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 but 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 generically and 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. Rare but potentially severe adverse events include myocardial ischemia or infarction, hypotension, hepatotoxicity and severe hypersensitivity reactions including Stevens Johnson syndrome and toxic epidermal necrolysis.
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% above 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 did not require dose modification. Nevertheless, two cases of acute hepatocellular injury arose in patients receiving maraviroc in prelicensure clinical trials. Both were women, ages 24 and 27, who developed fever, fatigue and rash followed by liver tests abnormalities within 1 to 3 weeks of starting maraviroc. One patient remained anicteric (peak bilirubin 1.5 mg/dL) while the other developed marked jaundice (peak bilirubin 31 mg/dL) and underwent emergency liver transplantation 16 days after onset. In both instances, other potential causes were present but no other diagnosis was confirmed. For these reasons, 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. There have been no further reports of liver failure attributed to maraviroc therapy.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
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. The reported cases have had features suggestive of a hypersensitivity reaction.
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: 06 June 2019
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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).
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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).
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Hepatic safety of maraviroc in patients with HIV-1 and hepatitis C and/or B virus: 144-week results from a randomized, placebo-controlled trial.
Antivir Ther 2017; 22: 263-9. PubMed Citation (Among 137 patients with HIV and HBV or HCV coinfection who were treated with maraviroc or placebo in addition to their standard antiretroviral regimen for 144 weeks, rates of ALT or AST elevations and hepatobiliary adverse events were similar in the two groups).
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Drug Hepatotoxicity: Newer Agents.
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