key: cord-0008153-p4s7x79d
authors: Savarino, Andrea
title: Use of chloroquine in viral diseases
date: 2011-05-05
journal: Lancet Infect Dis
DOI: 10.1016/s1473-3099(11)70092-5
sha: 83b86f72f2a42376a665b8796b4602ca86772f71
doc_id: 8153
cord_uid: p4s7x79d

nan

In The Lancet Infectious Diseases, Paton and colleagues 1 report results of a clinical trial investigating chloroquine for prevention of infl uenza, which show that this antimalarial drug had no eff ect 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 eff ects on diff erent viruses. 2 Although these eff ects proved highly reproducible, 2 the antiviral eff ects of chloroquine in vivo have been shown only in a mouse model for coronavirus infection. 3 The antiviral eff ect of hydroxychloroquine was shown in two clinical trials of individuals infected with HIV-1; 4,5 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 eff ects to in-vivo settings: narrow therapeutic indexes (ie, the ratio between the 50% cytotoxic concentration [CC 50 ] and the 50% antivirally eff ective concentration [EC 50 ]); EC 50 in the micromolar range (about three orders of magnitude greater than that necessary to inhibit chloroquinesensitive malaria parasites-the microorganisms against which the drug was originally prescribed); poor penetration in specifi c tissues; and high interstrain variability of the eff ects of chloroquine on infl uenza 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 eff ects.

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 eff ect that merits consideration is inhibition, by chloroquine, of some cellular proteins, including the P-glycoprotein and multidrug-resistanceassociated proteins, which extrude drugs from the cells and other anatomic compartments. 8 Although current anti-infl uenza 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 effi cacy of this drug against pandemic infl uenza disease severity shown by Paton and colleagues 1 can be explained not only by absence of an antiviral eff ect in vivo, but also by the fact that pandemic infl uenza 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 eff ective in counteracting the deleterious immune activation associated with the disease. 2,4,6 A recent study by Murray and colleagues 6 showed that chloroquine signifi cantly 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 cells 10 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-infl ammatory eff ects 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 eff ects 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 effi cacy of chloroquine for infl uenza prevention, the results reported by Paton and colleagues 1 will help to address the process of drug repositioning for treatment of infectious diseases.

Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy andrea.savarino@iss.it I declare that I have no confl icts of interest.

In The Lancet Infectious Diseases today, Sarah Hawkes and colleagues 1 review the eff ect of interventions to increase the coverage of screening and treatment for syphilis in pregnancy on the uptake of testing and treatment, and on adverse pregnancy outcomes averted. This study is a timely reminder that syphilis has not disappeared, and remains a major, although entirely preventable, cause of death in newborn babies.

Syphilis is estimated to be responsible for almost 500 000 perinatal deaths per year in sub-Saharan Africa alone. 2 Many of these are stillbirths, which have been largely ignored by the global-health community. They are rarely counted, are not included in national statistics, or in estimates of the global burden of disease, and are not mentioned in the Millennium Development Goals (MDGs). The Lancet's Stillbirths Series is a welcome attempt to redress the balance. Lawn and colleagues 3 estimated that 2·65 million stillbirths occur annually, 98% of them in developing countries. In northern Tanzania, 51% of stillbirths in women who had not been screened for syphilis during pregnancy could be attributed to syphilis after adjustment for other possible causes. 4 In live born infants, most deaths from syphilis occur in the fi rst weeks of life. As many countries make progress towards achieving MDG 4-to reduce mortality by two thirds in children younger than 5 years-neonatal mortality (in the fi rst 4 weeks of life) remains high, now accounting for some 40% of the total mortality. Early neonatal mortality (in the fi rst week of life) has been a

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