A Case Report on Lactic Acidosis Induced by Biktarvy in a Patient With Renal Impairment: A Rare Complication of Antiretroviral Therapy

Abstract

Biktarvy, a once-daily combination of bictegravir, emtricitabine, and tenofovir alafenamide (TAF), is a highly effective antiretroviral therapy for HIV management. Although well-tolerated, rare but serious complications such as lactic acidosis can occur, particularly in patients on nucleoside reverse transcriptase inhibitors. We present the case of a 36-year-old male with HIV/AIDS and chronic kidney disease, who was admitted with altered mental status and acute hypoxic respiratory failure. Imaging confirmed atypical pneumonia. Initial labs revealed elevated lactate and creatinine. He was treated with broad-spectrum antibiotics, and after clinical improvement, Biktarvy was resumed. Within 24 h, his lactate spiked to 21.8 mmol/L. Suspecting TAF-induced lactic acidosis, Biktarvy was discontinued. Continuous renal replacement therapy, along with L-carnitine and thiamine, was initiated based on a literature review. The patient's condition improved significantly. Upon discharge, lactate and creatinine returned to baseline. At outpatient follow-up, he remained clinically stable on Dolutegravir-Rilpivirine and Entecavir.

Introduction

Biktarvy, a combination of bictegravir, emtricitabine, and tenofovir alafenamide (TAF), is a highly effective antiretroviral therapy (ART) for the management of HIV infection. Biktarvy is one of the combination ART regimens that has revolutionized HIV treatment by providing patients with a convenient once-daily option for achieving viral suppression. Despite its favorable safety profile, Biktarvy—such as other regimens containing nucleoside reverse transcriptase inhibitors (NRTIs)—carries a rare risk of mitochondrial toxicity that can lead to lactic acidosis. ¹ The prevalence of asymptomatic hyperlactatemia among patients receiving NRTIs is estimated at 15%–35%, while symptomatic, severe hyperlactatemia and lactic acidosis occur much less frequently, with reported incidences ranging from 1.3 to 25.2 cases per 1000 person-years of NRTI exposure. The mortality rate for severe lactic acidosis in this setting is substantial, ranging from 30% to 60% in published case series. ² The pathogenesis of ART-induced lactic acidosis is primarily linked to the inhibition of mitochondrial DNA polymerase-γ by NRTIs, which impairs mitochondrial DNA replication and oxidative phosphorylation. This mitochondrial dysfunction leads to reduced aerobic metabolism and a shift toward anaerobic glycolysis, resulting in excessive lactate production and decreased lactate clearance. Patients with renal or hepatic impairment are particularly vulnerable due to reduced lactate metabolism and drug clearance. In this report, we present a rare case of severe lactic acidosis following the re-initiation of Biktarvy in a patient with chronic kidney disease (CKD), underscoring the need for close monitoring of high-risk individuals and awareness of this potentially life-threatening complication.

Case Presentation

A 36-year-old male with HIV/AIDS, chronic hepatitis B, syphilis, and CKD was admitted with altered mental status and acute hypoxic respiratory failure. Chest imaging showed bilateral pleural effusions and ground-glass opacities. Computed tomography abdomen/pelvis was only remarkable for hepatomegaly and a small amount of ascites. Laboratory evaluation revealed an anion gap metabolic acidosis with elevated lactate levels ranging from 4.3 to 5.9 mmol/L, hyperkalemia, and an elevated creatinine of 1.8 mg/dL, though the patient's baseline renal function was unknown. Transaminases were also elevated, and together with renal dysfunction and a plasma lactate >4 mmol/L, these findings raised concern for sepsis with organ dysfunction. The patient's HIV viral load measured 963 copies/mL, and his CD4 count was 134 cells/μL. Given the clinical suspicion for sepsis, the degree of immunosuppression, and suboptimal virologic control, broad-spectrum antimicrobial coverage was initiated with IV Vancomycin, Cefepime, Azithromycin, and Trimethoprim-Sulfamethoxazole (Bactrim). The transaminitis was attributed to underlying chronic hepatitis B, supported by a reactive hepatitis B surface antigen and a Hepatitis B virus (HBV) DNA level of 9520 IU/mL. He was hemodynamically stable during the admission process; however, the patient deteriorated overnight, requiring transfer to the intensive care unit. A bedside cardiac ultrasound was performed, which revealed a decreased ejection fraction of 15%–20%.

Bronchoscopy performed the following day revealed no abnormal findings, and bronchial cultures were negative. By hospital day 3, the patient demonstrated clinical improvement in both respiratory status and metabolic acidosis, with persistently negative cultures. His home medications, including Biktarvy, which had been initially withheld at admission due to altered mental status, were reintroduced. Within 24 h, his plasma lactate level rose to 10 mmol/L, and his serum creatinine peaked at 2.3 mg/dL. Liver function tests also showed up trending aspartate aminotransferase and alanine aminotransferase. Despite this, his vital signs remained stable. Lung imaging showed an improvement in his pleural effusions and pulmonary infiltrates. Urinalysis was unremarkable for any infection. Repeat blood and sputum cultures remained negative, and no infectious source was identified. The bronchoalveolar lavage pneumocystis pneumonia DNA polymerase chain reaction returned negative, leading to the discontinuation of Bactrim as well. After ruling out alternative etiologies such as hypoperfusion and nosocomial infections, it was concluded that Biktarvy was the most likely cause of type B lactic acidosis, leading to its discontinuation. Further discussion was held with the patient, who stated that he had previously been on Biktarvy from 2017 to 2021; however, due to a lack of medical insurance, he could no longer afford his medication. He was restarted on Biktarvy a few weeks before his admission.

Despite initial supportive measures, the patient's lactate levels continued to rise (Figure 1), prompting initiation of a bicarbonate infusion and continuous renal replacement therapy (CRRT). Following consultation with poison control and a thorough review of the literature, case reports were identified recommending the discontinuation of the suspected offending agent and the addition of mitochondrial support therapy with L-carnitine and thiamine. These agents play a crucial role in enhancing mitochondrial function and correcting cofactor deficiencies that impair oxidative phosphorylation, contributing to lactate accumulation. In conjunction with renal replacement therapy and withdrawal of Biktarvy, the administration of thiamine and L-carnitine led to a gradual improvement in lactic acidosis. The patient's clinical status improved, and upon resolution of his metabolic derangements, he was decannulated from CRRT. He was discharged with plans to continue outpatient follow-up with the infectious disease clinic.

Figure 1.

Trend of the Patient's Plasma Lactate Levels Throughout His Inpatient Stay.

One month after discharge from our hospital, the patient followed up as an outpatient with our Infectious Disease specialist. He reported that he was doing well after discharge on his current ART, which consisted of Dolutegravir-Rilpivirine (Juluca) and Entecavir. At subsequent visits over the next 3 months, the patient remained clinically stable. No further episodes of lactic acidosis were reported, and his renal function remained stable on repeat labs. Unfortunately, the patient has not followed up with our Infectious Disease clinic for his most recent appointments due to logistical issues.

Discussion

Lactic acidosis is a rare but potentially life-threatening complication of ART in HIV-positive patients, especially those taking NRTIs. ³ NRTIs (such as Tenofovir and emtricitabine), which are employed to inhibit the DNA polymerase activity of both HBV and HIV, also mildly inhibit DNA polymerase-γ within human mitochondria. This interference with DNA polymerase-γ can disrupt mitochondrial DNA replication and lead to impaired electron transport chain. This impairs mitochondrial aerobic metabolism, particularly through the Krebs cycle, and causes a shift toward anaerobic metabolism. This results in the accumulation of lactic acid and an insufficiency of the adenosine triphosphate (ATP) required for cellular functions.^4,5 The U.S. Food and Drug Administration labeling for both Emtriva (Emtricitabine) and Biktarvy warns of lactic acidosis and recommends discontinuation of therapy if clinical or laboratory findings suggest lactic acidosis. Bictegravir, an integrase inhibitor, does not share this mitochondrial toxicity and is not implicated in the development of lactic acidosis. ¹

Under normal physiological conditions, the liver is responsible for up to 70% of whole-body lactate clearance, making it the principal organ for lactate removal from the blood. ⁶ In chronic liver disease, such as our patient, lactate clearance is reduced, leading to elevated plasma lactate, especially in critically ill patients. ⁷ Renal impairment also increases the risk of lactic acidosis in patients taking NRTIs because reduced renal function leads to decreased clearance of both lactate and NRTIs or their metabolites, resulting in higher systemic exposure and greater mitochondrial toxicity. Although Tenofovir and Emtricitabine share the potential to induce lactic acidosis through their class effects as NRTIs, contemporary literature highlights Tenofovir as the more common contributor. TAF is considered a newer prodrug of tenofovir, which is more efficient than tenofovir disoproxil fumarate (TDF). ⁸ TAF is metabolized in the liver and excreted mainly through the kidneys. ⁹ While TAF has a superior renal safety profile as compared to TDF, there are still sporadic cases of TAF-induced renal tubular injury.^10,11

Additionally, background factors such as underlying metabolic disorders or a history of malignancy may serve as contributing factors to mitochondrial dysfunction and the subsequent development of lactic acidosis. However, our patient had no known history of metabolic disease or malignancy, and there were no clinical signs suggestive of such during his hospitalization. As such, these conditions were considered lower on the differential diagnosis and were not specifically investigated further.

The 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America on Clinical practice guideline for the management of CKD in patients infected with HIV highlights that tenofovir can accumulate in proximal tubular cells, especially in the setting of renal impairment, leading to mitochondrial DNA depletion and proximal tubular injury. This process is mechanistically linked to the development of lactic acidosis, as mitochondrial dysfunction directly impairs the cell's ability to metabolize lactate. The risk is further compounded by the fact that TAF, while less nephrotoxic than TDF, still poses a risk when renal excretion is compromised, as intracellular accumulation can occur and lead to metabolic complications such as Fanconi syndrome and lactic acidosis.^12,13

Our patient presented with renal impairment, as evidenced by a creatinine level of 1.8 mg/dL, an estimated creatinine clearance of 56.4 mL/min, and an estimated glomerular filtration rate of 49.4 mL/min. This renal impairment likely led to reduced elimination of the active metabolite of tenofovir, increasing its concentration and further exacerbating lactic acidosis. A case-control study demonstrated that a creatinine clearance of <70 mL/min was strongly associated with an increased risk of lactic acidosis in HIV-infected patients on NRTIs, with an odds ratio of 15.8, highlighting the clinical significance of renal impairment as a risk factor. ¹⁴

Several risk factors can contribute to the development of TAF-associated lactic acidosis, including liver or kidney dysfunction. In mild cases of lactate elevation where the serum lactate level is <5 mmol/L, discontinuation of the offending nucleoside analog often leads to resolution. However, treatment strategies for severe lactic acidosis remain limited. In a case published by Arnouk et al, ⁴ TAF-induced lactic acidosis was successfully managed with the discontinuation of TAF and supplementation with cofactors supporting mitochondrial oxidative phosphorylation, including coenzyme Q10, levocarnitine, riboflavin, and thiamine.

Thiamine, a critical coenzyme in the pyruvate dehydrogenase complex, enhances aerobic glucose metabolism and helps clear lactate. ¹⁵ L-carnitine facilitates mitochondrial fatty acid transport and β-oxidation, both of which are essential in generating ATP and preventing mitochondrial failure. ¹⁶ These supplements may mitigate mitochondrial toxicity and aid recovery from drug-induced lactic acidosis. Bhatia et al ¹⁷ similarly report favorable outcomes using L-carnitine in ART-associated lactic acidosis.

Additionally, background factors such as underlying metabolic disorders or a history of malignancy may serve as contributing factors to mitochondrial dysfunction and the subsequent development of lactic acidosis. However, our patient had no known history of metabolic disease or malignancy, and there were no clinical signs suggestive of such during his hospitalization. As such, these conditions were considered lower on the differential diagnosis and were not specifically investigated further.

In patients with HBV co-infection, treatment options can be limited if NRTI toxicity emerges. Entecavir is an effective option for HBV with a favorable mitochondrial toxicity profile. Although rare case reports of entecavir-associated lactic acidosis exist, it remains a viable alternative. ¹⁸

Logistical issues for this patient mean our case report is limited in how much we are able to follow up on the patient's condition and his long-term recovery.

Conclusion

This case highlights how a commonly prescribed ART can, in specific clinical contexts (ie, renal impairment), lead to severe complications. Clinicians must remain vigilant for TAF-associated lactic acidosis, particularly in patients with renal impairment. Early recognition, cessation of the offending drug, and supportive therapies such as CRRT, L-carnitine, and thiamine can be lifesaving.