Rhabdomyolysis is a syndrome characterized by muscle necrosis and release of intracellular muscle constituents into the circulation. CK levels are typically markedly elevated, and muscle pain with myoglobinuria may be present. The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-threatening disease associated with extreme enzyme elevations, electrolyte imbalances, and acute kidney injury.[1,2] Serum CK levels at presentation are usually at least 5 times the upper limit of normal, but range from ∼1500 to 100,000 international units/L. The mean peak CK reported for each of a variety of different causes and for patients with both single and multiple causes ranged from ∼10,000 to 25,000 in the largest series.[2,3]
Rhabdomyolysis is common in the HIV positive population, particularly in those with advanced disease.[3,5] Risk factors unique to this population includes HIV infection itself, opportunistic infections, co-infection with HCV, medication-related adverse effects (including pentamidine, trimethoprim-sulfamethoxazole, sulfadiazine, and antiretroviral agents, such as zidovudine, raltegravir and abacavir), drug–drug interactions, malignancy, alcohol and/or illicit drug abuse.[3,6,7] While infection is the most frequently encountered etiology of rhabdomyolysis among the HIV positive population, with sepsis being identified as major cause, Koubar et al demonstrated that 6% of cases of rhabdomyolysis in patients with HIV infection could be attributed to medications.[5,8] Of the listed risk factors, our patient had co-infection with HCV and how it contributed to his presentation is unknown to us, but our suspicion of HCV as a major causative of rhabdomyolysis in our case was low, given the fact that after discontinuation of the offending drug, he did not developed any further episodes of rhabdomyolysis.
Triumeq is a combination of abacavir, dolutegravir and lamivudine, initially approved by the US Food and Drug Administration (FDA) in 2014 and is promoted as an effective, generally well tolerated once-daily fixed-dose tablet option for the management of HIV infection. Lamivudine is a nucleotide reverse transcriptase inhibitor, present in the market since 1995 in the form of other combinations and is comparatively well studied in terms of its adverse effect profile; It can cause allergic reaction, nausea, vomiting, diarrhea, lactic acidosis, and rarely rhabdomyolysis due to mitochondrial toxicity.[9,10] There have been few cases reported in the literature regarding lamivudine induced rhabdomyolysis. Baharin et al reported a case of rhabdomyolysis associated to lamivudine administration in acute viral hepatitis B infection, which resolved after fluid therapy and 2 weeks of drug cessation. The suspicion for this agent as culprit for the development of rhabdomyolysis in our patient is low given mildly elevated lactic acid level on presentation, which has been associated as well to be elevated in the case of lamivudine associated rhabdomyolysis.
Dolutegravir is an integrase inhibitor FDA approved in 2013 with a range of adverse effects including liver enzyme abnormalities and more recently neuropsychiatric effects and weight gain[12,13] however, to date there is no literature report of acute rhabdomyolysis with dolutegravir. Further investigation into the literature regarding adverse effects of myopathy or rhabdomyolysis derived from other integrase inhibitors (INSTI), reveals sporadic reports of muscle toxicity associated with raltegravir therapy and CK elevation of >200U/L in approximately 8.9% of patients without clinical signs of myopathy. Although the FDA has advised checking a CK level before initiation of raltegravir, no cases have been reported regarding treatment cessation secondary to rhabdomyolysis. The mechanism for muscle toxicity induced by raltegravir can be explained by either elevation of its level due to impaired hepatic glucuronidation associated with liver dysfunction or elevated levels owing to kidney failure. Whether it is a class effect is not known since to the best of our knowledge no cases have been reported with dolutegravir in the literature and hence its mechanism of muscle injury remains unclear. Another hypothesis proposed is variable pharmacodynamics of dolutegravir with other component drugs in Triumeq which could lead to an exaggerated dolutegravir muscle effect. Our patient did not have any classically associated risk factors for rhabdomyolysis such as alcohol use, antipsychotics, strenuous physical activity or underlying renal impairment. Liver enzymes elevation in our patient was suspected to be as a direct result of rhabdomyolysis, however drug toxicity may have also played a role, as literature reports elevation of liver enzymes as well.[16–18] The transaminitis in this case also resolved after cessation of the medication and administration of intravenous fluids.
Another component of Triumeq is abacavir, which is a nucleotide reverse transcriptase inhibitor. It carries relatively notorious adverse effect profile including hypersensitivity reaction, fever, nausea and diarrhea. Abacavir related hypersensitivity ranges from 3% to 6% and the median time to develop a hypersensitivity reaction is 11 days after starting the medication is started. The HLA-B5701 haplotype is listed as a significant risk factor for the development of hypersensitivity reactions, yet only 55% of HLA-B5701 positive individuals develop such reactions. Abacavir-induced hypersensitivity has been postulated to stem from mitochondrial toxicity, production of reactive metabolites, altered peptide repertoire presentation by the Major Histocompatibility Complex (MHC) I complexes and covalent haptenation of endogenous peptides. In our patient, HLA-B5701 was negative, thus hypersensitivity to abacavir would be unlikely. Abacavir induced rhabdomyolysis is rare, with a post marketing study done at Japan showing that this complication happened in 1 case out of 306 subjects analyzed[21–23] and other reports stated that 6% of patients with abacavir hypersensitivity develop rhabdomyolysis.[,6,7,19,21]
Finally, Triumeq related postmarketing adverse reactions are reported, including rhabdomyolysis. Van Dam and Van Geffen described a case of young man who presented with Triumeq overdose and developed hypokalemia and lactic acidosis, which resolved after intravenous fluids and drug cessation without description of muscle toxicity or CK elevation. To the best of our knowledge, our patient did not overdose with Triumeq or had traditional risk factors for myositis/myopathy, yet developed acute rhabdomyolysis.
Rhabdomyolysis can be a common finding in the HIV infected population, with a myriad of etiologies reported, including medication. While rare, rhabdomyolysis is a possible adverse reaction in patient receiving Triumeq and this case illustrates a suspected direct causal link with this medication. We consider that clinicians should be aware of this adverse event when managing patients with HIV infection using Triumeq. As mentioned above, rhabdomyolysis can be multifactorial in HIV infected patients, and Triumeq should be considered as an etiology in the appropriate setting. More data is warranted to elucidate the mechanism of rhabdomyolysis associated with Triumeq.
Supervision: Paul Kelly.
Writing – original draft: Muhammad Saad, Fernando Casado-Castillo.
Writing – review & editing: Muhammad Saad, Paul Kelly, Fernando Casado-Castillo.
. Torres P, Helmstetter J, Kaye A. Rhabdomyolysis
: pathogenesis, diagnosis, and treatment. Ochsner J 2015;15:58–69.
. Miller M. Clinical manifestation and diagnosis of rhabdomyolysis
. Available at: Uptodate.com (Feb 2018). Accessed March 31, 2018.
. Fontaine C, Guiard-Schmid JB, Slama L. Correspondence: severe rhabdomyolysis
during a hypersensitivity reaction to abacavir in a patient treated with ciprofibrate. AIDS 2005;19:1927.
. Garcia-Cortes M, Lucena MI, Pachkoria K, et al. Spanish Group for the Study of Drug-Induced Liver Disease. Evaluation of Naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008;27:780–9.
. Koubar S, Estrella M, Warrier R. Rhabdomyolysis
in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrol 2017;18:242.
. Chanson N, Bossi P, Schneider L, et al. Case report: rhabdomyolysis
after ezetimibe/simvastatin therapy in an HIV-infected patient. NDT Plus 2008;3:157–61.
. Parsonage M, Barlow G, Lillie P, et al. Severe myositis on commencement of efavirenz, abacavir and lamivudine, in the absence of lactic acidosis or classical abacavir hypersensitivity. BMJ Case Rep 2009;2009:bcr01.
. Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis
––an overview for clinicians. Crit Care 2005;9:158–69.
. Mendila M, Walter GF, Stoll M, et al. Rhabdomyolysis
in antiretroviral therapy with Lamivudin. Dtsch Med Wochenschr 1997;122:1003–6.
. Adani GL, Baccarani U, Risaliti A, et al. Rhabdomyolysis
due to Lamivudine administration in a liver transplant recipient. Am J Transplant 2005;5:634.
. Baharin J, Saharai NS, Lim SM. Rhabdomyolysis
due to Lamivudine administration in acute viral hepatitis B infection: a case report from Malaysia 2014;6:863–7.
. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med 2017;18:56–63.
. Norwood J, Turner M, Bofill C, et al. Brief report: weight gain in persons with HIV switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. J Acquir Immune Defic Syndr 2017;76:526–31.
. Tsai WJ, Lee SS, Tsai HC, et al. Rapid onset of rhabdomyolysis
after switching to a raltegravir-based antiretroviral regimen. J Microbiol Immunol Infect 2016;49:286–8.
. Croce F, Vitello P. Severe raltegravir-associated rhabdomyolysis
: a case report and review of the literature. Int J STD AIDS 2010;21:783–5.
. Madeddu G, Soddu V, Ricci E, et al. Muscle symptoms and creatine phosphokinase elevations in patients receiving raltegravir in clinical practice: results from a multicenter study. J Int AIDS Soc 2010;13(suppl 4):422–5.
. Lee FJ, Carr A. Tolerability of HIV integrase inhibitors. Curr Opin HIV AIDS 2012;7:422–8.
. Clay PG. The abacavir hypersensitivity reaction: a review. Clin Ther 2002;24:1502–4.
. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B5701, HLA-DR7 and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727–32.
. Hass C, Rodriguez M, Borgman J. Abacavir-induced fulminant hepatic failure in a HIV/HCV co-infected patient. BMJ Case Rep 2015;2015:bcr2015212566.
. Kurita T, Kitaichi T, Nagao T. Safety analysis of Ziagen® (abacavir sulfate) in postmarketing surveillance in Japan. Pharmacoepidemiol Drug Safety 2014;23:361–71.
. Spiegel L, Schreib P, Shah H. Severe recurrent rhabdomyolysis
-induced acute kidney injury in a HIV-infected patient on antiretroviral therapy. Ren Fail 2013;35:1186–90.
. ViiV Healthcare. Triumeq
(abacavir, dolutegravir, and lamivudine) tablets, for oral use: US prescribing information. 2014. Available at: http://www.fda.gov
. Accessed February 9, 2018.
. Van Dam PM, Van Geffen MW. Intentional overdose of dolutegravir/abacavir/lamivudine (Triumeq
) in a 26-year-old man. Antivir Ther 2018;549–52.
. Joshi MK, Liu HH. Acute rhabdomyolysis
and renal failure in HIV-infected patients: risk factors, presentation, and pathophysiology. AIDS Patient Care STDs 2000;14:541–8.
Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
HIV infection; rhabdomyolysis; Triumeq