Acute Myocarditis after Switch to Dolutegravir

The spectrum of cardiac disease that can occasionally complicate the course of HIV infection is broad and varied. Focal myocarditis was not an unusual autopsy finding in the pre-HAART era [1], although clinically evident disease is rare. Myocarditis in HIV-infected patients occasionally results from an infectious [2] or neoplastic [3] insult. A direct or indirect effect of HIV itself on myocardial cells, as well as selected nutritional deficiencies, may also play a role in heart muscle disease in some HIV-infected patients [4]. Antiretroviral therapy, most notably regimens that include zidovudine, a drug known to induce toxic myopathy, has been reported as a potential cause of cardiomyopathy in individual patients [5,6]. Recently, Mahlab-Guri et al.[7] reported two cases of severe myocarditis associated with the integrase inhibitor (INI) dolutegravir. An additional patient is known to have been diagnosed with acute myocarditis while on a dolutegravir study [8]. We wish to report the case of a Brazilian HIV-infected man who developed acute myocarditis a few weeks after switching his antiretroviral therapy to a dolutegravir-including regimen. A 35-year-old HIV-infected white male patient presented with acute precordial and retrosternal pain that started 90 min after preforming vigorous-intensity physical activity (running). The pain radiated to the right mammary and palmar region. There was no preceding fever, constitutional, or cardiovascular symptoms. He was an otherwise healthy, athletic man who engaged in regular physical activity. The patient did not smoke, had no history of hypertension, alcohol, cocaine, or other illicit drug use, and did not use athlete performance or dietary supplements. He had no family history or other risk factors for cardiovascular disease other than HIV infection and antiretroviral treatment. The diagnosis of HIV infection had been made 6 years previously when he developed an acute retroviral syndrome and seroconversion of the previously negative HIV serologies was documented. Two months later, the HIV plasma viral load was 21 968 (4.34 log) copies/ml and the CD4+ cell count was 420 cells/μl. An antiretroviral regimen consisting of lamivudine, tenofovir, and efavirenz was then initiated. Transient, generalized rash attributed to efavirenz was recorded 8 days after treatment initiation. Treatment was not interrupted and the plasma HIV viral load dropped to consistently bellow detection limits. Secondary syphilis was diagnosed and treated 5 years earlier. Six months before the current presentation, the CD4+ cell count was 687/μl. Two months before the acute cardiovascular event, efavirenz had been switched to dolutegravir (50 mg/day) due to central nervous system adverse effects (sleep disturbance). On admission, an ECG showed ST-segment elevation in several leads, a pattern which was considered suggestive of myocarditis. There was no evidence of ventricular dysfunction or pericardial effusion on echocardiography. The creatine phosphokinase was 1172 U/l (normal range 23–300 U/l) and the troponin I level was 0.75 ng/ml (normal range 0–0.023 ng/ml). Three hours later, the creatine phosphokinase was 1223 U/l and the troponin I level was 1.98 ng/ml. The aspartate aminotransferase was within normal limits. Cardiac catheterization revealed no evidence of coronary disease. A cardiac MRI study confirmed the diagnosis of myocarditis by exhibiting the features of delayed gadolinium enhancement in the mid-endocardial region, mainly in the inferior and lateral walls, with sparing of the subendocardial region. Endomyocardial biopsy was not performed. He completely recovered and was discharged 9 days later on enalapril 5 mg/day and aspirin 100 mg/day. Due to the previous reports of myocarditis associated with dolutegravir-containing regimens, his antiretroviral combination was changed to lamivudine, tenofovir, and ritonavir-boosted darunavir. Our patient presented with an acute cardiovascular event 2 months after switching efavirenz for dolutegravir. The temporal relationship between the development of myocarditis and the initiation of dolutegravir in this antiretroviral-experienced patient strongly suggests a drug-related event. The present case report adds data to the previously described cases of severe acute myocarditis reported by Mahlab-Guri et al.[7]. One of their patients died and the other was left with severe heart failure. It should be highlighted that the first approved INI, raltegravir, has been associated with several cases of skeletal muscle toxicity and severe rhabdomyolisis [9–12]. Severe rhabdomyolisis has also been reported when elvitegravir-containing regimens where combined with certain HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors [13,14]. INIs have also been associated with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) [15–18], including fatal cases linked to raltegravir [19] and dolutegravir [20]. An association of raltegravir-related DIH/DRESS and HLA-B*53:01 has recently been proposed [21]. A case of subacute liver failure requiring transplantation following initiation of dolutegravir is also known [22]. It is therefore clear that a subset of HIV-infected patients is prone to the development of severe, potentially fatal drug-related toxicities shortly after initiation of INI-including HAART. Physicians caring for HIV-infected patients should be aware of these dramatic drug-related toxicities. Acknowledgements Informed consent Informed consent of the patient was obtained for publication of the case report. Conflicts of interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.