Mass administration of the antimalarial drug mefloquine to guantnamo detainees: a critical analysis

Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 Mass administration of the antimalarial drug mefloquine toGuanta´namo detainees: a critical analysis Department of Preventive Medicine, Bayne-Jones Army Community Hospital, Ft. Polk, LA, USA Recently, evidence has emerged from an unusual form of mass drug administration practised amongdetainees held at US Naval Station Guanta´namo Bay, Cuba (‘Guanta´namo’), ostensibly as a publichealth measure. Mefloquine, an antimalarial drug originally developed by the US military, whose use isassociated with a range of severe neuropsychiatric adverse effects, was administered at treatment dosesto detainees immediately upon their arrival at Guanta´namo, prior to laboratory testing for malariaand irrespective of symptoms of disease. In this analysis, the history of mefloquine’s development isreviewed and the indications for its administration at treatment doses are discussed. The statedrationale for the use of mefloquine among Guanta´namo detainees is then evaluated in the context ofaccepted forms of population-based malaria control. It is concluded that there was no plausible publichealth indication for the use of mefloquine at Guanta´namo and that based on prevailing standards ofcare, the clinical indications for its use are decidedly unclear. This analysis suggests the troublingpossibility that the use of mefloquine at Guanta´namo may have been motivated in part by knowledge ofthe drug’s adverse effects, and points to a critical need for further investigation to resolve unansweredquestions regarding the drug’s potentially inappropriate use.
keywords malaria, mefloquine, military medicine, United States, Cuba FOIA release (Figure 1) indicate that mefloquine was administered by mouth (‘PO’) upon arrival, at treatment Evidence has recently emerged (Denbeaux et al. 2010; doses of 1250 mg (‘750 mg PO now, 500 mg PO in Leopold & Kaye 2010; Shane 2011) from an unusual form 12 h’) (DoD 2007) before laboratory testing for malaria of mass drug administration (MDA) practised among and irrespective of the presence of symptoms of disease.
detainees held at US Naval Station Guanta´namo Bay, Cuba Representatives from DoD have recently defended this (‘Guanta´namo’). Documents released in 2007 by the practice by claiming that ‘[a]llowing the disease to Department of Defense (DoD), in response to a Freedom of spread would have been a public health disaster’ Information Act (FOIA) request, indicate that many, if not (Shane 2011) and contending that this MDA was all, of the detainees held at the facility received treatment therefore ‘completely appropriate’ (Shane 2011). Others doses of the antimalarial drug mefloquine immediately have concluded that this use of mefloquine was upon their arrival to Guanta´namo (DoD 2007). Although medically inappropriate at best, and at worst constituted the island is currently free of malaria, competent vectors a form of abuse (Denbeaux et al. 2010; Leopold & Kaye for disease transmission (Bawden et al. 1995) including Anopheles albimanus (Molina-Cruz et al. 2004) still exist.
This analysis reviews the history of mefloquine’s devel- Thus, the migration into Cuba of individuals infected with opment and discusses indications for the administration of malaria creates a theoretical risk of reintroduction via treatment doses of antimalarial drugs including mefloqu- autochthonous transmission. Most of the detainees held at ine. The stated rationale for the use of mefloquine among Guanta´namo had been captured from malaria-endemic Guanta´namo detainees is evaluated in the context of countries. Mefloquine treatment as a public health measure accepted forms of population-based malaria control. Pos- was ostensibly motivated by a desire to prevent such sible indications for the use of mefloquine at Guanta´namo are discussed, and recommendations made for further Individual detainee medical records and the ‘Standard investigation to resolve critical unanswered questions Inprocessing Orders for Detainees’ contained within the Published 2012. This article is a US Government work and is in the public domain in the USA Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 R. L. Nevin Administration of mefloquine to Guanta´namo detainees Symptoms, Diagnosis, Treatment, Treating organization (Sign each page) JTF, JMG, Medical Department, Guantanamo Bay, Cuba 09593(updated 24 September 2003//sed) Standard inprocessing orders for detainees: 1. Mefloquine 750 mg PO now, 500 mg PO in 12 h Figure 1 Extract of ‘Standard Inprocessing Orders for Detainees’ (from DoD 2007).
(Patchen et al. 1989) and were later demonstrated to affect History of mefloquine’s development and use a majority of healthy adults with use at treatment doses Mefloquine is a 4-methanolquinoline structurally related to quinine. US military scientists at the Walter Reed Army Notwithstanding early concerns from the World Health Institute of Research (WRAIR) developed the compound in Organization (WHO) of severe CNS reactions including the early 1970s in response to concerns of rising chloro- hallucinations, depression and suicidal behaviour associ- quine resistance (United Nations Development Programme ated with its use (WHO 1989), mefloquine was approved (UNDP) et al. 1983). Initially known as WR142,490, the by the US Food and Drug Administration (FDA) for drug underwent Phase I testing on US prisoners (Alving prophylaxis of malaria and was soon widely prescribed et al. 1948) beginning in 1972 (Trenholme et al. 1975; among US military personnel at a weekly dose of 250 mg UNDP et al. 1983) and Phase II testing for treatment (Wallace et al. 1996; Nevin 2010; Whitman et al. 2010).
(Maugh 1977) and prophylaxis (Clyde et al. 1976) of In the years since the drug’s approval, awareness has malaria throughout the 1970s (Pearlman et al. 1980) and grown of an unexpectedly high risk of CNS adverse effects early 1980s (UNDP et al. 1983). Following initial testing, (Overbosch et al. 2001), as well as the potential for the drug was transferred to F. Hoffmann-La Roche Ltd. for neurotoxicity (Dow et al. 2003, 2006; Hood et al. 2010) commercial development (Fernex 1981), where it was and associated long-term adverse effects (Nevin 2012) with given the trade name LariamÒ. The drug had initially use even at this lower prophylactic dose. This risk is proven highly effective against the illness-causing blood- thought to be increased among those with a history of stage schizonts of chloroquine-resistant Plasmodium falci- mental illness or other CNS contraindication (Nevin et al.
parum and P. vivax (Clyde et al. 1976), but was later shown to lack the effectiveness of the related 8-amino- Despite administrative policies (Department of the Army quinolines against liver-stage schizonts and hypnozoites, Office of the Surgeon General 2002) and restrictive and against the blood-stage gametocytes that transmit the labelling changes intended to reduce the risk of adverse disease (Karbwang et al. 1992; Price et al. 1999).
effects, inappropriate prescribing of the drug has remained During initial testing, transient dizziness and nausea widespread (Nevin 2010; Office of the Assistant Secretary were reported at high treatment doses of 1750–2000 mg of Defense for Health Affairs (OASDHA) 2012). In (Trenholme et al. 1975). During subsequent testing, lower response, the US military has now sharply restricted the treatment doses ranging from 750–1500 mg were also drug’s use (OASDHA 2009) amid new concerns that the found to carry a risk of nausea, abdominal pain and CNS adverse effects of mefloquine might also complicate explosive vomiting (Hall et al. 1977), as well as central the diagnosis and management of post-traumatic stress nervous system (CNS) adverse effects including dizziness disorder and other neuropsychiatric conditions associated (de Souza 1983; Kofi Ekue et al. 1983) and ‘giddiness’ (Tin et al. 1982). Evidence later emerged of a risk of severe Mefloquine is no longer considered the drug of choice behavioural disturbance (Kofi Ekue et al. 1983) associated for the treatment of malaria; the WHO now recommends with the use of mefloquine including disorientation (UNDP only artemisinin-based combination therapies (ACTs), et al. 1983) and psychosis (Harinasuta et al. 1983). Soon particularly artemisinin–lumefantrine (marketed in the after the initial European licensure of mefloquine in 1985, USA as CoartemÒ) (WHO 2010). ACTs containing confusion (Bjo¨rkman 1989; Rouveix et al. 1989), amnesia mefloquine, while effective, are controversial owing to the (Castot & Garnier 1988; Lapras et al. 1989), loss of concerns of potential synergistic neurotoxicity and poor mental focus and an inability to concentrate (Patchen et al.
tolerability (Toovey 2009; WHO 2010). Similarly, 1989) were not uncommonly reported. Symptoms of often mefloquine is decreasingly utilised for prophylaxis among debilitating dizziness and vertigo were also reported civilian travellers in favour of safer and better-tolerated Published 2012. This article is a US Government work and is in the public domain in the USA Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 R. L. Nevin Administration of mefloquine to Guanta´namo detainees antimalarial medications (LaRocque et al. 2011). LariamÒ higher priority on screening for infection prior to treatment was recently withdrawn from the US market without (Tagbor et al. 2010). Similarly, in an example of IPT explanation (Strauch et al. 2011), although generic targeted to travellers (IPTt), individuals returning from formulations of mefloquine remain available.
prolonged exposure in areas endemic for P. vivax orP. ovale are frequently prescribed gametocidal and hyp-nozoiticidal primaquine (Oliver et al. 2008; Burgoine et al.
Indications for use of antimalarial drugs at treatment 2010) in a treatment referred to as presumptive antirelapse therapy (PART), but only after testing for a contraindi- Unlike their widespread use in prophylaxis, the adminis- cating glucose-6-phosphate dehydrogenase (G6PD) enzyme tration of treatment doses of antimalarial medications to individuals without confirmation of disease is typically Empiric treatment is the controversial practice of undertaken only for very specific indications. As all routinely administering antimalarial treatment doses to available drugs, and particularly mefloquine, are associated symptomatic individuals from populations with a high with an increased risk of toxicity and adverse effects when prevalence of disease, who are in settings with limited administered at treatment doses as compared to at lower, diagnostic capacity (Parikh et al. 2010). Unlike in MDA or prophylactic doses (WHO 2001), such use must very IPT, empiric treatment presumes malaria disease based on carefully balance potential individual and population a perceived high predictive value of appropriate clinical benefits against these risks. Historically, forms of such symptoms, such as fever. Empiric treatment has fallen out treatment have included MDA (von Seidlein & Greenwood of favour in the context of rising concerns of risk 2003; Greenwood 2010), intermittent preventive treatment associated with the indiscriminate use of antimalarials (IPT) (Greenwood 2010) and empiric treatment, with (Parikh et al. 2010; WHO 2010). Efforts at global malaria only IPT today remaining a critical component of global control now emphasise expanding diagnostic capacity through rapid diagnostic tests (RDT) (WHO 2010), to Primarily used to attempt eradication of malaria from a permit confirmation of disease prior to targeted treatment.
defined geographical region, MDA involves the universaladministration of antimalarial treatment doses irrespective Rationale for the use of mefloquine at Guanta´namo of infection status (Greenwood 2004). This is bestaccomplished by encouraging all individuals in the defined The mass administration of mefloquine at treatment doses region to accept treatment that targets not only the illness- to detainees at Guanta´namo does not correspond well with causing blood-stage schizonts, but also gametocytes and any of these three indications. True MDA involves a liver-stage hypnozoites in areas where relapsing P. vivax or universal administration of treatment designed to eradicate P. ovale is prevalent. A potentially strong method in any potential source of infection, yet not all individuals theory, MDA has achieved only modest success in practice arriving at Guanta´namo received treatment consistent with (von Seidlein & Greenwood 2003; Greenwood 2004).
MDA. Investigative news reports suggest that South Asian Some believe that a more viable role for MDA may be in contractor personnel, hired to work on construction the final stages of geographical eradication efforts, using projects at Guanta´namo, and arriving from malaria- gametocidal and hypnozoiticidal primaquine or the newer endemic areas, were not administered mefloquine at 8-aminoquinoline agents (Greenwood 2010).
treatment doses (Kaye & Leopold 2011).
Intermittent preventive treatment, which is also occa- Empiric treatment, involving a selective use of antimal- sionally referred to as intermittent presumptive treatment arials guided by symptoms, is generally motivated by cost (White 2005), is the practice of universally administering or diagnostic limitations. Neither was a factor at Guanta´- treatment doses to asymptomatic individuals who are at namo. All detainees had regular access to medical care and increased risk of morbidity or mortality from disease received a comprehensive medical evaluation upon arrival, (Milner et al. 2010). In practice, IPT differs from MDA by which included assessment of vital signs (Figure 2) and targeting treatment to specific and individual patient risk thick and thin-smear microscopic testing for malaria.
factors, rather than solely to geographical location. A large These smears were first screened at the Guanta´namo Bay body of evidence supports the benefits of IPT among Naval Hospital and then sent for confirmation to Naval pregnant women (IPTp), particularly the use of the Hospital Portsmouth, Virginia (DoD 2007).
generally well-tolerated drug combination sulphadox- While inconsistent with either true MDA or empiric ine ⁄ pyrimethamine (SP) (Sirima et al. 2006; Greenwood treatment, the mass administration of mefloquine to 2010). Growing concerns of antimalarial resistance Guanta´namo detainees might arguably conform to a type (Nosten et al. 2003; White 2005), however, are placing a of IPTt referred to as post-arrival (or pre-departure) Published 2012. This article is a US Government work and is in the public domain in the USA Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 R. L. Nevin Administration of mefloquine to Guanta´namo detainees 7. Vitals are done & medications are given (Mefloquine, Albendazole) before the detainee 8. Tetanus and influenza vaccines are administered and PPD placed on forearm 9. Height and weight taken and recorded (BMI calculated later).
10. Radiologist reads chest x-ray before detainee leaves the building and if’No Active Disease’ (NAD) noted surgical face mask may be removed and disposed of. Also removethe scopolamine patch from behind ear (used to prevent airsickness during transit).
11. Perform quality assurance check on medical record. Verify that the detainee has stopped at each station, by checking the tracking sheet, before allowing the detainee’s departure.
12. Detainee leaves the building through the medical side exit escorted by 2 MP’s.
Figure 2 Extract of ‘Nursing Standard Operating Procedures for Detainees’ (from DoD 2007).
presumptive treatment (PPT). PPT is frequently justified, (CDC 2010), and a military author at WRAIR has particularly among refugees and other dislocated popu- commented that ‘[w]ith the availability of better-tolerated lations to which detainee populations might be compared drugs, there is no need to use mefloquine for treatment (Stauffer et al. 2008). Among the motivations for unless other options are unavailable’ (Magill 2006).
administering PPT to dislocated persons arriving in the Absent a highly improbable shortage of such better- USA is that such patients typically face barriers to tolerated drugs, the indication for the use of mefloquine at accessing medical care after their arrival and that US Guanta´namo, in what appears to be a questionable clinicians may have limited clinical experience with application of PPT, is therefore decidedly unclear. The use malaria, thus contributing to delays in diagnosis (Phares of mefloquine for this purpose finds no precedent in the et al. 2011). Neither of these rationales should be literature on PPT (Slutsker et al. 1995; Miller et al. 2000; applicable among detainees held at Guanta´namo, where Barnett 2004; CDC 2010), and researchers at WRAIR have ample and timely medical care was presumably available, even emphasised that mefloquine will ‘likely not find use’ provided by military healthcare providers familiar with for this indication among ‘asymptomatic, otherwise the clinical and laboratory diagnosis and management of healthy’ persons ‘due to its association with adverse CNS the disease (Scsepko 2002, DoD 2007).
events at therapeutic doses’ (Milner et al. 2010). Today, in Additionally, the Centers for Disease Control and conformity with WHO recommendations, the treatment of Prevention (CDC) specifically recommends against the choice for PPT is the ACT CoartemÒ (Phares et al. 2011).
practice of PPT among populations relocated from outsidesub-Saharan Africa (CDC 2010), noting that among this Use of mefloquine as a public health measure group, ‘the risk and cost of post-arrival presumptivetreatment currently outweighs the potential benefits’.
The primary justification for the use of PPT has typically According to an analysis of US military documents been on clinical grounds and not for public health contained in the Wikileaks Guanta´namo files (Scheinkman purposes. Despite posing a theoretical risk of autochtho- et al. 2012), a substantial majority of detainees were nous transmission, no local cases of malaria transmission captured from areas of low malaria transmission intensity, have been linked to refugee resettlement in the USA (Phares including Pakistan, Afghanistan and Yemen (Matisz et al.
et al. 2011). Yet statements from US military officials 2011). In accordance with CDC recommendations, PPT clearly indicate that the motivation for the use of mefloq- would not be routinely indicated for these individuals.
uine at Guanta´namo was not clinical, but was ‘entirely for Even among individuals from areas of sub-Saharan public health purposes to prevent the introduction of Africa, for whom the practice of PPT may be appropriate, malaria to the Guanta´namo area’ (Shane 2011). Mefloq- CDC has previously recommended SP (CDC 2010) for this uine, however, is a schizonticide and clearly not well suited purpose. CDC later recommended the drug combination for this indication (UNDP et al. 1983; Price et al. 1999).
atovaquone ⁄ proguanil, marketed and widely available in Although effective at curing acute infection, mefloquine is the USA since 2000 as MalaroneÒ, which was noted to be incompletely effective against the mature gametocytes that ‘generally well tolerated with few adverse effects’ (CDC transmit disease (Price et al. 1999). Its use would therefore 2010). The CDC has noted that ‘other available medica- be insufficient to guarantee prevention of autochthonous tions have higher rates of adverse effects (e.g. mefloquine)’ transmission in the presence of competent vectors. The Published 2012. This article is a US Government work and is in the public domain in the USA Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 R. L. Nevin Administration of mefloquine to Guanta´namo detainees 8-aminoquinoline primaquine, also administered to nally motivated for other purposes, the claim that preven- detainees after laboratory testing for G6PD deficiency tion of malaria transmission was among them is firmly (DoD 2007), would alone have been sufficient for this indication, given its more effective gametocidal properties One possibility is that the use of mefloquine was simply erroneously directed by senior US military medical officials While competent vectors for the transmission of overly confident of the drug’s safety and unfamiliar with malaria are indeed found on the island of Cuba (Molina- its appropriate use, in an apparent foreshadowing of its Cruz et al. 2004; Gutie´rrez et al. 2009), concurrent later, broader misprescribing among US military personnel vector control methods were in use at Guantanamo (Nevin 2010). Another possibility, which is deeply trou- during the time that mefloquine was being administered.
bling to consider, is that the decision to administer the drug A US military publication noted that an aggressive was informed and motivated at least in part by knowledge mosquito surveillance programme was underway at of the drug’s adverse neuropsychiatric effects and the Guanta´namo as early as January 2002, with mosquito presumed plausible deniability of claims of misuse in the counts obtained every other day to guide insecticide context of its seemingly legitimate clinical or public health spraying (Scsepko 2002). This publication even emphas- ised that the specific environment at Guanta´namo was Unfortunately, available documentation from a meet- a ‘strong force working against mosquitoes’, and quoted ing held by senior US health officials to discuss malaria a military physician who commented that ‘[t]he arid, hot control among Guanta´namo detainees provides little environment here is not mosquito-friendly, unlike the insight into this decision (Leopold & Kaye 2010). The other side of Cuba where is rains all the time’ (Scsepko transcript from a February 2002 meeting of the Armed Forces Epidemiological Board (AFEB) discussing the care The mass administration of mefloquine to detainees at of detainees references only the use of primaquine in the Guanta´namo, ostensibly as a public health measure, also context of reducing autochthonous transmission, but contrasts oddly with methods of malaria control em- makes no mention of mefloquine (AFEB 2002). Regard- ployed a decade earlier in a comparable setting. In 1991, less, the recent justification offered by US military in response to a sudden wave of immigration from Haiti, representatives for the mass administration of mefloquine US military officials quickly housed over 14 000 poten- to Guanta´namo detainees suggests that the practice is tially infected refugees in temporary camps at Guanta´- familiar to current and senior US military medical namo (Bawden et al. 1995). Despite a comparable malaria risk, mass administration of antimalarials was Further formal investigation may yet reveal the precise never employed as a management strategy. Instead, rationale and motivation for the use of mefloquine among military physicians and malaria experts managing the Guanta´namo detainees. As the actions of junior medical camps correctly observed that ‘[t]o prevent transmission personnel assigned to Guanta´namo come under increased from immigrants to the indigenous human population, a ethical and legal scrutiny (Iacopino & Xenakis 2011), the vector surveillance and control programme is vital’. In actions of senior medical leaders involved in formulating apparent disagreement with the use of PPT, these experts and overseeing detainee mefloquine policy must bear further noted that at Guanta´namo, ‘the best strategy for handling malaria in displaced persons from an endemicarea was early laboratory diagnosis or, if necessary, presumptive clinical diagnosis, and prompt treatment’(Bawden et al. 1995). It is unclear, then, why the The views expressed in this article are those of the introduction of only a few hundred (Leopold & Kaye author alone and do not necessarily reflect the official 2010; Scheinkman et al. 2012) potentially infected policies or positions of the Department of the Army, detainees would prompt the abandonment of this Department of Defense or the US Government. The author is a US Army preventive medicine physician whoin a private capacity has commented critically on theissues described in this analysis and who has communi- cated with other authors investigating and reporting on This analysis raises many intriguing questions regarding this issue (Denbeaux et al. 2010; Leopold & Kaye 2010; the precise indications for the use of mefloquine among Kaye & Leopold 2011). The US Army had no role in the Guanta´namo detainees. While the mass administration of decision to publish or in the preparation of this manu- the drug to Guanta´namo detainees may have been ratio- Published 2012. This article is a US Government work and is in the public domain in the USA Tropical Medicine and International Health volume 17 no 10 pp 1281–1288 october 2012 R. L. Nevin Administration of mefloquine to Guanta´namo detainees Department of the Army Office of the Surgeon General. (2002) Memorandum: updated health care provider information on use The author acknowledges the research assistance of Cecelia of mefloquine hydrochloride (LariamÒ) for malaria prophy- Higginbotham of the Bayne-Jones Army Community laxis. Available at: http://www.pdhealth.mil/downloads/ Hospital Medical Library; and Jason Leopold, Jeffrey Kaye Mefloquine_Hyrochloride_Use.pdf (accessed 21 June 2012).
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Corresponding Author Remington L. Nevin, Department of Preventive Medicine, Bayne-Jones Army Community Hospital, Ft. Polk,LA 71459, USA. E-mail: [email protected] Published 2012. This article is a US Government work and is in the public domain in the USA

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