Comment

other enteroviruses, with acute flaccid paralysis as a rare manifestation. Greninger and colleagues4 reason that the reported substitutions in the viral proteome might play a part in the neurovirulence of the B1 strain infecting cases with acute flaccid paralysis in California and Colorado. However, other genetic differences might also play a part in virulence and neurotropism, such as differences in the 5ʹ-untranslated region, which are important for attenuation of polioviruses.11 In fact, strains within group B all have a longer 5ʹ-untranslated region than other enterovirus D68 strains—ie, those in groups A and C.2 The high number of individuals infected with the B1 strain could be the reason for the noticed cases of acute flaccid paralysis, which might not be more common in B1 than other B strain infections, since with more infected individuals, rarer manifestations will occur. To prove if any of the reported substitutions are important for the proposed changes in neurotropism in clade B1, experiments in susceptible cell systems are needed.12 Even though the mechanism underlying the recent global increase in enterovirus D68 infections remains unknown and whether the variations in disease manifestations are caused by viral properties or just the higher number of infected individuals, this outbreak is a wakeup call not to forget the non-polio enteroviruses, most of which have broad disease manifestations and can spread quickly over continents. Also, because of increased global hygiene, infection is becoming more likely at an older than younger age, in turn resulting in increased incidence of more severe illness, as occurred during the outbreaks of poliovirus in the 1940s and 1950s in Europe and the USA. Thus, continuous enterovirus surveillance is needed, possibly aided by the WHO network of national poliovirus laboratories, and competence in enterovirus isolation on

cell cultures needs to be maintained. Encouragement of the development of pan-enterovirus antiviral drugs is also important in case even more severe outbreaks occur in the future. *Heléne Norder, Lars Magnius Clinical Microbiology–Virology, Sahlgrenska University Hospital, Sahlgrenska Academy Guldhedsg 10B, 413 45 Gothenburg, Sweden (HN, LM) [email protected] We declare no competing interests. 1 2

3

4

5

6 7

8 9

10

11 12

Schieble JH, Fox VL, Lennette EH. A probable new human picornavirus associated with respiratory diseases. Am J Epidemiol 1967; 85: 297–310. Imamura T, Oshitani H. Global reemergence of enterovirus D68 as an important pathogen for acute respiratory infections. Rev Med Virol 2015; 25: 102–14. Ayscue P, Van Haren K, Sheriff H, et al, for the Centers for Disease Control and Prevention (CDC). Acute flaccid paralysis with anterior myelitis—California, June 2012–June 2014. MMWR Morb Mortal Wkly Rep 2014; 63: 903–06. Greninger AL, Naccache SN, Messsacar K, et al. A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012–14): a retrospective cohort study. Lancet Infect Dis 2015; published online March 31. http://dx.doi.org/10.1016/S1473-3099(15)70093-9. Brown BA, Nix WA, Sheth M, Frace M, Oberste MS. Seven strains of enterovirus D68 detected in the United States during the 2014 severe respiratory disease outbreak. Genome Announc 2014; 2: e01201–14. Wylie KM, Wylie TN, Orvedahl A, et al. Genome sequence of enterovirus D68 from St Louis, Missouri, USA. Emerg Infect Dis 2015; 21: 184–86. Piralla A, Girello A, Grignani M, et al. Phylogenetic characterization of enterovirus 68 strains in patients with respiratory syndromes in Italy. J Med Virol 2014; 86: 1590–93. Lang M, Mirand A, Savy N, et al. Acute flaccid paralysis following enterovirus D68 associated pneumonia, France, 2014. Euro Surveill 2014 19: pii:20952. Rahamat-Langendoen J, Riezebos-Brilman A, Borger R, et al. Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections. J Clin Virol 2011; 52: 103–06. Dussart P, Cartet G, Huguet P, et al. Outbreak of acute hemorrhagic conjunctivitis in French Guiana and West Indies caused by coxsackievirus A24 variant: phylogenetic analysis reveals Asian import. J Med Virol 2005; 75: 559–65. Minor PD, Macadam AJ, Stone DM, Almond JW. Genetic basis of attenuation of the Sabin oral poliovirus vaccines. Biologicals 1993; 21: 357–63. Figliozzi RW, Chen F, Balish M, Ajavon A, Hsia SV. Thyroid hormonedependent epigenetic suppression of herpes simplex virus-1 gene expression and viral replication in differentiated neuroendocrine cells. J Neurol Sci 2014; 346: 164–73.

Malaria resistance to non-artemisinin partner drugs: how to reACT People in the world of malaria therapeutics are gravely concerned by the situation, first described in western Cambodia in 2008,1 in which patients presenting with Plasmodium falciparum malaria do not clear parasitaemia after 3 days of artesunate monotherapy. Warnings of dire public health effects have been made since.2 However, investigators of follow-up www.thelancet.com/infection Vol 15 June 2015

studies deploying 7 days of artesunate monotherapy3 or, as in the pivotal multicentre Tracking Resistance to Artemisinin Collaboration (TRAC) study,4 3 days of monotherapy before a full course of locally appropriate artemisinin-based combination treatment (ACT) have noted excellent 42 day efficacy in all study sites.

Published Online April 13, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70080-0 See Articles page 683

621

Comment

Fabio Pupin/Visuals Unlimited, Inc. /Science Photo Library

These findings suggest that a new P falciparum genotype has arisen under ACT selection in western Cambodia and spread to surrounding countries, but, happily, this parasite does not survive artemisinin treatment courses longer than 3 days. This finding does not strictly constitute artemisinin resistance but, rather, a reduction in susceptibility, as 3 days of artesunate monotherapy has never been deemed a fully therapeutic regimen.5 Nevertheless, a threat to future efficacy exists. Importantly, the phenotype was shown to be strongly associated with mutations in the pfk13 gene that alter the aminoacid sequence of the P falciparum kelch13 (K13) propeller domain protein.6 Remarkably, different pfk13 mutations clearly arose independently in parasite populations in Cambodia, Myanmar, and Vietnam,7 and are also evident at low frequency across Africa, where no evidence thus far exists of reduced drug susceptibility due to pfk13 variants.4,8 In the Cambodian sites within the TRAC study,4 excellent 42 day therapeutic efficacy was afforded by short-course artesunate monotherapy before 3 days of dihydroartemisinin-piperaquine, an ACT of high efficacy in all studies so far. However, in The Lancet Infectious Diseases, Michele Spring and colleagues9 report alarming results. They show that reduction in P falciparum piperaquine susceptibility has now arisen in Cambodia on the background of earlier pfk13 mutations. The erosion of dihydroartemisininpiperaquine efficacy is so catastrophic that recruitment into their clinical trial was halted early after assessment of the first 50 participants.10 The study team went on to investigate pfk13 propeller domain sequences and two single-nucleotide polymorphisms previously identified as linked to the artesunate short-course monotherapy slow clearance phenotype: MAL13:1718319 (only 6000 nucleotides away from the pfk13 locus, so almost certainly subject to a linkage sweep) and MAL10:688956.7 Although a clear association was noted between dihydroartemisinin-piperaquine treatment failure and possession of both of these single-nucleotide polymorphisms, together with the pfk13 Cys580Tyr substitution,9 in our opinion, these associations could be misleading. The unusually low level of recombination in P falciparum genotypes in western Cambodia is a serious confounder of such relations and could itself have contributed to emergence of new susceptibility 622

phenotypes.7,11 Further association studies across all genomic loci are needed to tease apart the separate selection signals of artemisinin and piperaquine, if indeed they are separate. The in-vitro drug susceptibility results presented by Spring and colleagues9 are also new and important, being perhaps the first step towards definition of a sensitivity cutoff for piperaquine, but, as the authors acknowledge, this definition cannot be unambiguously derived from ex-vivo studies of parasites exposed to combination treatment. Further doubt is cast by the absence of increased 50% inhibitory concentration in ex-vivo assessments of recrudescent parasite isolates. Do these findings represent actual piperaquine resistance? Could this resistance cause possible serious reductions in dihydroartemisinin-piperaquine efficacy worldwide? In the absence of data on piperaquine’s performance as a monotherapy, resistance cannot be confirmed, but undoubtedly this level of failure of the dihydroartemisinin-piperaquine combination is unprecedented. Furthermore, the slow clearance phenotype at day 3 was not itself significantly associated with dihydroartemisinin-piperaquine failure at 42 days, consistent with occurrence of additional changes to parasite drug susceptibility after emergence of pfk13 variants, leading to dihydroartemisinin-piperaquine failure. For the Greater Mekong Subregion, falciparum malaria is clearly difficult to treat at all; the authors’ suggestion of extended regimens such as those used in the TRAC study is sensible and should be assessed as a matter of urgency. However, the best choice of ACT to include in such a regimen remains unclear. For Africa, where persistent submicroscopic parasitaemia in children given dihydroartemisinin-piperaquine and other ACT has been reported, no evidence of the reduced artemisinin susceptibility evident in Cambodia has yet been noted.12 Yet, rapid progression of P falciparum in the Greater Mekong Subregion towards being comprehensively less susceptible to components of ACT, our sole frontline strategy for treatment of malaria in Africa, should be taken as an urgent warning. Our first priority is to preserve the drugs that we have for as long as we can. We therefore strongly advocate safety and efficacy assessment of sequential 3 day courses of two different ACTs in African children as a ready response to the first signs of waning efficacy of our present treatment regimens—our way to reACT. www.thelancet.com/infection Vol 15 June 2015

Comment

Donelly A van Schalkwyk, *Colin J Sutherland Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK [email protected]

6 7

8

We declare no competing interests. 1

2 3

4 5

Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM, for the Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359: 2619–20. Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009; 361: 455–67. Bethell D, Se Y, Lon C, et al. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. PLoS One 2011; 6: e19283. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014; 371: 411–23. Price R, van Vugt M, Nosten F, et al. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. Am J Trop Med Hyg 1998; 59: 883–88.

9

10 11

12

Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisininresistant Plasmodium falciparum malaria. Nature 2014; 505: 50–55. Takala-Harrison S, Jacob CG, Arze C, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in southeast Asia. J Infect Dis 2015; 211: 670–79. Taylor SM, Parobek CM, DeConti DK, et al. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis 2015; 211: 680–88. Spring MD, Lin JW, Manning JE, et al. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect Dis 2015; published online April 13. http://dx.doi.org/10.1016/S1473-3099(15)70049-6. Saunders DL, Vanachayangul P, Lon C. Dihydroartemisinin-piperaquine failure in Cambodia. New Engl J Med 2014; 371: 484–85. Miotto O, Almagro-Garcia J, Manske M, et al. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet 2013; 45: 648–55. Beshir KB, Sutherland CJ, Sawa P, et al. Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin-combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. J Infect Dis 2013; 208: 2017–24.

The introduction of artemisinin-based combination therapy (ACT) as first-line treatment of malaria has opened up many possibilities in tackling this disease. Treatment with ACTs has been instrumental in reducing malaria mortality rates by 45% between 2000 and 2012.1 Unfortunately, reports of resistance to ACTs threaten the gains of malaria control efforts.2–4 In The Lancet Infectious Diseases, the Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group5 present a systematic review of the effect of dose on efficacy of artemether–lumefantrine in a large and diverse population of patients by examining published and a few unpublished studies done between 1998 and 2012. They concluded that the recommended dose of artemether–lumefantrine provides reliable efficacy in most patients with uncomplicated malaria, but that cure rates were lowest in young children from Asia and young underweight children from Africa. An interesting finding of their study is the significant interaction between regions and the dose of lumefantrine (pinteraction=0·005). The study group thus inferred that although the efficacy of artemether–lumefantrine remains high in Africa, it might be compromised in Asia because of reduced susceptibility to both artemether and lumefantrine. That artemether–lumefantrine retains its efficacy as an antimalarial drug is reassuring, because ACTs are the cornerstone of the present global strategy for the control and elimination of malaria. However, the fact that there www.thelancet.com/infection Vol 15 June 2015

are significant regional differences in the response to artemether–lumefantrine is a cause for concern. This regional difference in efficacy might seem to be a local threat; however, we believe it can easily get out of control, with serious implications for global health. To ensure maximum effectiveness, antimalarial drugs need to be given in an optimised treatment regimen tailored to the weight and age of the patient.5 The dose of lumefantrine was associated with risk of recrudescence especially in young children from Asia, but not in those from Africa. Therefore, the investigators suggested assessment of a higher dose of lumefantrine in this group of patients. Treatment response in children with falciparum malaria depends on many factors, including parasite resistance, host natural immunity, drug quality, pattern of drug use, and pharmacokinetics of the drug.6 Thus, an important parameter to monitor is the effect of pharmacokinetic variability on the therapeutic efficacy of antimalarial drugs. Therapeutic failure might be a result of inadequate concentrations of drug in a patient’s blood,7,8 and suboptimum dosing of either component of the ACT results in incomplete elimination of parasite biomass and subsequent recrudescence of infection.7,9 Unfortunately, antimalarial dosing is usually based on parameters generated from pharmacokinetic studies done mainly in adults; thus, dose adjustments are necessary in some vulnerable groups, including children. For instance, studies done after sulphadoxine–

Godong/Bsip/Science Photo Library

A localised threat to an excellent antimalarial drug

Published Online March 16, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70100-3 See Articles page 692

623

Malaria resistance to non-artemisinin partner drugs: how to reACT.

Malaria resistance to non-artemisinin partner drugs: how to reACT. - PDF Download Free
154KB Sizes 1 Downloads 7 Views