Severe hyperkalaemia due to a potential drug–drug interaction between eplerenone and antiretrovirals in a HIV-positive patient after a myocardial infarction

Abstract

We present a case of a 48-year-old white HIV-1 positive man who presented an acute myocardial infarction. The patient was on ART for the last ten years with emtricitabine/tenofovir and ritonavir-boosted fosamprenavir. Eplerenone 25 mg/day was also initiated due to a left ventricular dysfunction. A week after discharge a routine laboratory examination revealed severe hyperkalaemia. Due to suspicion of a potential drug–drug interaction, both eplerenone and ARVs were interrupted. Despite daily treatment for hyperkalaemia, serum potassium levels normalized after two weeks. Eplerenone is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4; therefore, concomitant administration with CYP3A4 inhibitors, like ritonavir, may increase plasma levels of eplerenone and, therefore, the risk of side effects, mainly hyperkalaemia. Based on this case, it is important to alert the medical community of this possible life-threatening drug-drug interaction between eplerenone and ritonavir-boosted protease inhibitor.

Keywords

HIV antiretroviral treatment HAART drug-drug interactions eplerenone myocardial infarction hyperkalaemia

Risk of cardiovascular disease (CVD), including myocardial infarction, heart failure and stroke, is significantly higher for people living with HIV, even in the setting of HIV viral suppression with effective antiretroviral therapy.¹ Drugs for CVD management have several significant drug–drug interactions (DDIs) with antiretroviral agents.²

A 48-year-old white HIV-1 positive man presented to the emergency department with a sudden onset severe chest pain in December 2018. The patient was on antiretroviral treatment for the last 10 years with emtricitabine/tenofovir and ritonavir-boosted fosamprenavir. He had a undetectable HIV viral load, and his current CD4 T-cell count was 1253 cells/uL. He had history of untreated hepatitis C co-infection, hyperlipidaemia and smoking. Despite medical advice, the patient had refused to switch antiretroviral treatment and start lipid-lowering treatment and smoking cessation.

A diagnosis of acute ST-elevation segment myocardial infarction was made. The patient underwent urgent coronary angioplasty, and a drug-eluting stent was placed. Treatment with losartan, carvedilol, aspirin, clopidogrel and atorvastatin was initiated. Eplerenone 25 mg/day was also initiated due to left ventricular dysfunction.

A week after discharge, the patient was stable and asymptomatic. A routine laboratory examination revealed severe hyperkalaemia (K⁺ 6.7 mEq/L) and mild hyponatraemia (Na⁺ 126 mEq/L). The patient had normal renal function, normoglycaemia and normal serum magnesium and phosphorus. An electrocardiogram (ECG) was performed, and no relevant findings were observed.

Hyperkalaemia was interpreted as secondary to eplerenone. Nebulised salbutamol, insulin–glucose infusion and furosemide were administered for hyperkalaemia treatment. Due to suspicion of a potential DDI, both eplerenone and antiretrovirals were interrupted. Despite daily treatment for hyperkalaemia, serum potassium levels normalised after 2 weeks (Table 1).

Table 1.

Laboratory evolution in a HIV-positive patient receiving eplerenone and antiretrovirals for an acute myocardial infraction.

		ART^a/EPL interruption				ART^b re-initiation	EPL re-initiation
	10/December	13/December	14/December	17/December	21/December	28/December	14/January	28/January	10/February
K+ (mEq/L)	6.7	6.16	5.77	6.1	6.3	4.7	4.5	4.6	4.6
Na (mEq/L)	126	128	125	130	132	135	135	136	138
Cl (mEq/L)	82	86	83	84	91	101	99	98	98
Cr (g/L)	1.08			1.38	1.28	1.08	1.12

ART: antiretroviral therapy; EPL: eplerenone.

^aEmtricitabine/tenofovir DF–fosamprenavir/ritonavir.

^bEmtricitabine/tenofovir DF–dolutegravir.

At discharge, antiretroviral treatment was reinitiated with emtricitabine/tenofovir and dolutegravir (DTG) to avoid possible DDIs. Two weeks later, eplerenone was initiated again. No recurrence of the hyperkalaemia was observed up to 12 months of follow-up.

Hyperkalaemia is a potentially fatal electrolyte disorder, due to severe cardiac arrhythmias and muscle paralysis. Hyperkalaemia with potassium level more than 6.5 mEq/L or ECG changes is a medical emergency.³

Eplerenone, a mineralocorticoid receptor antagonist (MRA), is recommended for patients with left ventricular dysfunction (ejection fraction ≤40%) after acute myocardial infarction.⁴ Due to its mineralocorticoid antagonism, MRA treatment is associated with the risk of hyperkalaemia as a side effect.⁵ Eplerenone is metabolised by the hepatic P450 cytochrome isoenzyme CYP3A4; therefore, concomitant administration with CYP3A4 inhibitors, such as ritonavir, may increase plasma levels of eplerenone and, therefore, the risk of side effects, mainly hyperkalaemia.⁶

Eplerenone product information and DDI databases advise about this hypothetical hazardous DDI with ritonavir or cobicistat boosted antiretroviral treatments.^6,7 However, pharmacokinetic in vivo data is only available for saquinavir.⁸

Dolutegravir, which was included in the second antiretroviral regimen of the patient, has a favourable DDI profile because it does not significantly induce or inhibit the cytochrome P450 or glucuronidation systems.⁹ For that reason, no DDIs were expected after eplerenone re-initiation.

To the best of our knowledge, this is the first report of severe hyperkalaemia as a result of a DDI between eplerenone and a boosted antiretroviral treatment. Although this could be solely a side effect of eplerenone, incidence rates of severe hyperkalaemia (K >6.0 mEq/L) are very low and tend to appear later in the course of treatment even in those patients with high risk of hyperkalaemia.¹⁰ Moreover, the fact that hyperkalaemia was consistent with the time course of the possible interaction, the lack of reappearance when eplerenone was re-administered after a switch to an antiretroviral that not exhibit inhibition of CYP450 enzyme, and the lack of reasonable alternative causes support our case. Another fact that supports a potential DDI is the delayed hyperkalaemia resolution despite supportive therapy and eplerenone interruption. A possible explanation is that ritonavir inhibition of eplerenone metabolism could have decreased the clearance of eplerenone and, as consequence, retained levels of eplerenone for a longer period of time than usually.⁸

It is important to remark that boosted antiretroviral regimens are associated with increased risks of potential DDIs. Therefore, it would be important to switch these regimens in patients who do not have a clear indication. When this is not feasible, it is essential to check for potential DDIs with all concomitant medications.

Based on this case, it is important to alert the medical community of this possible life-threatening DDI between eplerenone and ritonavir-boosted protease inhibitor.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Authors’ note

These data have been generated as part of our routine work at the Cosme Argerich Hospital.

ORCID iD

Ezequiel Cordova

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