Chemoprophylaxis Compliance and Tolerability
These results differ from previous experiences of Italian troops in malaria prevention; indeed, compliance with mefloquine prophylaxis was very high (90%–95%) in Mozambique, East Timor, and Sudan, whereas in Afghanistan it was about 80% in 2002 to 2006 and below 60% in 2007 to 2011. However, no significant changes concerning the regularity of chemoprophylaxis and the occurrence of AEs were registered during the study period.
Concerns over the safety profile of mefloquine arose soon after the introduction of drugs, and its tolerability in malaria prophylaxis is still a controversial issue. If mefloquine is, overall, less tolerated than other regimens, serious neuropsychiatric outcomes occur, however, at rates not higher than those observed with other prophylactic drugs. Mefloquine use in malaria prevention has been associated with an incidence of disabling neuropsychiatric AEs ranging from 0.008% to 0.1% among users or, more generally, of SAEs (requiring hospitalization) from 0.005% to 0.2%. Risk factors for mefloquine-associated neuropsychiatric AEs are female gender, low body mass index, and first-time use.
The absence of SAEs over 10 years among more than 20,000 soldiers, the fact that mefloquine suspension did not change significantly the evacuation rate from Afghanistan for any neuropsychiatric cause, the high proportion of subjects taking mefloquine regularly, the very low proportion of subjects taking irregularly or interrupting mefloquine because of AEs, and the fact that most AEs did not alter the regularity of chemoprophylaxis confirm the good tolerability of mefloquine for malaria prevention. These findings are consistent with previous experiences of Italian troops and, more recently, of other ISAF contingents. The decline in chemoprophylaxis compliance, the relevant proportion of soldiers who forgot some doses of mefloquine, and the poor adherence to personal protection measures suggest a low perception of malaria risk. Similarly, forgetfulness and low risk perception are important causes of noncompliance with chemoprophylaxis (mainly doxycycline) among US troops in Afghanistan.
This fact may represent a potential problem for future deployments in highly endemic areas, where it should be contrasted by frequently and regularly briefing troops about malaria risk, not only before entering the endemic area but also during deployment, and by a close monitoring of soldiers, to ensure high compliance with prevention measures. A similar procedure was followed with good results in past experiences.[5-7]
The Risk of Malaria in Afghanistan
Malaria is one of the main public health problems in Afghanistan. Although it was almost effectively controlled in the 1970s, the burden of disease increased gradually during the 1980s and the 1990s. Following the implementation of effective control measures after 2001, an important decline of malaria was documented, and the number of reported P falciparum and P vivax cases decreased by 95 and 77%, respectively. In particular, the proportion of P falciparum cases, which represented 20% of the reported cases in the 1990s, was reduced to 1% in 2008. Most malaria cases were reported in 2008 from the provinces of Helmand, Kunar, Khost, and Nangarhar. The contribution of the provinces where Italian troops were deployed since 2007 (Herat, Farah, Badghis, and Ghor) was <1% for P vivax malaria and virtually 0 for P falciparum cases.
As for malaria occurrence among coalition troops, an attack rate of 52.4 cases per 1,000 soldiers was reported in a US ranger task force deployed in 2002 in eastern Afghanistan; all cases were delayed clinical presentations of P vivax infections. However, this rate was referred to areas where the risk of malaria transmission is particularly high. Additional reports document malaria occurrence among ISAF troops, but represent only case reports among German, British,[17, 18] and US troops,[19, 20] and are not useful to outline the risk in the different areas of Afghanistan. Because of their large contingent of troops, the relevant proportion of malaria cases diagnosed after 2002 among the US military has been exposed to endemic areas of Afghanistan. Malaria risk for ISAF troops can therefore be assessed using US troops surveillance reports; overall, its incidence rate was lastly 0.1 cases per 100 soldiers, well below the minimal threshold incidence of an accumulated risk of 1.13 cases per 100 at which chemoprophylaxis has been considered as a cost-effective preventive measure.
Although Kabul is generally acknowledged as malaria-free, several cases of malaria in military members stationed in Kabul have been reported; apart from the only one case in the Italian troops described in this article, at least four cases occurred in 2002 to 2003 among UK troops and two cases in the German contingent. Therefore, it is possible that the risk of malaria in Kabul was very low, but not absent, during the first years of ISAF deployment.
Besides mosquito bite prevention measures, chemoprophylaxis is recommended for travelers to endemic areas of Afghanistan during the transmission season; the use of chloroquine/proguanil is recommended in the UK, and atovaquone/proguanil or doxycycline or mefloquine by the World Health Organization, United States, Canada, and France. Otherwise, Germany and Switzerland recommend only personal protection measures against mosquito bites and stand-by emergency treatment for countries where the risk is low and mainly represented by P vivax malaria, as the Indian subcontinent. Particularly, Swiss recommendations currently include Afghanistan in this last group of countries.
These considerations may be only partly applicable to soldiers whose risk of malaria is generally higher and exposure to endemic environment longer than among travelers; however, following the decrease of malaria incidence in Afghanistan in the last years, it should be evaluated if malaria chemoprophylaxis among ISAF troops is still justified.
Concerning the Italian contingent, in spite of the good tolerability of mefloquine prophylaxis, the risk of rare SAEs might not be balanced by the risk of contracting malaria. As a matter of fact, although contraindications to mefloquine use may be less frequently found in the military than among the general population, they are anyway present. Current screening procedures include anamnestic investigation about previous use of any prophylactic regimens, their compliance and tolerability, as well as the review of medical records and counseling before prescribing mefloquine or other regimens. However, chemoprophylaxis might anyway be prescribed to soldiers carrying contraindications to the chosen regimen, if they are not accurately screened.
Malaria chemoprophylaxis was discontinued among Italian troops in Kabul in 2006, and subsequently also for all other deployment areas of Afghanistan in 2012. About this matter, a predictive modeling suggested that the risk of malaria among Canadian forces in Afghanistan was similar or even lower than the expected incidence of SAEs for some chemoprophylactic regimens, particularly mefloquine; hence the discontinuation.
Another important issue is the use of primaquine terminal prophylaxis. This procedure seems to be prescribed only within several coalition contingents. Terminal prophylaxis is indicated for subjects with intense and prolonged exposure to P vivax malaria, but this does not seem to be the case in most areas of Afghanistan; this procedure is probably not generally warranted for the current situation, given the low risk of P vivax malaria and the potential hazards of the extensive use of primaquine, whose compliance seems even lower than the already low adherence to suppressive chemoprophylactic regimens.
Primaquine treatment can trigger severe hemolytic anemia in glucose-6-phosphate (G6PD)-deficient individuals. This genetic disorder is present all over Italy; its prevalence is 0.5% to 2.9%, and it is higher in the southern regions and the islands, where it can reach values of 15% or more in some areas of Sardinia. The Mediterranean variant, associated with severe clinical manifestations, is the most commonly found G6PD deficiency in Italy. Therefore, the use of primaquine for mass terminal prophylaxis in Italian troops may be particularly hazardous, even because most of the Armed Forces members come from the southern regions.
Limits and Strengths of the Study
This study presents some limitations. Chemoprophylaxis compliance was self-reported and therefore potentially overstated to evade any possible disciplinary action if nonadherence is admitted. However, filling the questionnaire is not mandatory and, according to completing instructions, all given information is processed for statistical purposes only. This is probably the main reason why only one fourth of deployed troops filled the questionnaire, and most of subjects who reported noncompliance did not indicate any cause; moreover, a non-negligible proportion of these subjects explained that chemoprophylaxis was not necessary. Finally, these results are consistent with those of other studies, both for withdrawal rate and occurrence of adverse effects. Therefore, we believe that most soldiers reported honestly their behavior about chemoprophylaxis.
Subjects with SAEs to mefloquine may not have been included in the study, but the analysis of all medical evacuations from Afghanistan due to any neuropsychiatric cause should intercept most of possible SAEs to mefloquine.
We found no significant differences between male and female genders concerning AEs, although mefloquine is reportedly less well tolerated in women. These results, however, may be due to the very small proportion of deployed women soldiers (2.7%), and may render these observations less generalizable, at least for women.
Some malaria cases could be missed by the surveillance. It is improbable, however, that malaria cases may go unnoticed in Afghanistan, where soldiers rely only on military health facilities. After returning to Italy, military personnel can rely also on the National Health Service, which should intercept part of the imported malaria cases possibly missed by the military surveillance; the proportion of missed cases should not therefore be relevant. Finally, although soldiers enrolled in the study represent a consistent proportion of deployed troops, they were not randomly selected, and may not therefore be fully representative of the eligible population.