THE PREVALENCE OF MALARIA IN MEFLOQUINE HYDROCHLORIDE - MEFLIAM® USERS DURING THE DEPLOYMENT OF MILITARY FORCES IN BURUNDI, EAST AFRICA.
E. Basson (MTech Env Health), Dr H. Roberts (DTech Env Health), Prof C. van der Westhuizen (D. Sc Agriculture), Dr H. De Beer (DTech Microbiology)

Malaria and the mosquito have hounded the military for decades (Borza, 1987). Malaria represents one of the most important infectious disease threats to deployed military forces (Sanchez, Bendet, Grogl, Lima, Pang, Guimaraes, Guedes, Milhous, Green and Todd, 2000:275–282). Malaria in soldiers has a serious economic impact in terms of both lost productivity and treatment cost for the state (Malaria among US military personnel returning from Somalia, 1994:397–399). A contingent of South African National Defence Force members has since November 2001 been deployed in Burundi, as part of a peacekeeping mission. No information is available regarding the prevalence of malaria among military personnel during deployments in Burundi and East Africa.

THE PROBLEM STATEMENT

Mefloquine hydrochloride – Mefliam® has been used for the treatment of malaria infections amongst military forces deployed in Burundi and East Africa. The chemoprophylactic efficacy and usability of this drug has never been determined in Burundi.

THE IMPORTANCE OF THE STUDY

Current information on drug-resistant malaria in the tropical and subtropical regions of Africa is insufficient and unreliable. Multidrug resistance necessitates the use of alternative drugs that may be expensive and difficult to administrate and often have side-effects (WHO Tropical Disease Research, 1993:22). Malaria is becoming more difficult to manage. This demands the use of alternative drugs, which are generally more expensive, more difficult to administer and often have adverse side-effects.

The “ABC” of malaria prevention (SCAT, 2003:6)

THE AIM OF THE STUDY

The aim of the study was to investigate the prevalence of Malaria in the users of Mefloquine Hydrochloride – Mefliam® when administrated to soldiers stationed in East Africa and specifically Burundi. The results of this study can also be expoliated to the local population. If Mefloquine is the drug of choice and prove to be effective during military deployments to East Africa and Burundi, the presumption can be made that the Plasmodium organism in areas are not resistant to the Mefloquine. Mefloquine will thus be an effective malaria management tool as a therapeutic and preventative drug. The information gathered in this study would aid the armed forces of the world. This information would help in selecting the most effective antimalarial prophylaxis to use during extended deployments to East Africa and specifically Burundi. The results of this study will prove if Mefloquine Hydrochloride - Mefliam® is an effective drug to use as an antimalarial and the risk of soldiers being deployed in East Africa contracting malaria will be reduced. The results of the study could also be helpful to international travellers visiting that part of the continent. The fact that 111 people used Mefliam® and four presented with malaria symptoms, is a good indicator that Mefliam® is a good option as an antimalarial drug in East Africa and specifically Burundi.

SAMPLE SELECTION

The target population was South African National Defence Force soldiers deployed in Bujumbura, Burundi, for more than three months. The group/population consisted of 336 members and the sample group size (chosen portion) of 111 members. Of the 336 members, 11 (3,29%) were females. The demographics of the different race groups were:
• 229 (68,37%) Black;
• 70 (20,84%) Coloured;
• 33 (9,87%) Caucasian; and
• 4 (0,91%) Asian.
No control group was established. This was done due to ethical and moral guidelines prohibiting people from entering an endemic malaria area without access to proper anti malarial prophylaxis. The sample was selected by using simple random sampling.
QUESTIONNAIRES
The questionnaire aims of determining the following:
• Perception of the user regarding the malaria threat;
• compliance with taking the medication;
• possible side-effects which may have occurred due to the chemoprophylaxis; and
• the prophylactic efficacy of Mefliam®.
Each respondent gave his/her written consent. The questionnaire was in English, the thread language of the South African National Defence Force. This information enabled the research team to detect what kind of prophylaxis each member is using. The alternative drugs to be used were Mefliam® and Doxycycline.

The airforce pilots and two female soldiers used Doxycycline. The female soldiers used Doxycycline due to the side-effects of Mefliam® indicated in the Mefliam® package insert (1997:2).

SAMPLE REALISATION

Questionnaires were handed to 120 participants. Eight participants used Doxycycline, and due to the aim of the study they were not included. The other 112 respondents used Mefliam®. One of the questionnaires was returned back incomplete. The return rate for the questionnaires was 100%. Hundred and eleven (92,5%) of the initial 120 questionnaires were relevant to the study.

RESULTS

Only relevant results that emerged were dealt with. The following results were reported:
• perceptions of malaria threat;
• awareness of preventative methods of malaria;
• malaria history of members;
• perceptions of malaria and the use of antimalarial prophylaxis during deployments;
• knowledge of the antimalarial drugs which are currently being used;
• the importance of taking the antimalarial prophylaxis; and
• ascertaining whether the users of Mefliam® contracted malaria during their deployment in Burundi.
In this following section the emphasis will fall on the behaviour of the mosquito and the stimuli attracting it to the host. Although the compound eye of the mosquito has less resolving power than that of most mammals, the aperture allows better vision in the dark (Hutchinson, 2004:Internet). The eye of a mosquito forms a number of functions. It detects movement, colours, shapes and edges of objects (Hutchinson, 2004:Internet). The studies by Bellamy and Reeves in 1952, reported that mosquitoes followed the CO2 plume upwind, but then visual cues led them to the unbaited traps. This proves that visual stimuli would lead a mosquito to fly towards a prominent object when lacking an odour plume (Hutchinson, 2004:Internet). Although the Anopheles mosquito prefers to rest on dark surfaces (Maharaj, 2004:Personal communication), mosquitoes are visually stimulated by objects that are in contrast with the background (Hutchinson, 2004:Internet). Since the Anopheles mosquito feeds exclusively during the night, especially at dusk and dawn, lighter skins would be perceived as contrasting on the black background of the night and would therefore attract the Anopheles mosquito. African populations have traditional perceptions concerning disease prevention, treatment and management. Some diseases are considered suitable for management by western medicines, while other diseases are considered the exclusive domain of local traditional health practitioners. The decision to use western medicine for an illness is often considered as a last resort (Nchinda, 1998:398). There is no medical evidence to support the use of homeopathic preparations for the prevention or treatment of malaria (SCAT, 2003:15; Barnes, 2005:Personal communication).
Services
The service or unit where the member is working is an important variable during the deployment in an endemic malaria area. This is also an indication of the level of exposure to malaria and the chemoprophylaxis that should be consumed. The service where the respondent is working were determined and provided. Logistics, transportation and other support units scattered in the deployment area are not always part of the communication lines and disciplinary structures. This makes the compliance with the antimarial regimen of these members more of a challenge. Engineering units are involved in construction projects in tropical conditions with the building of roads, sewerage works, networks, water pumps and pipelines. These members are sometimes compelled to overnight in tropical conditions with constant rains, living in wet and humid conditions. These conditions is the optimal breeding ground for mosquitoes and therefore these individuals are at great risk of contracting malaria (SCAT, 2003:9). Military Police members work in shifts. These personnel are working at night and are more exposed to the bites of the Anopheles mosquito (WHO, 2002). They are working in and around artificial light, which attract mosquitoes (Hutchinson, 2004:Internet). Kitchen personnel often work during the dark hours of the day between dusk and dawn. This is the time of day when members are the most exposed to the bites of the Anopheles mosquito (Wood, 1993:67¬-68; SCAT, 2003:10). Around the kitchens in temporary military bases stagnant water, due to the constant cleaning of the facility, and kitchen sewerage water as part of the normal processes in the kitchen facilities, is usually found. This stagnant water attracts mosquitoes for breeding purposes. Mosquitoes need relatively clean water to lay their eggs (Curtis, 1996:1-7; SCAT, 2003:9). Constant pest control and mosquito control in and around these facilities is crucial. Army guards patrol the area during the night or stand guard at entrances. Due to the high temperatures at night in the area, it is uncomfortable to wear long sleeve shirts and therefore skin is exposed for the mosquitoes to feed on. The stationary and roaming guards must constantly be reminded to take precautions to prevent mosquito bites. The guards must be issued with the prescribed repellents. Health care workers (SAMHS) are potentially exposed to the plasmodium organisms by means of a needle stick. This is called “induced malaria” (MacArthur et al., 2001:28). Military personnel that are involved in tasks requiring fine coordination and spatial discrimination such as scuba diving (Navy), piloting an aircraft (SAAF) and those driving heavy machines (Engineers) are discouraged to use Mefliam®, as dizziness and vertigo have been reported as side-effects (www.cdc.gov/search.htm; SCAT, 2003:15).

According to clinical trials done in Kenya, East Africa, Mefloquine got a 95% prophylactic efficacy (Meuhlberger, Jelinek, Schlipkoeter, von Sonnenbeurg and Nothdurft, 1997:357-363). Barnes (2005:Personal communication) and Talmut (2005:Personal communication) claimed a 95% prophylactic efficacy of Mefloquine internationally. Mefloquine had a 100% prophylactic efficacy in a double-blind, placebo controlled trial with 204 Indonesian soldiers, using the drug for 13 weeks. (Ohrt et al., 1997:963-972). The evidence from a number of large trails on the continent indicated a prophylactic efficacy of over 90% in Africa (Steffen, Fuchs, Schildknecht, Naef, Funk and Schlagenhauf, 1993:1299-1303). This study showed that 4 out of 111 persons that used the Mefloquine (Mefliam®) tablets contracted malaria within the first five months of deployment to Burundi. The following is statistical feedback:

The value of this section is to determine statistically if Mefloquine is an effective anti malarial prophylaxis. The confidence interval and Wilson reliance interval (Score Method) will be utilised as statistical guidance.
Confidence interval (CI)
p = proportion of positive responses
n = individuals
r = characteristics of interest
z = 1,96 for a 95 percent confidence interval
begin value; top value = [p - z√; p + z√]
n = 111
r = 4
p = r/n = 4/111 = 0,036 = 3.6%
CI of population: p ± z√[p (1-p)]/n = 0,036 + 1,96√[(0,036)(0,97)]/111
0,036 ± 1,96√[0,03492/111 = 0,036 ± 1,96√0,0003145
0,036 ± 1,96.0,0177 = 0,036 ± 0,0348
CI = [0,0708; 0,0012]
Because (p) is so small, a false indication can be experienced regarding the prophylactic efficacy of the drug. A more reliable test is thus necessary. For this purpose, the Wilson reliance interval is to be used.
Wilson Reliance Interval (Score Method)
A = 2r+z²; B = z√[z²+4r(1-r/n)]; C = 2(n+z²)
CI = [(A-B)/C; (A+B)/C]
A = 2r+z² = 2(4) + (1,96)² = 8 + 3,842 = 11,842
B = z√[z²+4r(1-r/n)] = 1,96√[1,96²+4(4)(1-0,036)] = 1,96√[3,842+16(0,964)]
B = 1,96√[3,842+16(0,964)] = 1,96√19,266 = 1,96.4,389 = 8,603
C = 2(111 + 1,96²) = 2(114,842) = 229,683
CI = [(11,842-8,603)/229,683; 11,842+8,603)/229,683
CI = 3,239/229,683; 20,445/229,683
CI = [0,0141; 0,0890]

According to this statistical method there is a 95% certainty that, when a population is using Mefloquine, the chance of getting malaria will be between 0,0141 and 0,0890. In other words an individual got a 1,4% to 8,9% chance of contracting malaria when he/she is using Mefloquine (Mefliam®). Using the score method the confidence interval out of a population of 336 is 4,7 to 29,9 members. The results of the study indicate that the prevalence of malaria in the users of Mefloquine hydrochloride was 3,6% with 95% Wilson reliance interval of (1,4%; 8,9%) (Altman, Machin, Bryant, Trevor, Gardner and Martin, 2000:9-11). According to the study Mefloquine (Mefliam®) got a high prophylactic efficacy in Burundi, East Africa. This result is in line with international tendencies and standards.

DISCUSSION

According to studies done by Col Robert DeFreitas of the Medical Corps of the US Army during 2003, relapsing malaria is the primary military medical problem of malaria cases worldwide. The conclusion is that antimalarial prophylaxis courses are either not taken or is ineffective. Falciparum malaria is the greatest threat to the lives of soldiers in the military due to drug resistance (DeFreitas, 2003:Presentation). Complications can present very rapidly and the drug resistance can present as an epidemic. The type of military mission also plays a role in the malaria health threats. Most malaria exposure and least compliance occur during combat operations (DeFreitas, 2003:Presentation). During combat operations soldiers are living and sleeping in tents or in the open. Soldiers have to work during night (dusk and dawn) when mosquitoes are most active (Wood, 1993:67–68). Soldiers are working under pressure and there is sometimes no time or little opportunity to take the antimalarial chemoprophylaxis. During non-violent operations such as peacekeeping operations or humanitarian assistance, low or absent threat of hostile action may permit more emphasis on disease and non-battle injury threats. It should therefore be the opportunity for military forces during such times to actively evaluate their malaria programme, to do rectifications, educate and train the soldiers and medical personnel and to conduct research regarding antimalarial and therapeutic drugs. During repeated insertions and extractions and the short exposures in malarious areas, members are reluctant to take the antimalarial drugs, due to initial side-effects and the fact that, when they start using it, they have to use it for four weeks after the last possible exposure in the case of the users of Mefliam®. This is especially the concern for people deployed for less than two weeks at a time or those persons having to go to the area with short intervals, for instance every four weeks. That means that the person has to use the Mefloquine chemoprophylaxis for a long time, although he/she is not permanently exposed during that time. This scenario necessitates a different antimalarial drug regimen or more intense research for the quest of the ideal drug. Military members vary greatly in need for and response to prophylaxis. The regular infantry troops are normally more disciplined with a stricter disciplinary structure. They are normally a bigger group and are living and working in the same areas for better control and observation. It is therefore easier to manage each member’s compliance with the antimalarial prophylaxis. In some instances older, experienced military members often believe themselves to be above the need to take antimalarial medication. The non-compliance with taking antimalarial drugs may create a reputation of legendary status among soldiers, fame or infamy, regardless of the merit of such actions. Military pilots and scuba divers are using Doxycycline due to the possible side-effects of Mefliam®. No reliable studies have been done on the effectiveness of Doxycycline in certain parts of the world and, until such research is done, or by experience with the drug, its effectiveness will always be in doubt (Ohrt et al., 1997:963–972).

Leadership and command emphasis regarding malaria prevention is crucial in achieving compliance among military members. According to the study 75,7% of the soldiers receive their medication from the medical personnel. The antimalarial drugs should be distributed to the respective commanding officers and they should, in turn, distribute it to the leaders of the different sections. The structured and organised way in which the drugs are managed emphasises the importance of achieving compliance with routine among the soldiers. If the section leaders are issuing out and controlling the use of the drugs, it will form part of the weekly routine. This behaviour will be associated with a disciplined structure and negative conduct will be sanctioned. Awareness education must form part of the pre-deployment training, namely:
• how the troops perceive the malaria threat; and
• whether military members have practised taking antimalarial medication in the past.
In research studies by DeFreitas (2003:Presentation), he made the observation that the longer the mission, the greater the malaria risk. The cumulative risk of contracting malaria is proportional to the length of in an endemic malaria area. A stay of three months carries a risk six times higher than a two week visit (Bradley & Warhurst, 1997: 138-152). This is especially true for relapsing malaria. DeFreitas completed a range of studies on the optimum duration of military deployments and one of his conclusions was that long deployments almost always resulted in chemoprophylaxis compliance failure. This was due to the fact that command emphasis evaporated, the perception of disease waned and side-effects might persist. He found compliance with only 40% after five months among soldiers using the daily medication regime. Long deployments insured that the military members got exposed during the high malaria transmission season. The highest transmission typically followed the rainy season.
Troops may be lulled into non-compliance if they do not notice other members becoming sick during the low transmission seasons. The geographical distribution of malaria complicates the threat assessment. Soldiers living in drier areas are a bad influence on other soldiers when they do not use their antimalarial medication regularly. Due to the low presence of malaria mosquitoes in those areas, they do not contract malaria. In return, soldiers working near stagnant water sources perceive the threat as over-exaggerated and start to fall in the groove of non-compliance, with the expected consequences. Soldiers generally do not like to take pills (DeFreitas, 2003:Presentation). A single episode of vomiting and/or dizziness will stop some soldiers from taking the antimalarial chemoprophylaxis again.

RECOMMENDATIONS

The motto of the war against malaria is to stay one step ahead. It is also important to learn more about our common malaria parasite enemy and to develop the means to combat it. We must also learn from our experiences of current and previous deployments. Problems regarding compliance with and intolerability towards the medication should be documented, while a surveillance programme should also support this feedback. With a surveillance network in place, there will be a better understanding of the clinical relevance of antimalarial drug resistance. It is critical that education regarding the proper use of chemoprophylaxis forms part of the pre-deployment training of soldiers. The members must be informed regarding the possible build-up of resistance of the malaria parasite against antimalarial drugs if the medication is not used correctly. As part of the malaria education programme the military personnel should practise taking malaria medications.

Military personnel perceptions should also be tested regarding possible side-effects and allergic reactions. A herd mentality could easily develop between soldiers during deployment as a result of bad experiences with the medication. If a member does not use the drugs at all or not according to the prescriptive method, other soldiers may catch onto the idea and shortly an entire group may be involved. The gathering of these data will also allow health care providers to manage patients more effectively. Medical planners can effectively select the best possible drug regimens for different geographic areas. Critical to patient management and triage, is a prompt and accurate diagnosis. The ability to rapidly diagnose malaria in remote military healthcare echelons will help healthcare professionals treat malaria patients sooner and avoid necessary evaluation.
A register must be kept of military personnel who have taken the Mefliam® prophylaxis for more than three (3) months consecutively. Periodic monitoring that includes liver function tests must be performed (Mefliam® package brochure, 1997:3) on such members. Mefliam® should not be used longer that three (3) months consecutively. Mefliam® is not a long term prophylaxis. This practise is thought to contribute to the development of resistant strains of P falciparum (Mefliam® package brochure, 1997:3). More research regarding drug resistance is required. It is necessary to initiate monitoring of drug resistance in Africa, using standardised methods. Drug efficacy studies using vivo methods have been standardised by the World Health Organisation (WHO, 1995–96). Management guidelines should be developed concerning when and under which conditions to change the treatment regimen for different levels of resistance. Development and field testing of new malaria drugs are required to replace present drugs when resistance makes them unusable. The emergence of multi-drug resistant malaria will continue to confound the drug development of antimalarial drugs. The medical community must have a better understanding of the mechanics of drug resistance. Resistance to Mefloquine has been documented in East Africa and sporadic cases are occurring in West Africa. As these and other reports of drug resistance continue to evolve, the need for a replacement drug for weekly prophylaxis will continue to escalate. Halofantrine was developed as a backup drug for Mefloquine in a collaboration effort between the US Army and SmithKline Beecham. However, its usefulness is limited by possible cross-resistance with Mefloquine, cardiac toxicity and poor absorption.
The military should document the clinical relevance of drug resistance. They should also examine the potential for spread of resistance in the field. There is mutual agreement that the critical methodology and approach required to describe antimalarial drug resistance required well documented clinical studies with adequate follow up, confirmation that adequate drug levels were reached in the users of antimalarial prophylaxis and that the drugs were used regularly. Mapping malaria transmission intensity and resistance using geographic positioning systems has to be developed for the mapping of malaria across the continent. This process will have the potential for predicting potential malaria epidemics and monitoring control. Results of these studies in other international armies have facilitated documentation of clinically relevant resistance to Mefloquine, Halofantrine, Chloroquine, Proguanil plus dapsone and atovaquone (Queguiner, P. and Engers, 2001:149-151). These and other data will help guide the selection of the next generation of prophylactic drugs. Future directions must focus on basic and applied research for a better understanding of the modes of actions. Future directions should also concentrate on the mechanisms of resistance to these drugs. The synthesis and design of new drugs would hopefully result in the development of safe and effective drugs that circumvent the malaria parasites elusive mechanics of drug resistance. Multiple drug resistance in falciparum malaria will continue to pose problems for targeting the blood stages of malaria (Queguiner et al., 2001:149–151).
There must be an increased emphasis towards developing drugs with true causal prophylactic properties. An increased emphasis towards developing drugs with radical curative properties before blood stages emerge and cause clinical disease must also be clear. The solution for the current malaria problem is to establish a critical mass of investigators, collaborators and clinical centers that are focused and committed to document and evaluate malaria resistance, examine the potential for spread of resistance in the field and the discovering and development of new medication. Military research on malaria in Africa is a serious requirement. Collaborations with other defence forces for information on clinical trials and drug resistance surveillance are pivotal for future drug selection and malaria management. No other private or government organisations will adopt this process, due to the limited monitory possibilities. Should this endeavour not be successful, we cannot expect to protect deployed soldiers who will be scattered on missions in diverse geographic locations all over the world against malaria.

THE OPTIMAL ANTIMALARIAL REGIMEN

• A short course of antimalarial medication that would result in several weeks of protection would be highly desirable. Tafenoquine for 3 days protects for 10 weeks (Queguiner et al., 2001:149–151).
• The taking of daily medication without supervision is not successful. Daily Doxycycline requires supervision.
• Weekly regimens are generally superior to daily regimens.
• Antimalarial chemoprophylaxis with a longer half-life allows missed doses to be made up.
• Antimalarial chemoprophylaxis with a longer half-life keeps the intravenous and intracellular chemoprophylactic levels high to prevent the build-up of resistance among malaria plasmodiums.
• Commands emphasis on all the deployed military members in a malarious area to create a routine of the consumption of the antimalarial drugs, for example once weekly "Malaria Monday." This routine will lead to more streamlined supervision.
• Simpler is better.
• A single drug is a necessity; two drugs are easily confused or forgotten.
• Antimalarial medication administered before deployment for short exposures would be highly desirable. During short exposures/visits to malarious areas, people tend to easily forget, because they are not part of the unit routine.
• Consistent malaria policy among military personnel.
• The ultimate malaria prophylaxis would be a single dose of medication or immunisation administered during basic training that is 100% efficacious against malaria worldwide without any adverse effects.

CONCLUSION

Malaria is an important social, economic and developmental health problem affecting military members, their families and their communities. The best chance to successfully combat the disease will require collaboration between those who control and the researchers. The irradication of malaria is placed on a strong research base, international collaboration and sustained governmental support. Mefloquine is closely aligned with military needs. This biodefence agent addresses the operationally relevant malaria species, P. falciparum, and drug-resistant phenotypes of this species. It has an operationally suitable frequency of dose. The shortcomings of Mefloquine have been the adverse event profile on the background of military use, particularly neuropsychiatric events and limitations in suppressive management of vivax malaria. In terms of a biodefence system, these are not critical, as they are reasonably predictable and manageable. While chemoprophylaxis remains the cornerstone of malaria casualty control, attention will always need to be paid to compliance. With comparable attention to tailoring Mefloquine use, as that paid to appropriate uniform fit or weapon allocation, most service personnel will be well protected with Mefloquine during military operations in malarious areas.

Article by Capt E. Basson
AMHU Northern Cape