To the Editor:

In the paper authored by Christophe Moreno and colleagues, a more pronounced hepatotoxic reaction and an increased rate of liver associated mortality was observed in CCR5 deficient mice after exposure to Concanavalin A.1 This observation is of particular interest as CCR5 inhibitors are currently studied as antiretroviral drugs for the treatment of HIV infection.2, 3 However, the development of aplaviroc was stopped recently due to hepatotoxic adverse events associated with jaundice observed in four study participants.4 For maraviroc, another CCR5 inhibitor currently in phase III trials, at least one case of liver failure resulting in liver transplantation was observed (personal communication). However, details concerning this case were not disclosed by the manufacturer of the drug to the public.

The mechanism for the possible hepatotoxic reactions under treatment with CCR5 inhibitors remains unknown. In this context, the paper by Moreno and colleagues provides an intriguing hypothesis.1 The results from the paper suggest an increased vulnerability to hepatotoxic agents due to CCR5 deficiency or pharmacological inhibition due to an imbalance in the cytokine response rather than a direct hepatotoxic action of the drug itself.

The impact of CCR5-Δ32 mutation on the clinical course of hepatitis C is still controversial: increased susceptibility to chronic HCV infection, decreased necro-inflammatory activity and a reduced sensitivity to interferon monotherapy have all been reported in different populations.5, 6

Given the relevant proportion of HIV-seropositive patients with hepatitis B or C coinfection in addition to other conditions of liver injury prevalent in the HIV-infected individuals (drugs, alcohol, steatosis) the potential of CCR5 blockade or deficiency to affect liver inflammation and progression of fibrosis deserves further attention.

In addition, the hypothetical vulnerability of patients with CCR5 deficiency due to the non-functional homozygous CCR5-Δ32 allele may explain why individuals with this mutation represent only a small minority of the population <2% in most parts of the world.7 Even in Northern Europe the prevalence is at most 10% of the population despite the partial protection against such deadly infections as the plague.7


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  • 1
    Moreno C, Gusto T, Nicaise C, Quertinmot E, Nagy N, Parmentier M, et al. CCR5 deficiency exacerbates T-cell–mediated hepatitis in mice. HEPATOLOGY 2005; 42: 854862.
  • 2
    Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman A, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: 11701172.
  • 3
    Schuermann D, Pechardschek C, Rouzier R, Nougarede R, Faetkenheuer G, Ochlast I, et al. SCH 417690: antiviral activity of a potent new receptor antagonist. Third IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, July 24-27, 2005. Abstract TuOa0205.
  • 4
    Nichols WG, Steel HM, Bonny TM, Min SS, Curtis L, Kabeya K, et al. Hepatotoxicity observed in clinical trials of aplaviroc (APL 873140). Tenth European AIDS Conference. November 17-20 2005. Dublin.
  • 5
    Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P, et al. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. HEPATOLOGY 2003; 38: 14681476.
  • 6
    Ahlenstiel G, Woitas RP, Rockstroh J, Spengler U. CC-chemokine receptor 5 (CCR5) in hepatitis C—at the crossroads of the antiviral immune response? J Antimicrob Chemother 2004; 53: 895898.
  • 7
    Galvani AP, Novembre J. The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Microbes Infect 2005; 7: 302309.

Stefan Mauss*, Massimo Puoti†, * Center for HIV and Hepatogastroenterology, Duesseldorf, Germany, † University of Brescia, Italy.