Skeletal muscle toxicity associated with emtricitabine/rilpivirine/tenofovir fixed-dose combination: a case report.

French, European and US guidelines recommend earlier initiation of combined anti-retroviral treatments (cART) [1–3]. Currently, cARTs are overall associated with fewer adverse events. Fixed dose combinations (FDCs) and single treatment regimen are more and more frequently used in HIV-infected patients because they are easier to take and thus considered to improve adherence. However, hindsight is still needed to fully assess the rare adverse events. We describe here the first case of skeletal muscle toxicity associated with rilpivirine (RPV). A 63-year-old man was consulted in June 2013 for subacute weight gain, fatigue and muscular pain. He had an A1 stage past medical history of HIV infection since 1985, with good immunologic profile and an undetectable plasma HIV-1 RNA for 12 years. His cART history began with zidovudine/lamivudine/abacavir FDC, continued with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)/efavirenz (EFV) FDC during 12 years recently changed from January 2013 for FTC/TDF/RPV FDC due to lipid abnormalities. Apart from HIV, he had a stable history of heart angina. He also presented HCV infection successfully treated in 2011 with sustained viral response. He was a semi-professional swimmer and still recently in excellent physical condition. Since the last switch to TDF/FTC/RPV FDC, he rapidly complained of change in his body shape, a gain of 8 kg of abdominal fat, myalgia at mild efforts and proximal muscular loss. Physical examination showed dual lipodystrophia with android obesity and amyotrophy of the proximal muscles. Creatine phosphokinase, aldolase and aspartate aminotransferase were normal. An abdominal computed tomographic scan showed inter-visceral fat accumulation. A muscular biopsy was performed and diagnosed a toxic myopathy with mitochondrial proliferations and cyclo-oxygenase (Cox)-negative fibres. There were no lipid inclusions, no vasculitis and no infiltrates. Tumour necrosis factor-alpha (TNF)-alpha and leptin circulating levels increased whereas adiponectin decreased during the acute cytopathy event (2.4, 5.6 and 4.2 pg/ml; 4.4, 5.7 and 4.5 ng/ml, respectively, before and during the cytopathy event). RPV, tenofovir and FTC concentrations 12 h after the last drug intake were at 377, 180, and 429 ng/ml, respectively. All were above the upper limit of acceptable concentrations. Consequently, RPV was discontinued in this patient and the EFV reinitiated with the same TDF/FTC backbone. Two months after the switch, the patient was doing well, no more complaining of fatigue and muscular pain; he has lost 6 kg in less than 2 weeks after switching. Circulating levels of TNF-alpha, leptin and adiponectin went back to normal values after the RPV switch (5.8, 3.6 and 5.3 μg/ml). Six months after the switch, he has now returned to his original weight (a total loss of 10 kg) and was able to practice swimming as well. Figure 1 presents disease slides with succinate dehydrogenase and Cox activities.Fig. 1: Histo-Enzymology on frozen section of deltoid muscle fragment.(a) Succinate dehydrogenase activity (arrow show fiber with mitochondrial proliferation). (b) Cyclo-oxygenase (Cox) activity (arrow show fiber with no Cox activity).RPV is a recently approved second-generation non-nucleoside reverse transcriptase inhibitor, marketed in coformulation with TDF and FTC in fixed-dose combination. It has demonstrated its noninferiority when compared with EFV as a first-line therapy and is an attractive option for switching therapy. Since the first clinical trials in 2008 and its approval in 2011, RPV has shown an excellent safety profile, compared in particular to EFV. The latest follow-up at 96 weeks has shown few neurologic or psychiatric symptoms, dermatologic abnormalities and mild changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride [4,5]. A case report of severe induced hepatitis on RPV has been published [6,7]. We describe here, to our knowledge, the first case of muscle toxicity associated with a FDC containing RPV. Although we have no clear causal relationship, the accountability of RPV is strong because it was the only changed drug during this period, and its discontinuation has led to an improvement of the symptoms. It was not ruled out whether this adverse event was the result of an excessive concentration or an intrinsic property of RPV. Both EFV and RPV plasma concentrations were above the respective toxicity cut-offs (4000 and 300 ng/ml, respectively). For EFV, such high concentrations might be explained by Cytochrome P450 2B6 genetic polymorphism. For RPV, the recent HCV liver disease (despite the successful treatment in 2011 and any significant fibrosis) might be an explanation of the higher plasma exposure observed. To conclude, even with new FDC regimens considered to be much better tolerated than previous ART regimens, data regarding follow-up of the new drugs are still scarce. This case report describes the first case of skeletal muscle toxicity. Our data suggest that it could be dose-dependent. Plasma concentrations must be of interest when adverse events are suspected to rule out toxicity. Acknowledgements Conflicts of interest S.H. has received travel grants from BMS and MSD. G.P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare and Splicos. Y.Y. is a board member and reports receiving consultancy honoria from Abbott, BMS, Gilead, MSD, Roche, Tibotec and ViiV Healthcare; he also reports receiving honoraria for development of educational presentations from Abbott, BMS, Gilead, Tibotec and ViiV Healthcare. F.X.L. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare.