Maraviroc is a chemokine co-receptor 5 (CCR5) antagonist, the first of a new class of agents active against the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS). Maraviroc was approved for use in the United States in 2007 and has had limited use. Maraviroc has been associated with elevations in serum aminotransferase levels and to several cases of acute, clinically apparent liver injury.
Maraviroc (mar" a vir' ok) is relatively new antiretroviral drug that targets one of the receptors for HIV that is present on the surface of lymphocytes. Maraviroc interrupts the binding of HIV to target cells by blocking the chemokine coreceptor 5 (CCR5), a necessary receptor in the uptake of HIV into cells. Maraviroc has both in vitro and in vivo activity against HIV and several randomized controlled trials have shown that it leads to significant decline in HIV RNA levels and rises in peripheral CD4 T cell counts. Maraviroc was given accelerated approval for use in HIV infection in the United States in 2007 and is currently used in a relatively small proportion of antiretroviral regimens, being recommended largely for HIV-treatment experienced adult patients with CCR5-tropic strains of HIV. Maraviroc is available as 150 and 300 mg tablets under the brand name Selzentry. The recommended dose is 150 to 600 mg twice daily in combination with other classes of antiretroviral agents. Common side effects include cough, fever, rash and dizziness.
Therapy with maraviroc was associated with alanine aminotransferase (ALT) elevations in up to 10% of patients, but elevations above 5 times normal are less common. Furthermore, rates of ALT elevations with maraviroc were similar to rates in comparator groups receiving similar background optimized antiretroviral therapy [2.6% vs 3.4% >5 times ULN in one study and 3.9% vs 4.0% in a second]. These elevations have not been associated with clinical symptoms and generally do not require dose modification. Two cases of liver failure arose in patients receiving maraviroc in prelicensure clinical trials, but other causes were thought to have contributed. Nevertheless, hepatitis and hepatic failure are listed as adverse events in the product label which includes a boxed warning about hepatotoxicity. Aplaviroc, the initial CCR5 antagonist developed, was abandoned during preclinical testing because of concerns about hepatotoxicity. The clinical features of hepatotoxicity related to maraviroc have not been described in detail and the drug has had limited use.
Mechanism of Injury
Maraviroc is extensively metabolized in the liver via the CYP 450 system and is a substrate for P-glycoprotein, making it susceptible to multiple drug-drug interactions. Thus, liver injury from maraviroc may be due to its hepatic conversion to a toxic or immunogenic intermediate.
Outcome and Management
The serum aminotransferase abnormalities that occur during maraviroc therapy are usually mild and self-limited, not requiring dose modification or discontinuation. The course and outcome of more clinically apparent hepatotoxicity has not been characterized. There is unlikely to be any cross sensivity to hepatic injury between maraviroc and other antiretroviral agents.
REPRESENTATIVE TRADE NAMES
Maraviroc – Selzentry®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 10 February 2014
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Crabb C. GlaxoSmithKline ends aplaviroc trials. AIDS 2006; 20: 641. PubMed Citation (News article that Glaxo stopped trial of aplaviroc, a CCR5 inhibitor for HIV infection, after 3 patients given drug for 4 weeks developed ALT elevations; none had jaundice or developed liver failure).
Telenti A, Egger M. Identifying safety concerns from genetic data: lessons from the development of CCR5 inhibitors. Antivir Ther 2007; 12: 147-8. PubMed Citation (Editorial discussing the safety of inhibition of CCR5; CCR5 plays an important role in host immune defenses and its inhibition may have adverse effects on susceptibility to other infections, although this has yet to be shown).
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Two new drugs for HIV infection. Med Lett Drugs Ther 2008; 50: 2-4. PubMed Citation (Concise summary on the safety and efficacy of ralegravir and maraviroc in treatment-refractory or treatment-experienced patients with HIV infection; hepatotoxicity reported with maraviroc [with rash and eosinophilia], but not with raltegravir).
Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, Nadler J, et al.; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008; 359: 1429-41. PubMed Citation (Two controlled trials of maraviroc versus placebo combined with optimized antiretroviral therapy in 1049 patients treated for 48 weeks; there were "no significant differences in the rates of treatment-related adverse events"; ALT elevations >5 times ULN occurred in 3.5% on maraviroc vs 3.3% on placebo; no mention of clinically apparent hepatotoxicity).
Emmelkamp JM, Rockstroh JK. Maraviroc, risks and benefits: a review of the clinical literature. Expert Opin Drug Saf 2008; 7: 559-69. PubMed Citation (Review of structure, mode of action, clinical efficacy and safety of maraviroc, the first CCR5 coreceptor antagonist approved for HIV infection; elevations in serum ALT levels occurred as frequently in control as in maraviroc-treated patients; discuss a case of acute liver failure occurring in a patient receiving maraviroc in registration trial who was also on isoniazid and trimethoprim-sulfamethoxazole).
Abel S, van der Ryst E, Rosario MC, Ridgway CE, Medhurst CG, Taylor-Worth RJ, Muirhead GJ. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers. Br J Clin Pharmacol 2008; 65 Suppl 1: 5-18. PubMed Citation (Results of single and multiple dose pharmacokinetic studies of maraviroc in normal controls; no serious adverse events but ALT elevations occurred in 11% and levels were >3 times ULN in one; high dose arm was discontinued because of postural hypotension).
Hughes CA, Robinson L, Tseng A, MacArthur RD. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother 2009; 10: 2445-66. PubMed Citation (Review of tipranavir, darunavir, etravirine, rilpivirine, maraviroc and raltegravir; hepatotoxicity seen with aplaviroc does not appear to be a class effect and only one case of severe hepatotoxicity reported in registration trials of maraviroc; no differences in side effects in cohorts with HCV or HBV coinfection, but maraviroc was approved with a "black box" warning about hepatotoxicity).
Saag M, Goodrich J, Fäenheuer G, Clotet B, Clumeck N, Sullivan J, Westby M, et al.; A4001029 Study Group. A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis 2009; 199: 1638-47. PubMed Citation (Placebo controlled trial of maraviroc [in two doses] in 167 treatment-experienced patients with non-R5 strains of HIV [strains not requiring CCR5 for cell entry] for 24 weeks found no difference in HIV RNA suppression; ALT elevations >5 times ULN in 1% on maraviroc vs 5% on placebo and no clinically apparent liver injury or liver related deaths).
Ayoub A, Alston S, Goodrich J, Heera J, Hoepelman AI, Lalezari J, Mchale M, et al. Hepatic safety and tolerability in the maraviroc clinical development program. AIDS 2010; 24: 2743-50. PubMed Citation (Summary of the hepatic safety of maraviroc from prelicensure controlled trials found no difference in rates of liver enzyme elevations between maraviroc and control treated arms; however, two participants had severe hepatotoxicity that was possibly related to maraviroc, but other potential causes of liver injury were present).
Sierra-Madero J, Di Perri G, Wood R, Saag M, Frank I, Craig C, Burnside R, et al. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials 2010; 11: 125-32. PubMed Citation (In a controlled trial of maraviroc vs efavirenz combined with optimized background therapy continued to 96 weeks, ALT elevations >5 times ULN occurred in 4% of both groups, most elevations occurring during the first 48 weeks).
Hardy WD, Gulick RM, Mayer H, Fätkenheuer G, Nelson M, Heera J, Rajicic N, Goodrich J. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr 2010; 55: 558-64. PubMed Citation (In an extended treatment of patients in two controlled trials of maraviroc to 96 weeks, the rate of ALT elevations >3 times ULN per 100 patients years was 7.8 for maraviroc vs 10.0 for placebo combined with optimized background therapy).
Ortu F, Weimer LE, Floridia M, Manconi PE. Raltegravir, tenofovir, and emtricitabine in an HIV-infected patient with HCV chronic hepatitis, NNRTI intolerance and protease inhibitors-induced severe liver toxicity. Eur J Med Res 2010; 15: 81-3. PubMed Citation (43 year old woman with HIV/HCV coinfection who developed symptomatic elevations of serum enzymes on saquinavir, fosamprenavir and again on darunavir, was adequately maintained on tenofovir/emtricitabine and raltegravir).
Wasmuth JC, Rockstroh JK, Hardy WD. Drug safety evaluation of maraviroc for the treatment of HIV infection. Expert Opin Drug Saf 2012; 11: 161-74. PubMed Citation (Systematic review of the safety of maraviroc from randomized controlled trials in the published literature and from presentations at meetings concluded that “no relevant toxicities or co-morbidities such as ... hepatotoxicty have been described”).
Lazzarin A, Than S, Valluri SR, Heera J, Mukwaya G. Safety profile of maraviroc in patients coinfected with HIV-1 and hepatitis B or C included in the
maraviroc expanded access program. HIV Clin Trials 2012; 13: 83-9. PubMed Citation (Analysis of maraviroc expanded access program of 1032 patients found hepatobiliary events more common in HIV-infected patients with HCV coinfection [10 vs 3.1 per 100 patient years]; rates of ALT elevations >5 times ULN were similar in patients receiving expanded access maraviroc vs placebo recipients in the Motivate trial [Hardy 2010] including those with HIV monoinfection [1.5% vs 3.1%], HIV/HBV coinfection [5.9% vs 8.3%] and HIV/HCV coinfection [8.7% vs 3.3%]).
Perja M, Fusco F, Riva S, Mago D, Gringeri A. Safety and effectiveness of
raltegravir in patients with haemophilia and anti-HIV multidrug resistance.
Haemophilia 2012; 18: 108-11. PubMed Citation (Among
7 patients with hemophilia and HIV-HCV coinfection on antiretroviral regimens
including raltegravir, only 1 had an increase in liver enzyme levels and
“cholestasis”, which resolved promptly when maraviroc was discontinued while
raltegravir was continued).
Surgers L, Lacombe K. Hepatoxicity of new antiretrovirals: a systematic
review. Clin Res Hepatol Gastroenterol 2013; 37: 126-33. PubMed Citation (Review of the rates of liver test abnormalities in large clinical trials of new antiretroviral agents [etravirine, rilpivirine, maraviroc, raltegravir, elvitegravir, dolutegravir and darunavir] concludes that "the overall hepatic tolerance is far bettter with the novel drugs in this review than with former ARV regimens"; only darunavir and maraviroc had warnings about liver injury when they were released).
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