Successful Treatment of Tenofovir Alafenamide-Induced Lactic Acidosis: A Case Report

Introduction

Severe lactic acidosis is a rare but life-threatening complication of nucleoside or nucleotide analogue (NA) therapy used for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Nucleoside/nucleotide-associated lactic acidosis (NALA) occurs as a result of mitochondrial toxicity from inhibition of human mitochondrial DNA polymerase-γ, leading to impaired oxidative phosphorylation. Due to the lack of energy, cells engage in an aggressive anaerobic pathway, resulting in increased lactic acid levels.^1-3 The primary reported NA offenders are zidovudine, stavudine, and didanosine, whereas newer agents such as entecavir and tenofovir alafenamide (TAF) have demonstrated less interference with mitochondrial function in vitro.^4–7 Patients may be asymptomatic, have mild non-specific symptoms, or present in multisystem organ failure. The majority of cases of hyperlactatemia are asymptomatic, reported to occur in 8-21% of patients on NA therapy. Symptomatic hyperlactatemia (without acidosis) is less common, with an incidence of 8-10 cases per 1000 person years of treatment. Finally, severe symptomatic NALA is estimated between 0.57-8.5 cases per 1000 person-years of treatment, with mortality rates reported to be up to 60%.^1,2 When lactate elevation is mild (ie serum lactate value is less than 5 mmol/L), there is often complete resolution with discontinuation of the offending NA. ¹ However, there is a paucity of data to guide treatment in the setting of severe lactic acidosis. Anecdotal therapies include renal replacement therapy, intravenous (IV) sodium bicarbonate, antioxidants, and cofactors with the intent of supporting mitochondrial health. ¹ In this case report, we describe a patient with cirrhosis from chronic HBV who developed severe NALA from TAF that was successfully treated with mitochondrial cofactor supplementation.

Case Report

A 60-year-old man with chronic, untreated HBV initially presented to an outside hospital after being found unresponsive by emergency medical services when he failed to come to work that morning. On arrival to the hospital, the patient had normal vitals but was obtunded and jaundiced on physical exam. Admission labs were significant for white blood cell count (WBC) 1.5 x 10³ u/L, platelet count 22 x 10³ u/L, total bilirubin 26.9 mg/dL, AST 3041 U/L, ALT 2549 U/L, and INR 4.5. His HBV core IgM antibody was positive and viral load was 560,000 IU/mL. His initial lactate was 4.8 mmol/L but improved to 2.1 mmol/L after IV fluids and empiric antibiotic therapy for sepsis with piperacillin-tazobactam and vancomycin. A computed tomography (CT) scan of the brain did not demonstrate any abnormality, and a CT scan of the abdomen and pelvis revealed cirrhotic liver morphology and small volume ascites. He was transferred to our center for further care and possible liver transplantation evaluation. The patient had recently been prescribed entecavir for outpatient treatment of his HBV but had not yet taken the medication. On hospital day 1, HBV treatment with TAF 25 mg daily was initiated. Blood cultures returned positive for Group B Streptococcus and antibiotics were continued. On hospital day 2, a CT scan of the brain was repeated for persistently altered mentation, and he was found to have a new 7 mm hemorrhage within the left parieto-occipital region with minimal surrounding vasogenic edema. He received thromboelastography-guided resuscitation with blood products, including fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrate, for correction of his coagulopathy.

Early the next morning on hospital day 3, the patient became acutely tachycardic and tachypneic, with worsening mental status, requiring intubation for airway protection. He was hypertensive and required low-dose clevidipine for maintenance of systolic blood pressure between 140-160 mm Hg in the setting of recent acute intracranial hemorrhage. Labs demonstrated severe lactic acidosis with a lactate of 9.4 mmol/L which continued to rise over several hours to a peak value of 13.8 mmol/L. Imaging was pursued of the brain, chest, abdomen, and pelvis to determine a potential cause of the acute decompensation, however all were unremarkable. After excluding alternative etiologies for lactic acidosis including new sepsis, heart failure, seizures, bleeding, and mesenteric ischemia, it was determined that TAF may have been the etiology of this rise in serum lactate. Antiviral therapy was discontinued and the patient was started on a regimen designed to provide mitochondrial support in the setting of what was believed to be drug-induced mitochondrial injury. The administered medication regimen included coenzyme Q10 200 mg via nasogastric tube (NGT) every 8 hours, levocarnitine 50 mg/kg/day IV divided every 6 hours, riboflavin 100 mg via NGT daily, and thiamine 400 mg IV every 8 hours. The patient also received supportive care with sodium bicarbonate and crystalloid fluid boluses. Over the next 24 hours, his lactic acid improved and plateaued between 2-3 mmol/L. While continuing the medication regimen, entecavir was initiated as an alternative therapy for HBV, without recurrence of his lactic acidosis. Doses of the supplements were subsequently reduced over the following week, and the patient remained on maintenance doses of riboflavin, thiamine, and coenzyme Q10 while receiving entecavir therapy.

Discussion

Severe NALA was first reported in a patient with HIV receiving didanosine who developed acute liver failure and fatal lactic acidosis. ⁸ Subsequent cases of severe and fatal NALA mainly described patients with HIV on multi-drug regimens, and this clinical phenomenon became rarer after didanosine and stavudine were no longer recommended as preferred antiretroviral therapy for HIV. Nucleoside/nucleotide analogues which are designed to impair the DNA polymerase of HBV and HIV, also have a mild inhibitory effect on DNA polymerase-γ of human mitochondria. Inhibition of DNA polymerase-γ can impair mitochondrial DNA replication and cripple mitochondrial aerobic metabolism via the Krebs cycle. This leads to accumulation of lactic acid and insufficient adenosine triphosphate (ATP) production required for cellular activities.^3,9 Milder lactic acidosis may present without symptoms or with indolent, non-specific symptoms such as nausea, emesis, and abdominal pain. Severe lactic acidosis arising in the background of significant mitochondrial toxicity can lead to multi-system organ failure, particularly affecting organs with high concentrations of mitochondria such as the liver, nerves, and muscles. Other reported manifestations of this syndrome include hepatic steatosis, neuropathy, pancreatitis, and rhabdomyolysis. ¹⁰ Lactic acidosis may further be exacerbated in the setting of acute or chronic hepatic injury, due to the inability to properly clear lactate from the bloodstream. ⁹ In a review by Falco and colleagues of 60 cases of HIV patients with NALA, the median level of lactic acid was 14.6 mmol/L with a range from 4.3-70.3 mmol/L. On multivariable analysis, a serum lactate level above 10 mmol/L was associated with higher mortality. ¹

All current NAs used in the treatment of HBV—entecavir, lamivudine, tenofovir, adefovir, and telbivudine—have a potential to cause mitochondrial toxicity. ⁷ Because of its lower affinity for DNA polymerase-γ, tenofovir disoproxil fumarate (TDF) has traditionally been thought of as less toxic to mitochondria when administered as monotherapy, particularly when compared to older therapies for HIV such as the thymidine analogues zidovudine and stavudine, or combination NA therapy.^11-13 However, case reports of lactic acidosis with TDF monotherapy are reported in the literature, including several fatalities.^14,15 Tenofovir alafenamide is a prodrug of TDF that was approved by the FDA in 2016 for its better safety profile. In an in vitro study by Stray et al, TAF did not demonstrate significant inhibition of mitochondrial DNA synthesis in HIV-infected T-cells. ¹⁶ However, here we report a case of life-threatening lactic acidosis in a patient receiving TAF for decompensated HBV cirrhosis. The Naranjo adverse drug reaction probability scale yielded a score of 7, indicating a probable likelihood of a drug-induced adverse event. ¹⁷ To date, only one prior case report exists of NALA with TAF that was ultimately fatal in a patient with chronic HBV who underwent hematopoietic stem cell transplant. This syndrome occurred 6 weeks into therapy, in contrast with our patient where it occurred after only 2 doses. ⁷ The onset of NALA has been reported in the literature to occur as early as one month and as late as 20 months after NA initiation. ¹ It is unusual how early it manifested in our patient; however, we hypothesize that his severity of liver dysfunction and critical illness imparted a greater baseline predisposition to mitochondrial dysfunction.

Risk factors for the development of NALA include supratherapeutic drug exposure, liver or kidney dysfunction, and deficiencies in cofactors supporting mitochondrial health. In the large review of patients with NALA by Falco et al, 18.3% received one or more cofactors for treatment, including coenzyme Q10, thiamine, riboflavin, L-carnitine, vitamin C, or antioxidants. Mortality was lower on multivariable analysis among patients who received cofactor(s) compared with those who did not (OR 0.17, 95% CI 0.04-0.73), and the authors concluded that these therapies should be considered when faced with this life-threatening syndrome. ¹ Of note, the majority of these cases reported use of just one of the aforementioned cofactors, whereas we initiated a combination of therapies. These agents are utilized for the treatment of various genetic mitochondrial pathologies, and therefore may have a role in drug-induced mitochondrial toxicity. Coenzyme Q10 is essential for the carriage of electrons along the mitochondrial respiratory chain (MRC) and the protection of cells from free radical oxidation by acting as a lipid-soluble antioxidant. ¹⁸ Riboflavin serves as an important precursor to cofactors flavin mononucleotide and flavin adenine dinucleotide, which are necessary for proper functioning of the electron MRC.^19,20 Thiamine is a cofactor for pyruvate dehydrogenase, a necessary precursor for aerobic metabolism and lactate clearance. ²¹ Lastly, L-carnitine is an important cofactor for intra-mitochondrial transportation of fatty acids as acylcarnitine esters, which are oxidized to acetyl CoA for Krebs cycle entry. ²² To our knowledge, this is the first case report of the use of a regimen of cofactors supporting mitochondrial oxidative phosphorylation in a patient with severe NALA. It is unclear whether the syndrome would have resolved solely with TAF discontinuation or if these cofactors played a role in the patient’s outcome.

After the offending agent is discontinued and the NALA syndrome resolves, it is advisable to avoid NA therapy where possible. For example, a different class of antiretroviral medication should be considered in patients with HIV. However, for patients with HBV, it may be reasonable to re-challenge with a different NA due to limited alternative treatment options. In Falco et al’s review, several patients with NALA tolerated re-challenge with a different NA. Interestingly, in some cases of severe NALA in the setting of combination therapy with lamivudine and stavudine, there was no recurrence when lamivudine was reinstated with an alternative NA. ¹ While lamivudine has low affinity for human mitochondrial DNA polymerase-γ, it does have a low barrier to the development of HBV resistance.^23,24 We therefore chose to switch our patient to entecavir for the treatment of his active HBV. Entecavir has demonstrated little evidence of mitochondrial toxicity in an in vitro study which used concentrations exceeding 100 times the maximum concentration seen in humans. Nevertheless, case reports of entecavir-induced lactic acidosis do exist. ²⁵ All NAs, regardless of in vitro affinity for DNA polymerase-γ, should be considered culprits for this potentially fatal syndrome.

Conclusion

Nucleoside/nucleotide analogues for the treatment of HIV and HBV have been implicated in life-threatening lactic acidosis. Aside from NA discontinuation, there is a dearth of literature to support the treatment of severe phenotypes of this syndrome. Promising case reports outline treatment with mitochondrial cofactor supplementation to combat the underlying pathophysiology of NA-associated mitochondrial toxicity. Here, we reported a case of severe TAF-induced lactic acidosis which occurred 2 days after initiation in a patient with acute decompensated HBV cirrhosis. The positive response to TAF discontinuation and treatment with a regimen of mitochondrial cofactors has not been reported before, and we hope that this report contributes to the growing body of literature which addresses this topic.