Severe rhabdomyolysis and acute asymptomatic pancreatitis following the concomitant use of Biktarvy in the setting of hyperosmolar diabetic crisis

Abstract

Biktarvy (bictegravir/emtricitabine/tenofovir alafemanide), which has been recently approved for the treatment of HIV, is a single-pill regimen that associates bictegravir and a novel integrase strand transfer inhibitor (INSTI) with a combination of two nucleoside reverse transcriptase inhibitors (NRTI) of emtricitabine and tenofovir alafemanide. Among treatment complications, rhabdomyolysis has been reported in association with some NRTI and INSTI but never with bictegravir. Acute pancreatitis has also been reported recently with another INSTI, dolutegravir. We report here a 62-year-old man with diabetes and HIV infection, and receiving Biktarvy for 1 month. He presented to the emergency department for muscular pain and fatigue. He was on treatment with Descovy (tenofovir alafenamide/emtricitabine) and Viramune (nevirapine) for 2 years but he recently asked for a regimen simplification. Severe rhabdomyolysis and acute pancreatitis were diagnosed. Although the aetiology of these events could be multifactorial, it cannot be ruled out that this episode could be linked to a potential side effect of bictegravir.

Background

Rhabdomyolysis is a syndrome characterised by muscle necrosis and release of the intracellular muscle constituents into the circulation. Creatine kinase (CK) is typically very high, and muscle pain and myoglobinuria may be present. Acute kidney injury (AKI) is often associated with it.¹ Acquired causes of rhabdomyolysis include traumatic, non-traumatic exertional and non-traumatic non-exertional (substance abuse, medication or toxic exposures, endocrine disturbance and electrolyte anomalies).² Among the involved medications, the most frequent triggers are statins, antiretroviral therapy (ART) and colchicine.³ Rhabdomyolysis-induced AKI is a potentially life-threatening complication.

Risk factors for rhabdomyolysis in patients with HIV-1 include HIV infection itself, coinfection with HCV infection, opportunistic infections, medication-related adverse events, ART and malignancy.⁴ Among ART, nucleoside reverse transcriptase inhibitors (NRTI), such as tenofovir and zidovudine, protease inhibitors (PI) and integrase strand transfer inhibitor (INSTI) are associated with rhabdomyolysis.^{3 5–8} The single-pill regimen Biktarvy, recently commercialised, is known to have a safe profile. It associates an INSTI, bictegravir (BTG) and two reverse transcriptase inhibitors: tenofovir alafenamide (TAF)/emtricitabine (FTC). This regimen is recommended as a first-line agent for HIV-1 infection treatment.⁹ Despite previous reports of rhabdomyolysis with other integrase inhibitors, there is currently no association between BTG and rhabdomyolysis reported in the literature.¹⁰

Next to rhabdomyolysis, acute pancreatitis has been often reported in HIV-infected people.^{11 12} The yearly incidence of acute pancreatitis among HIV-seropositive patients reaches 40% compared with 2% in the general population.¹² Risk factors for acute pancreatitis in HIV-seropositive patients include comorbid conditions (alcohol exposure and biliary disease), opportunistic infections, medication-related adverse events and ART.¹¹ Among ART, zidovudine, didanosine, efavirenz and PI are commonly associated with acute pancreatitis, secondary to metabolic issues (lactic acidosis and hyperlipaemia).¹³ Recent descriptions of acute pancreatitis due to dolutegravir, an INSTI, have been reported several times.^{14 15} Yet, there are no data concerning acute pancreatitis nor rhabdomyolysis linked to BTG. We present here a case, with diabetes and HIV infection, of severe rhabdomyolysis with concomitant acute pancreatitis and acute kidney failure, who was referred to the intensive care unit.

Case presentation

A 62-year-old man with diabetes, from African origin, was referred to the emergency department with a 1-week history of fatigue, myalgia and throat pain. His status went worse with time until he could not stand up anymore. The duration of HIV infection was 15 years with no history of virological failure and a good immune status (last CD4 cell count 676 cells/mm³). His previous ART was changed a month ago to Biktarvy for simplification considerations. The patient is diabetic, treated with metformin (500 mg two times per day) with a haemoglobin A1c (HbA1c) of 5.8%. The patient was also treated with acenocoumarol (Sintrom) for multiple episodes of venous thromboembolic disease (deep venous thrombosis, pulmonary embolism and portal vein thrombosis). Previous treatment with simvastatin was stopped a month ago. The patient denied any alcohol consumption. A previous renal evaluation was normal 3 months ago (serum creatinine 1.19 mg/dL with an estimated glomerular filtration rate of 65 mL/min/1.73 m² and normal kidney echography). Physical examination at admission revealed overweight (body mass index 27.1 kg/m², weight 72 kg and height 1.63 m), disorientation (Glasgow Coma Scale 14/15), with muscular pain and weakness predominant at both thighs without sensitive loss. There was no abdominal pain. Biological investigations showed hyperglycaemic hyperosmotic state (plasma glucose 797 mg/dL, normal range <126 and plasma osmolarity 334 mOsm/kg, normal range 280–308), elevated C-reactive protein (CRP) (200 mg/L, normal range <10), rhabdomyolysis (CK 46 526 U/L, normal range 39–308), AKI (creatinine 2.67 mg/dL, normal range 0.70–1.20), acute liver cytolysis (GPT 161 U/L, normal range <41 and GOT 658 U/L, normal range <40), increased lactate dehydrogenase (977 U/L, normal range <214), hyperlactataemia (2.6 mmol/L, normal range <2), without acidosis (pH 7.39, normal range 7.35–7.45), and hypernatraemia (Na 166 mmol/L, normal range 136–145). Influenza virus, respiratory syncytial virus and metapneumovirus were negative on throat smear. The chest X-ray was unremarkable. Biktarvy was stopped. Correction of dehydration was started followed by insulin therapy. The clinical evolution was marked by the occurrence of dyspnoea, worsening of rhabdomyolysis (CK 12 8310 U/L), liver cytolysis (GPT 389 U/L and GOT 2053 U/L) and inflammatory syndrome (CRP 220 mg/L). Renal function and natraemia were stationary. The patient was therefore transferred to the intensive care unit where a massive fluid resuscitation and intensive insulin therapy were provided.

This pattern was suggestive of severe rhabdomyolysis complicated by AKI, acute liver cytolysis and hypernatraemia in the setting of a hyperglycaemic hyperosmolar state. The infectious serologies, including cytomegalovirus, Epstein-Barr virus, adenovirus, coxsackievirus, varicella and hantavirus, were negative. HIV-1 viral load remains undetectable. Tests for antinuclear antibodies with myositis pattern and rheumatoid factor were negative. Hyperlipasaemia was found (lipasaemia 2613 U/L, normal range 13–60). A new chest X-ray found moderate bilateral pleural effusion. A CT pulmonary angiogram was performed and no pulmonary embolism was found. There was partial atelectasis of both lungs. A magnetic resonance cholangiopancreatography was performed and revealed a pancreas divisum with infiltration of the dorsal pancreas with the stigma of chronic pancreatitis (figure 1). IgG4 and carcinoembryonic antigen (CEA) were within normal range (0.2 g/L, normal range 0.12–1.26 for IgG4 and IgG5, normal range <5.2 for CEA), whereas CA 19-9 was slightly elevated 44 kU/L (normal range <27 kU), total cholesterol 163 mg/dL (normal range <190) and triglycerides 204 mg/dL (normal range <150). The Naranjo score for both toxicities was 5.¹⁶

Figure 1.

Magnetic resonance cholangiopancreatography findings. (A) Dilatation of the dorsal principal duct upstream of short stenosis. (B) Diffuse infiltration of the dorsal pancreas.

Outcome and follow-up

The patient clinical evolution was marked by normalisation of CK, renal function, liver cytolysis, glycaemia and lipasaemia. The patient presented during the admission nosocomial pneumonia due to Klebsiella pneumoniae sensitive to ceftriaxone which was treated for 7 days. The patient was discharged on day 15 of admission with stabilised glycaemia, normalised renal function test and almost normalised CK (482 U/L). Figure 2 presents the evolution of CK, creatinine and lipasaemia during admission. Endoscopic ultrasonography of the upper digestive tract was performed 2 months after the admission to the emergency department, showing chronic pancreatitis, no suspicious mass and moderate dilation of the main pancreatic duct in relation to chronic pancreatitis. No puncture was performed.

Figure 2.

Evolution of CK, lipasaemia and creatinine during the admission. CK, creatine kinase.

Discussion

We describe here a case of severe rhabdomyolysis and asymptomatic acute pancreatitis in a patient with diabetes and HIV infection treated with Biktarvy. There are no cases reported of rhabdomyolysis and acute pancreatitis related to BTG, whereas cases have been reported with dolutegravir and raltegravir, and the aetiology here could be multifactorial.^{15 17–23} A flare of chronic pancreatitis related to previous ART or statin use (simvastatin was stopped a month before symptoms) has been considered at first. However, the duration between treatment interruption and the beginning of symptoms and also the fact that this patient was treated for a long time with TAF and FTC were not consistent with this hypothesis.

Rhabdomyolysis is frequent in patients with HIV and its incidence ranges from 265 to 943 per 100 000 person-years.²³ It is usually multifactorial. Risk factors for rhabdomyolysis include CD4+ cell count, HIV viral load, black race, substance abuse, diabetes, opportunistic infections and medications. In patients with high viral load, HIV itself seems to be associated with rhabdomyolysis. In patients with suppressed viral load, ARTs are more likely to be responsible for rhabdomyolysis.7 8 24 25 Among ARTs, NRTI, such as tenofovir and zidovudine, PI and some INSTI are associated with rhabdomyolysis.^{3 5–8} Currently, to the best of our knowledge, there is no report of BTG-associated rhabdomyolysis. Although it could be a class effect of INSTI, our patient had confounding factors such as hyperosmolar hyperglycaemic state, presentation as viral infection (even though viral serologies carried out returned negative) and previous treatment with simvastatin. If the role of BTG in the occurrence of this severe rhabdomyolysis remains unclear (we cannot argue of whether it was the real trigger or just a cofactor of this severe rhabdomyolysis), then the Naranjo score at 5 suggests drug toxicity.

Acute pancreatitis is also frequent in patients with HIV and its incidence reaches 40%–50% compared with 2% in the normal population.^{12 26} It is reported to be associated with almost the same factors as rhabdomyolysis, such as HIV itself, low CD4+ cell count, high viral load, opportunistic infections, race, alcohol or drug abuse, history of hepatobiliary or pancreatic disease, and ART.¹³ Among ARTs, previous NRTI regimens (such as didanosine and stavudine via mitochondrial toxicity) and PI (due to severe hypertriglyceridaemia) were associated with acute pancreatitis.¹¹ However, there is no case reported of acute pancreatitis associated with BTG, recent case reports are showing an association of acute pancreatitis with other INSTI such as raltegravir and dolutegravir.^{15 27 28} Interestingly, dolutegravir has been associated with rhabdomyolysis and acute pancreatitis.^{15 23} As dolutegravir belongs to the same therapeutic class, it might be class-effect toxicity. In this patient, chronic pancreatitis seems more likely due to the pancreas divisum.²⁹ Rhabdomyolysis is associated with poor prognosis among HIV-infected patients, whereas the morbidity of acute pancreatitis in this group remains unknown. The association of both in the same patient is therefore potentially lethal.^{5 13}

Learning points.

• Rhabdomyolysis and acute pancreatitis are common findings in the HIV-infected population, usually with a multifactorial pattern, including medication.

• Although these toxicities have not been described yet with bictegravir use, the presence of both rhabdomyolysis and acute pancreatitis, in this case, in association with the Naranjo score at 5 suggests drug toxicity.

• These findings must be confirmed in a large population sample.