Use of chloroquine in viral diseases

Use of chloroquine in viral diseases

The Lancet Infectious Diseases

online 5 May 2011

Article Outline In The Lancet Infectious Diseases, Paton and colleagues¹ report results of a clinical trial investigating chloroquine for prevention of influenza, which show that this antimalarial drug had no effect on disease acquisition and clinical course. Chloroquine, and its hydroxyl analogue hydroxychloroquine, became plausible candidates for treatment of several viral diseases after many reports of their in-vitro inhibitory effects on different viruses.² Although these effects proved highly reproducible,² the antiviral effects of chloroquine in vivo have been shown only in a mouse model for coronavirus infection.³ The antiviral effect of hydroxychloroquine was shown in two clinical trials of individuals infected with HIV-1;^{[4] and [5]} the results, however, could not be reproduced with an equivalent dose of chloroquine.⁶

Several possible reasons exist for the failure of translation of the in-vitro effects to in-vivo settings: narrow therapeutic indexes (ie, the ratio between the 50% cytotoxic concentration [CC₅₀] and the 50% antivirally effective concentration [EC₅₀]); EC₅₀ in the micromolar range (about three orders of magnitude greater than that necessary to inhibit chloroquine-sensitive malaria parasites—the microorganisms against which the drug was originally prescribed); poor penetration in specific tissues; and high interstrain variability of the effects of chloroquine on influenza A viruses.⁷ Maybe, in the future, chloroquine derivatives with improved pharmacokinetics will be able to bridge the gap between the in-vitro and in-vivo effects.

For treatment of RNA-virus infections, I think that monotherapy should be avoided because of the potential for rapid development of drug resistance. Therefore, chloroquine and hydroxychloroquine could still be considered for treatment in combination with other antiviral drugs. An effect that merits consideration is inhibition, by chloroquine, of some cellular proteins, including the P-glycoprotein and multidrug-resistance-associated proteins, which extrude drugs from the cells and other anatomic compartments.⁸ Although current anti-influenza drugs act on extracellular or transmembrane targets, new intracytosolic drug targets in the viral life cycle are being explored.⁹

My colleagues and I proposed the use of chloroquine as a therapeutic agent for some viral infections (eg, SARS and AIDS; the pathogenesis of which is characterised by deleteriously strong or persistent immune activation).² Chloroquine is a well known immunomodulatory agent, as shown by its continued use for treatment of rheumatoid arthritis and other immune-mediated diseases.² In this context, poor efficacy of this drug against pandemic influenza disease severity shown by Paton and colleagues¹ can be explained not only by absence of an antiviral effect in vivo, but also by the fact that pandemic influenza shows, in most patients, a benign clinical course and is generally uncomplicated by immune-mediated damage.

In individuals with HIV/AIDS, chloroquine was repeatedly reported to be effective in counteracting the deleterious immune activation associated with the disease.^{[2], [4] and [6]} A recent study by Murray and colleagues⁶ showed that chloroquine significantly decreased expression of CD38 (a marker of treatment failure and progression to AIDS, which is associated with immune activation induced by viral replication) on CD8 T cells¹⁰ and induced downmodulation of Ki67 (a marker associated with immune-activation-induced lymphocyte mitosis) on memory T cells;¹¹ in-vitro and in-vivo anti-inflammatory effects were in good agreement. One reason behind this agreement is suggested by a recent study of hydroxychloroquine,¹² which showed that the drug accumulates at high concentrations in lymphoid tissues of patients infected with HIV. These reproducible in-vivo effects of quionoline antimalarials could be used as, or added to, new strategies for restricting the HIV reservoir, which are aimed at counteracting the residual immune activation during antiretroviral therapy (favouring sustained viral replication in anatomic sanctuaries), and targeting activation or proliferation of central and transitional memory T cells harbouring silent copies of the HIV proviral DNA (contributing to maintenance of the virus's genome during treatment).¹¹ Notwithstanding the poor efficacy of chloroquine for influenza prevention, the results reported by Paton and colleagues¹ will help to address the process of drug repositioning for treatment of infectious diseases.

I declare that I have no conflicts of interest.

References

1 NI Paton, L Lee and Y Xu et al., Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial, Lancet Infect Dis (2011) 10.1016/S1473-3099(11)70065-2 published online May 6..

2 A Savarino, JR Boelaert, A Cassone, G Majori and R Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis 3 (2003), pp. 722–727. Article |  PDF (291 K) | View Record in Scopus | Cited By in Scopus (79)

3 E Keyaerts, S Li and L Vijgen et al., Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice, Antimicrob Agents Chemother 53 (2009), pp. 3416–3421. Full Text via CrossRef| View Record in Scopus | Cited By in Scopus (0)

4 K Sperber, M Louie and T Kraus et al., Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1, Clin Ther 17 (1995), pp. 622–636. Abstract |  PDF (1030 K) | View Record in Scopus | Cited By in Scopus (51)

5 K Sperber, G Chiang and H Chen et al., Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1, Clin Ther 19 (1997), pp. 913–923. Abstract | PDF (732 K) | View Record in Scopus | Cited By in Scopus (40)

6 SM Murray, CM Down and DR Boulware et al., Reduction of immune activation with chloroquine therapy during chronic HIV infection, J Virol 84 (2010), pp. 12082–12086. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)

7 L Di Trani, A Savarino and L Campitelli et al., Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses, Virol J 4 (2007), p. 39. Full Textvia CrossRef | View Record in Scopus | Cited By in Scopus (6)

8 M Vezmar and E Georges, Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs,Biochem Pharmacol 59 (2000), pp. 1245–1252. Article |  PDF (482 K) | View Record in Scopus | Cited By in Scopus (35)

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Celis Salinas Juan Carlos

Médico Infectólogo/Tropicalista

Medicina del Viajero

CMP 40900 RNE 18872

Hospital Regional de Loreto, Iquitos, Perú