Severe rhabdomyolysis associated with raltegravir use

Raltegravir, the first in a new class of antiretrovirals (ARVs) called HIV integrase inhibitors, was approved by the United States Food and Drug Administration (FDA) in October 2007. Approval was granted on the basis of results from two 24-week controlled trials conducted in 699 ARV-experienced HIV-infected patients with multidrug resistant virus who demonstrated reductions in plasma viral load (HIV RNA) [1–3]. Among the reported laboratory abnormalities were transient elevations in serum creatine kinase that did not necessitate drug interruption, and elevations in serum creatinine (SCr) that were often associated with concomitant tenofovir use [4]. The FDA and the manufacturer recommend that raltegravir be used with caution in individuals at increased risk for muscle problems, and they listed renal failure as a potential but uncommon adverse event [3,5]. Case report We report the case of a 46-year-old African–American male with multidrug resistant HIV, first diagnosed in 1996, who experienced severe rhabdomyolysis while receiving a raltegravir-containing highly active antiretroviral therapy (HAART) regimen. His medical history was significant for cytomegalovirus retinitis, Pneumocystis jiroveci pneumonia, disseminated Mycobacterium avium complex, cryptococcemia, Candida albicans esophagitis, genital Herpes simplex virus, and chronic renal insufficiency attributed to long-term foscarnet use. Prior to raltegravir initiation, his CD4 count was 17 cells/μl, HIV RNA 270 000 copies/ml, SCr 2.3 mg/dl, CK 117 U/l, and liver function tests were normal. In April 2007, his HAART regimen was changed from didanosine EC 125 mg daily, emtricitabine/tenofovir fixed-dose combination 200/300 mg every other day, enfuvirtide 90 mg subcutaneously twice daily, darunavir 600 mg twice daily and ritonavir 100 mg twice daily to a regimen of enfuvirtide, darunavir, ritonavir, etravirine 200 mg twice daily and raltegravir 400 mg twice daily. Concomitant medications included clarithromycin 500 mg twice daily, ethambutol 1000 mg daily, rifabutin 150 mg every other day, itraconzaole 400 mg daily, trimethoprim/sulfamethoxazole (TMP/SMX) 800/160 mg every Monday, Wednesday and Friday, valacyclovir 500 mg daily, foscarnet 6000 mg daily and bilateral ganciclovir intravitreal implants. He also received intravenous (i.v.) infusions of normal saline at least 3 days per week and intermittently required i.v. potassium and magnesium supplementation, filgrastim and intravitreal foscarnet injections. Of note, intravitreal foscarnet was increased to induction doses due to progressive cytomegalovirus retinitis 6 weeks prior to the initiation of the new HAART regimen, but was at maintenance dose when the regimen began. By August 2007, his CD4 count was 288 cells/μl (7%) and HIV RNA was less than 50 copies/mm. All medications except TMP/SMX and HAART were discontinued. At this time, his SCr was 3.1 mg/dl which was attributed to foscarnet use. On 15 October 2007, SCr increased to 3.5 mg/dl and HAART was withheld. Over the next 5 days, he received i.v. fluids, SCr decreased to 2.9 mg/dl and HAART was resumed. However, by 23 October, SCr rose to 3.7 mg/dl and HAART was discontinued. Off HAART, his SCr stabilized and daily i.v. fluids were discontinued. He began experiencing muscle pain, weakness and difficulty walking on 6 November 2007 and presented for evaluation on 12 November with a SCr of 3.5 mg/dl, creatine kinase (CK) 15 636 U/l, alanine aminotransferase (ALT) 337 U/l, and aspartate aminotransferase (AST) 962 U/l. He was hospitalized and received aggressive i.v. hydration. Symptoms were resolved and he was discharged home on hospital day 4 when laboratory values decreased to CK 2373 U/l, SCr 3.0 mg/dl, ALT 209 U/l and AST 298 U/l. He remained off HAART until 13 December 2007 when a new regimen of lamivudine, enfuvirtide, darunavir, ritonavir, etravirine and maraviroc was initiated. The CK values declined to 681 U/l 10 weeks after raltegravir cessation, SCr ranged between 2.7 and 3.2 mg/dl and liver function tests returned to normal. This is the first reported case of severe rhabdomyolysis associated with raltegravir use. It became clinically apparent only after the frequent administration of i.v. fluid was discontinued. Although the FDA and manufacturer advise caution in patients deemed to be at increased risk for muscle problems, our patient had no identifiable risk factors when raltegravir was begun. He experienced acute worsening of his chronic renal insufficiency after raltegravir initiation and, unlike the majority of renal failure cases reported in clinical trials, was not receiving concomitant tenofovir. In our patient, it is not possible to determine the exact etiology of the acute renal failure or to discern the proportional contribution of raltegravir versus rhabdomyolysis. Clinicians should be alerted to the possibility of rhabdomyolysis in patients receiving raltegravir, even when discernable risk factors are not apparent, and should closely monitor creatine kinase and SCr values. Further study is warranted to determine the epidemiology of raltegravir-associated rhabdomyolysis. Acknowledgements Principal contributions: All authors contributed to the conception, design and performance of this submission. Financial support was received from Feinberg School of Medicine, Northwestern University. Disclaimers: T.R. Zembower, L.Gerzenshtein, K. Coleman-no disclaimers; F.J. Palella, Jr. serves on the Gilead Sciences, Bristol-Myers Squibb and Merck & Co.