discontinuation. Later, HBV DNA 1E+03 IU/mL and normal ALT were noted. On November 17 (after 4 months of entecavir discontinuation), a blood gas analysis showed improved results. However, some liver parameters were worsened. Hence, he visited the clinic for treatment. Because of virological rebound and abnormal biochemistry, reactivation of hepatitis B was considered. Subsequently, he was treated with tenofovir-alafenamide. During that time, his respiratory symptoms and mitochondrial myopathy were closely monitored. In March 2021, at follow-up, he was not receiving tenofovir-alafenamide because of the concerns for tenofovir-alafenamide induced respiratory failure and had only received diammonium glycyrrhizinate and polyenylphosphatidylcholine. His liver function indexes had decreased but were not recovered completely. At that time, entecavir was stopped for 8 months. Slight improvement in his dysosmia was noted. Further, dyspnoea, fatigue, poor appetite were improved. Blood lactate level was decreased to 2.1 mmol/L. However, the serum muscle zymogram had not decreased. Electrocardiogram was still normal. During his last follow-up, in August 2021, dyspnoea and fatigue were improved and he could tolerate activities of daily living. But, the tracheotomy was required to be kept open when he was lying flat at night. His liver function indexes had not completely reduced to normal. The serum muscle zymogram were decreased.