Causal Prophylaxis

Of the six drugs included in this report, three exhibit causal prophylactic activity: A/P, primaquine, and tafenoquine. A/P exhibits causal prophylactic activity only against P. falciparum, and it is not effective against hypnozoites associated with P. ovale or P. vivax. Causal prophylaxis, also called exo-erythrocytic stage prophylaxis, kills the Plasmodium parasite before it can complete its development in the liver, thereby inhibiting the parasite’s ability to replicate or cause clinical disease (60 Degrees Pharmaceuticals, 2018). The use of causal prophylaxis to prevent infection with P. vivax and P. ovale is critical; these species can remain dormant in the liver for long periods (up to several years) after an infection occurs and can result in relapse of disease. Causal prophylaxis should be taken for 7–14 days after returning from an area with endemic malaria because the parasites are killed early in their life cycle and they never enter the bloodstream. Figure 2-1 illustrates the way in which causal prophylaxis interferes with the exo-erythrocytic phase of the Plasmodium life cycle (A; steps 1–4). Because causal prophylaxis acts on the exo-erythrocytic stage of the life cycle, it can prevent human infection by all Plasmodium parasites. It is believed that causal prophylactic drugs work by interfering with some key cellular processes necessary for replication and cell survival, including deoxyribonucleic acid (DNA) replication and mitochondrial function (Schwartz, 2012).

Suppressive Prophylaxis

Whereas some of the drugs used for causal prophylaxis also demonstrate suppressive prophylactic activity (e.g., A/P, primaquine, and tafenoquine), mefloquine, chloroquine, and doxycycline are defined exclusively as suppressive antimalarial prophylactic drugs. Suppressive prophylaxis has no effect on Plasmodium parasites until the liver phase of the life cycle is complete and the parasite has invaded red blood cells. Suppressive prophylaxis is ineffective against hypnozoites of P. vivax or P. ovale, but it will kill P. vivax or P. ovale parasites that have entered the bloodstream (Schwartz, 2012). Figure 2-1 shows how suppressive prophylaxis interferes with the erythrocytic phase of the Plasmodium life cycle (B; steps 5–7). Taking suppressive prophylaxis as directed will suppress the symptoms of malaria in individuals who are infected with the malaria parasite. However, if suppressive prophylaxis is not taken as directed, symptoms of the disease will likely appear. Because these drugs act only on parasites in red blood cells, an individual must take them for 4 weeks after leaving an area with endemic malaria in order to eliminate parasites that may appear in the bloodstream during that time (Moss and Morrow, 2014).

The mechanisms of action for suppressive prophylactic drugs vary but are known to include blocking the production of hemozoin, which is a chemical that the parasite produces to protect itself from the toxic products produced as a result of its digestion of hemoglobin by turning them into a non-toxic compound; inhibiting vesicle functions that may interfere with phospholipid metabolism; binding to and altering the parasite’s DNA; blocking transcription and translation of DNA into RNA and proteins; and impairing the expression of the apicoplast (a collection of structures present in Plasmodium parasites that allows for the invasion of host cells and the establishment of the parasite–host interaction) genes in the parasite, resulting in the inability of the parasite to replicate its DNA (Parhizgar and Tahghighi, 2017).

Presumptive Anti-Relapse Therapy

PART, also known as terminal prophylaxis, is the use of an antimalarial drug toward the end of the exposure period (or immediately thereafter) to prevent relapses or the delayed onset of clinical malaria caused by hypnozoites (dormant exo-erythrocytic stages) of P. vivax or P. ovale. PART is generally indicated for people who have had prolonged exposure in malaria-endemic areas (such as military personnel, Peace Corps volunteers, or missionaries) (CDC, 2019a). Two of the drugs included in this report, primaquine and tafenoquine, can be used both as primary prophylaxis and as PART. When used for PART, these drugs are often given in combination with chloroquine or another blood schizonticide. PART is an important factor in preventing relapse of malaria. Because PART agents act on both the exo-erythrocytic and erythrocytic stages, they affect the malaria life cycle at the same points as causal and suppressive prophylactic agents (see A and B in Figure 2-1).

Treatment

An inherent distinguishing factor between the prophylaxis and the treatment of malaria is how the antimalarial drugs are used: prophylaxis prevents disease, while the goal of treatment is to cure infection. Each of the drugs included in this report can be used for either prophylaxis or treatment; however, the dosage at which each drug is used for the treatment of malaria is significantly higher than when it is used for prophylaxis. For example, the treatment dose of A/P is four times higher than its prophylactic dose. As a result of the higher blood concentrations achieved with treatment regimens, adverse events may occur with treatment that are not observed when the drug is used for prophylaxis, or adverse events may be more severe in their presentation (Arguin and Magill, 2017; CDC, 2019b). Whereas the FDA package insert for A/P lists diarrhea, dreams, oral ulcers, and headache as common adverse events (≥4% of adults) when A/P is used as directed for prophylaxis, the common (≥5% of adults) adverse events when A/P is used for treatment include abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, and dizziness (FDA, 2019).

8-Aminoquinolines

The 8-aminoquinoline class of antimalarials is unique in that it owes its ability to prevent the relapsing forms of malaria by acting against the malaria hypnozoites that lie dormant in the liver (Marcsisin et al., 2014). Primaquine, the prototype 8-aminoquinoline, was developed in 1945 and has prophylactic activity against the liver stage of all malaria parasites, against the asexual and sexual stages of P. vivax, P. ovale, P. malariae, and P. knowlesi, and the sexual stages of P. falciparum (it is only weakly active against the asexual blood stages of P. falciparum), and it has radical curative activity in P. vivax and P. ovale malaria. It is the most widely used 8-aminoquinoline for malaria prophylaxis, but its exact mechanism of action is still unknown. Primaquine localizes within the Plasmodium mitochondria and impairs the mitochondrial metabolism, which suggests drug-induced mitochondrial dysfunction as a potential mechanism of action (Schlagenhauf et al., 2019).

In general, 8-aminoquinolines are metabolized by the cytochrome P450 CYP2D family (particularly CYP2D6), which is required for both their antimalarial activity and their toxicity. Several possible modes of action on the parasite have been proposed. One hypothesis is that active metabolites of 8-aminoquinolines may lead to mitochondrial dysfunction (Schlagenhauf et al., 2019) and the alteration of intracellular membrane structures in both erythrocytic and pre-erythrocytic stages of the parasite. Another hypothesis is that the highly reactive metabolites generate intracellular reactive species, which cause oxidative damage. The primaquine metabolite, 5-hydroxyprimaquine, and its downstream oxidation products such as the corresponding 5,6-orthoquinone (Fasinu et al., 2019) cause a substantial generation of reactive oxygen species, most notably hydrogen peroxide (Camarda et al., 2019). This leads to the killing of the malaria parasite (Camarda et al., 2019), methemoglobinemia (Liu et al., 2011), and oxidative damage to the erythrocyte cytoskeleton (Bowman et al., 2005).

Tafenoquine was first identified in 1978, but it was only recently approved (2018) for the prophylaxis and radical cure of malaria. Clinical trials of tafenoquine have not definitively determined whether it works via a causal or a suppressive prophylaxis mechanism (Baird, 2018). Tafenoquine is substantially more active against the erythrocytic stages of the Plasmodium life cycle than primaquine, and it is more slowly metabolized with a terminal elimination half-life of 14–17 days. Tafenoquine is active against all pre-erythrocytic and erythrocytic forms of human malaria as well as against the gametocytes of P. falciparum and P. vivax (FDA, 2018a).

Neither the precise mechanism of action of tafenoquine nor its molecular target have been determined. In vitro studies with the erythrocytic forms of P. falciparum suggest that tafenoquine may exert its effect by inhibiting hemozoin formation and inducing apoptotic-like death of the parasite (FDA, 2018b; Vennerstrom et al., 1999). This may explain why tafenoquine is active against the asexual blood stage of parasites, unlike primaquine, which does not inhibit hemozoin formation (Ebstie et al., 2016). Otherwise, the mechanism of action of tafenoquine is similar to that of primaquine (Ebstie et al., 2016) in which the spontaneous oxidation of metabolites generates hydrogen peroxide and hydroxyl radicals. The reactive oxygen species generated through P. falciparum ferredoxin-nicotinamide adenine dinucleotide phosphate (NADP⁺) reductase and diflavin reductase enzymes are thought to result in parasite death, a theory that is supported by the upregulation of these enzymes in tafenoquine-sensitive stages of the parasite (Ebstie et al., 2016).

One limitation of antimalarial 8-aminoquinolines is that they are contraindicated in people who have the X-linked glucose-6-phosphate dehydrogenase (G6PD) genetic defect. G6PD deficiency is the most common genetic human enzyme disorder, with 186 genetic variants that have been described. It is estimated to affect more than 400 million people worldwide, most of them in malaria-endemic areas and most commonly in males (Nkhoma et al., 2009). G6PD is the key enzyme in the oxidative pentose phosphate pathway. It converts NADP⁺ into its reduced form, NADPH. NADPH is essential for protection against oxidative stress in erythrocytes. G6PD deficiency causes an increased susceptibility of erythrocytes to hydrogen peroxide and other reactive oxygen species which can lead to hemolysis (the rupture of red blood cells and release of their contents into the plasma) and hemolytic anemia (red blood cells being destroyed faster than they can be replaced), which in turn can lead to other serious complications, including arrhythmias, cardiomyopathy, heart failure, and death (NIH, n.d.; Peters and Van Noorden, 2009). The extent of hemolysis depends on the dose and duration of drug exposure and the degree of G6PD deficiency. Persons with >80% of normal red-blood-cell G6PD activity are considered to be G6PD normal (WHO, 2016a). Males with <10% normal red-blood-cell G6PD activity are regarded as G6PD deficient; females with 30–80% of normal red-blood-cell G6PD activity are considered to be G6PD intermediate, and those with <30% are regarded as G6PD deficient. A study of more than 63,000 U.S. military personnel determined that 2.5% of men and 1.6% of women were G6PD deficient, with most of them having a moderate level of deficiency (Chinevere et al., 2006). The highest rates of deficiency were seen in African American men (12.2%) and women (4.1%) and Asian men (4.3%).

WHO recommends the use of ultraviolet spectrophotometry as the gold standard for measuring G6PD activity; however, this technique requires technology that is not suitable for field development or point-of-care testing. As a result, the most commonly used field test for G6PD deficiency is the fluorescent spot test (FST), a semi-quantitative assay that requires minimal laboratory supplies and does not require expertise for result interpretation. Several qualitative tests have been recently introduced that have better operational characteristics and similar detection capabilities as the FST. These tests can only distinguish G6PD homozygous females and hemizygous males with intermediate enzyme activities above 30% of normal from G6PD-normal individuals. Because G6PD deficiency is linked to the X chromosome, females can present with homozygous, heterozygous, or normal G6PD gene expression. The commonly used field tests are insufficient for detecting G6PD activity in heterozygous females with intermediate enzyme activities that fall outside of the 30% of normal threshold. As a result, heterozygous females may express G6PD-deficient characteristics that are not detected by the currently available field testing procedures (Ley et al., 2017); the presentation of these false-negative results may lead to inadvertent exposure to 8-aminoquinoline antimalarial drugs and their subsequent adverse events (Peters and Van Noorden, 2009). Recently, researchers have also begun exploring quantitative testing that can be administered in resource-limited settings; however, many of these tests are still in development or are undergoing evaluation (Pal et al., 2019).

Methemoglobinemia, usually mild and reversible, is a well-characterized feature in recipients of 8-aminoquinolines at therapeutic dosing (Baird, 2019). Methemoglobinemia occurs when the level of methemoglobin in red blood cells exceeds 1%, which can lead to decreased availability of oxygen to tissues (Denshaw-Burke et al., 2018). Severe methemoglobinemia can lead to complications, including abnormal cardiac rhythms, altered mental status, delirium, seizures, coma, and profound acidosis; if the level of methemoglobin in red blood cells exceeds 70%, death can result.

4-Aminoquinolines

As reviewed by Foley and Tilley (1998) and O’Neill et al. (2006), chloroquine, which was first discovered in 1934, is the prototype 4-aminoquinoline antimalarial drug. Both enantiomers of the racemic chloroquine have equivalent antimalarial activity. Chloroquine is active against the erythrocytic stages of all species of malaria, and it is also active against the gametocytes of P. vivax, P. malariae, and P. ovale. It is a diprotic weak base, and it works by concentrating in the parasite food vacuole and binding tightly to hematin as it is formed during the digestion of hemoglobin by the parasite. The binding of chloroquine to hematin interferes with the assembly of hematin into the non-toxic hemozoin, or malaria pigment, and this may increase the intrinsic toxicity of hematin to the parasite. As reviewed by Ecker et al. (2012), drug resistance to chloroquine in P. falciparum is mediated primarily by mutant forms of the chloroquine resistance transporter (PfCRT). These mutant forms of PfCRT effectively efflux chloroquine from the parasite digestive vacuole, the site of the drug’s action. Mutations in PfCRT allow the parasite to persist at drug levels that kill chloroquine-sensitive parasites. Some researchers have suggested that chloroquine-sensitive P. falciparum is returning in parts of Africa due to the discontinuation of the widespread use of chloroquine in the early 1990s, which may have resulted in the parasite’s reversal to a chloroquine-sensitive state (Schlagenhauf et al., 2019). Individuals who have G6PD deficiency should be closely monitored while receiving chloroquine because of the potential for hemolysis to occur; however, significant hemolysis is rare when the drug is given at prophylactic and therapeutic doses (Schlagenhauf et al., 2019).

Quinoline Methanols

Mefloquine is a synthetic structural analog of quinine (Hellgren et al., 1997). Mefloquine, as well as the other antimalarial quinolines such as chloroquine, primaquine, and tafenoquine, differs considerably from quinine with respect to both its mechanistic biology and the adverse events associated with its use. Furthermore, as numerous non-antimalarial drugs also contain quinoline substructures, overgeneralizations about adverse events of quinolines as a group are unwarranted (Dorwald, 2012). Mefloquine, a quinoline methanol, was first identified as a compound with antimalarial activity in animal models in the 1960s and was approved for prophylaxis and the treatment of malaria in humans in 1984. Mefloquine consists of a 50:50 racemic mixture of the erythro isomers available as tablets containing 250 mg of mefloquine salt. The formulation of mefloquine available in the United States contains 250 mg of mefloquine hydrochloride.

Mefloquine is a potent, long-acting blood schizonticide that is effective against all malarial species that infect humans (Schlagenhauf et al., 2010); however, it has no activity against the liver stages of parasite development (Palmer et al., 1993). Both the (+) and the (–) enantiomers are active against P. falciparum, but a higher activity for (+) mefloquine has been reported (Hellgren et al., 1997). One major reason for its importance in the malaria-prophylaxis armamentarium is its efficacy against chloroquine-sensitive and chloroquine-resistant P. falciparum, (Palmer et al., 1993), although resistance of P. falciparum to mefloquine is known to exist in parts of Cambodia, Laos, Myanmar, Thailand, and Vietnam (CDC, 2019a). The exact mechanism of action is unclear, but it is thought that inhibiting hemozoin formation in the P. falciparum food vacuole causes a toxic accumulation of the highly reactive hematin moiety, which in turn kills the parasite; oxidative damage is believed to play a role (Ridley et al., 1997; Sullivan et al., 1998). One study has found that in addition to inhibiting hemozoin, mefloquine can induce apoptosis in Plasmodium species by activating metacaspase and reactive oxygen species production (Gunjan et al., 2016). More recently, mefloquine was found to act by targeting the P. falciparum 80S ribosome to inhibit protein synthesis (Wong et al., 2017).

Antibiotics

Tetracyclines are a class of broad-spectrum antibiotic drugs that are used to treat a wide range of illnesses. Tetracyclines were first investigated for their antimalarial potential in the 1960s after the emergence of chloroquine-resistant P. falciparum parasites. The tetracycline drug doxycycline is a slow-acting schizonticidal agent. In addition to its activity against the erythrocytic stage of the parasite, doxycycline is thought to possess some pre-erythrocytic (causal) activity, but efficacy studies found unacceptably high failure rates for its use as a causal prophylactic. There is very limited evidence concerning doxycycline’s effect on gametocytes of Plasmodium species, and it has been shown to have no effect on the hypnozoites. In one study that examined gametocytemia and doxycycline, P. vivax gametocytemia increased from 32% pre-treatment to 44% immediately post-treatment, and the median gametocyte clearance time was 62 hours. Gametocytemia has no clinical implications, but malaria may still be transmitted through mosquitoes if they bite an individual being treated for malaria with doxycycline (Tan et al., 2011).

Although doxycycline is known to be a blood schizontocide, the exact mechanism of its action is not well defined (Schlagenhauf et al., 2019). In P. falciparum, doxycycline impairs the expression of apicoplast genes, leading to nonfunctional apicoplasts in subsequent progeny, and it impedes the development of viable parasites. Doxycycline’s antimalarial actions may be similar to its bacteriostatic actions of binding to ribosomal subunits and inhibiting protein synthesis, but this has only been observed in suprapharmacologic doses (Tan et al., 2011).

Combinations (Antifolates)

Atovaquone/proguanil (A/P) is a fixed drug combination made from atovaquone and proguanil for the prophylaxis of P. falciparum malaria. Atovaquone is a hydroxynaphthoquinone, and proguanil is a synthetic arylbiguanide (antifolate); the two drugs work synergistically against the erythrocytic stages of all the Plasmodium parasites and against the liver stage (causal prophylaxis) of P. falciparum. A/P is not active against hypnozoites in P. vivax or P. ovale, and it does not prevent relapse infections (Nixon et al., 2013).

Atovaquone acts by inhibiting the Plasmodium species’ mitochondrial electron transport at the cytochrome bc₁ complex, which collapses mitochondrial membrane potential. The electron transport system of the Plasmodium species is 1,000 times more sensitive to atovaquone than this system in mammals, which is thought to explain the selective action and limited adverse events of the drug (Schlagenhauf et al., 2019). Inhibition of the Plasmodium bc₁ complex by atovaquone affects the concentrations of metabolites in the pyrimidine bio-synthetic pathway and in the biosynthesis of purine, both of which are required for DNA replication in the Plasmodium parasite (Boggild et al., 2007). Proguanil is metabolized to cycloguanil, which inhibits dihydrofolate reductase, resulting in an impeding of the synthesis of folate cofactors required for parasite DNA synthesis.

When atovaquone and proguanil are given in combination, both in vitro and in vivo studies have found the mechanism of action to be synergistic between the two of them (Canfield et al., 1995; Looareesuwan et al., 1999). This leads to high cure rates of P. falciparum malaria, even in cases where the parasites have developed a resistance to cycloguanil conferred by DHFR mutations (Gay et al., 1997). The cause of the synergy between proguanil and atovaquone is thought to be found in the biguanide mode of action, not in the action of its metabolite(s) (Srivastava et al., 1999). Proguanil acts synergistically with atovaquone in individuals with proguanil-resistant parasites or in those who are unable to metabolize proguanil to cycloguanil because of CYP450 enzyme deficiencies (Helsby et al., 1990; Looareesuwan et al., 1999).

Environmental and Chemical Exposures

During deployments, service members may have had a variety of environmental exposures related to their deployment including solvents, fumes from kerosene heaters in unvented tents, and exposure to petroleum-based combustion products including diesel fuel and leaded gasoline that were used in cooking stoves and portable generators and to suppress sand and dust in desert environments and aid in the burning of waste and trash in open air burn pits. Such combustion products may contain many hazardous agents such as polyaromatic hydrocarbons, dioxins, furans, and methane.

In areas of conflict, pesticide exposures are generally widespread among troops as their units attempt to resist the local insect and rodent populations. DEET and permethrin-impregnated uniforms are nearly ubiquitous in deployments to Southeast Asia, Southwest Asia, and Africa. Other pesticides that have been reportedly used, particularly in Iraq and Afghanistan, include methyl carbamates (e.g., proxpur, carbaryl), organophosphates (e.g., chlorpyrifos, diazinon, malathion), pyrethroids, lindane, and chlorinated hydrocarbons (DoD, 2001; RAND, 2000). However, objective information regarding individual levels of pesticide exposure is generally not available, and reports by individual veterans as to their use of and possible exposure to pesticides are subject to considerable recall bias.

Many environmental and chemical exposures could be related to particular activities related to a service member’s or veteran’s military occupational specialty. In the conflicts in Iraq and Afghanistan, the majority of occupational chemical exposures appear to have been related to repair and maintenance (chlorinated hydrocarbons), sandblasting (abrasive particles), vehicle repair (carbon monoxide and organic solvents), weapon repair (lead particles), and welding and cutting (chromates, nitrogen dioxide, and heated metal fumes). In addition, troops painted vehicles and other equipment used in the Persian Gulf region with a chemical-agent-resistant coating either before they were shipped to the Persian Gulf or while they were at ports in Saudi Arabia. Working conditions in the field were not ideal, and recommended occupational-hygiene standards might not have been followed at all times (NASEM, 2016).

In addition to the requirements for service members to be up to date on standard vaccines, certain military deployments require additional vaccines or prophylactic agents, such as for cholera, meningitis, and typhoid. Deployment to malaria-endemic locations, such as Southwest Asia, Southeast Asia, and Africa, require the issue of an approved antimalarial drug. In some combat theaters additional protective measures may be needed. For example, during the 1990–1991 Persian Gulf War, about 150,000 troops received anthrax vaccine and about 8,000 troops received botulinum toxoid vaccine, although medical records from this period are notably lacking information regarding who received these vaccines, how frequently the vaccines were administered, or the timing of vaccinations relative to other putative exposures (IOM, 2000).

Some environmental exposures resulted from the conflict itself, such as exposures to the depleted uranium used in munitions, excessive heat or humidity, additional vaccines administered, and smoke from open burn pits. Some of the exposures could be constant, such as dust, heat, and pesticides, while other exposures were intermittent or infrequent.

Combat Exposures

Although modern warfare has resulted in fewer deaths and casualties than earlier conflicts—those in Vietnam and Korea, World War I and World War II—there are numerous opportunities for exposure to potentially harmful situations during deployment. Combat is widely acknowledged to be one of the most intense experiences that a person can have and may include many threatening situations such as killing or attempting to kill an enemy; being shot at by others; exposure to dead and wounded comrades, enemy combatants, and civilians; and being injured. For the 1990–1991 Gulf War and the OEF/OIF/OND conflicts, these situations included being in the vicinity of Scud missile explosions, contact with improvised explosive devices, contact with prisoners of war, direct combat duty, coming under small-arms fire, having artillery close by (Hoge et al., 2004; Kang et al., 2000; Unwin et al., 1999), and the fear of terrorist or chemical attacks. Many surveys have been conducted to assess veterans’ combat experiences and exposures (e.g., Millennium Cohort Study, National Health Survey of Gulf War Era Veterans and Their Families, National Health Study for a New Generation of U.S. Veterans), and in nearly all of them, veterans have reported exposure to a wide variety of threatening or harmful situations during their deployments. In one study that conducted a survey of the combat experiences and mental health problems of Army or Marine Corps service members deployed to either OEF or OIF, researchers found that many of the respondents indicated having had several of these experiences. For example, among the marines deployed to Iraq (n = 815), 97% reported being shot at or receiving small arms fire, 95% reported being attacked or ambushed, 94% reported seeing dead bodies or human remains, and 92% reported receiving incoming artillery, rocket, or mortar fire. Although the percentages were slightly lower, soldiers deployed to Iraq (n = 894) also indicated having had similar combat experiences (Hoge et al., 2004).

Psychological Stressors

Deployment to a war zone in general, and combat exposure in particular, may result in psychiatric and physical sequelae among service members. In addition to the cramped and uncomfortable living conditions, the many potential environmental and chemical exposures, and the threat of combat, a variety of other stressors may also exert psychologic effects. Rapid mobilization may exert additional substantial pressure on those who are deployed, disrupting lives and separating families. Uncertainty about the duration of deployment was a continuing concern for U.S. troops during the Gulf War, OEF, and OIF, particularly during the early phases of the buildup. For the large numbers of reservists and National Guard members who were mobilized, there was added uncertainly about whether their jobs would be available when they returned to civilian life (VA, 2011). Although better mechanisms for and access to communication with family in the United States exist than was the case for earlier conflicts such as Vietnam, deployment can still add to the stress of maintaining family relationships, particularly for reserve and National Guard personnel who may not have deployed with a familiar or cohesive unit. Surveys of both active-duty and reserve and National Guard soldiers deployed to Iraq in support of OIF found that the most important noncombat stressors were deployment length and family separation (MHAT, 2006a,b). Stressful working conditions, disrupted sleep patterns, and prolonged separation from families may exacerbate the psychological stressors (Adshead, 2014).

Although historically women who served in the military were not allowed to serve in direct combat specialties, they were deployed in combat support roles as administrators, air traffic controllers, logisticians, ammunition technicians, engineering equipment mechanics, ordnance specialists, communicators, radio operators, drivers, law enforcement specialists, aviators, and guards. Still others served on hospital, supply, oiler, and ammunition ships or served as public affairs officers and chaplains (DoD, 2004), and they experienced many of the same exposures and stressors as men when deployed. In addition, several studies of deployment experiences found that female military personnel were more likely to experience sexual harassment and assault than male personnel (Goldzweig et al., 2006; Kang et al., 2005; Vogt et al., 2005; Wolfe et al., 1998).

Following deployment, many veterans experience high levels of stress during the transition to civilian life (IOM, 2008, 2013; Mobbs and Bonanno, 2018). In particular, coming-home experiences may be challenging, with numerous stressors including relationships with spouses and family, and parenting roles (Mobbs and Bonanno, 2018; Steenkamp et al., 2017). Some of these coming-home stressors may be related to the military experience itself. Vietnam veterans, for example, frequently experienced social rejection and were stereotyped for being perceived as harming vulnerable Vietnamese populations, which placed them in a difficult position on top of other mental health issues they were experiencing (Marmar et al., 2015; Steenkamp et al., 2017). With a better understanding of those experiences by policy makers and professionals, Iraq and Afghanistan service members were treated more positively; however, a host of highly needed resources, such as access to mental health care, legal help, and vocational opportunities, has been limited (IOM, 2013). Whereas the lifetime prevalence of posttraumatic stress disorder (PTSD) in U.S. adults was estimated to be 6.8% according to the National Comorbidity Survey–Replication (Harvard Medical School, 2007), the prevalence of PTSD among post-9/11 veterans is much higher. Among post-9/11 veterans using VA health services, nearly one-quarter of them had a diagnosis of PTSD (IOM, 2014). Similarly, a meta-analysis of PTSD prevalence in post-9/11 veterans that included 33 studies published between 2007 and 2013 involving 4,945,897 OEF/OIF veterans estimated the overall prevalence of PTSD among these veterans to be 23% (Fulton et al., 2005). Despite some resources and programs available for returning veterans, the stresses of deployment and reintegration elevate their risk for a host of military-related psychiatric problems, including PTSD, depression, anxiety disorder, substance abuse, and suicidal ideation and attempts (Pietrzak et al., 2009; Thomas et al., 2017).

Living Conditions

Combat troops deployed to the conflicts in Southwest Asia were often crowded into warehouses and tents upon arrival in the Persian Gulf region and then often moved to isolated desert locations (NASEM, 2016). Most troops lived in tents and slept on cots lined up side by side, affording virtually no privacy or quiet. Sanitation was often primitive, with strains on latrines and communal washing facilities. Hot showers were infrequent, the interval between laundering uniforms was sometimes long, and desert flies were a constant nuisance, as were scorpions and snakes. Military personnel worked long hours and had narrowly restricted outlets for relaxation. Troops were ordered not to fraternize with local people, and alcoholic drinks were prohibited in deference to religious beliefs in the host countries. A mild traveler’s type of diarrhea affected more than half of the troops in some units; one study of ground forces found that 57% of those surveyed had experienced at least one episode of diarrhea within the first 2 months of deployment and of those, 20% were unable to perform their military duties while affected (Hyams et al., 1991). Among British and Australian medical teams that were part of the coalition forces, 69% of British troops and 36% of Australian troops experienced diarrhea, with some episodes lasting for several days (Rudland et al., 1996). Fresh fruits and vegetables from neighboring countries were identified as the cause and were removed from the diet. Thereafter, the diet consisted mostly of packaged foods and bottled water.

Depending on the deployment location, weather may create additional stressors. During the summer months in Iraq, the air temperatures could reach as high as 115°F and the sand temperatures as high as 150°F. Except for coastal regions, the relative humidity was less than 40%. Troops had to drink large quantities of water to prevent dehydration. Although the summers were hot and dry, temperatures in winter in Iraq and Afghanistan were low, with wind chill temperatures at night dropping to well below freezing. Wind and blowing sand made the protection of skin and eyes imperative. Goggles and sunglasses helped somewhat, but visibility was often poor.

Interindividual Variability

Differences among people in their genetic, biologic, psychologic, and social vulnerabilities add to the complexity of determining health outcomes related to specific agents (NASEM, 2016). The likelihood of observing a particular health outcome may differ for people with increased sensitivity to an agent, such as G6PD deficiency as described earlier in the chapter. For example, a person who is a poor metabolizer of a particular substance, depending on his or her genetic makeup, might be at higher or lower risk for specific health effects if exposed to the substance.

All antimalarial drugs used for prophylaxis in adults are prescribed as fixed dose regimens in which the amount of drug (e.g., one tablet) and unit of time (e.g., once daily, weekly) is specified. For example, the recommended dosing for A/P is one tablet (250 mg atovaquone and 100 mg proguanil) per day beginning 1–2 days before entering and continuing throughout the stay, and for 7 days after leaving an endemic area. Consistent with FDA indications, the same fixed dose is prescribed to all adult individuals, regardless of sex, weight, or age. As such, certain antimalarials may be more likely to be associated with side effects or adverse events in people with certain demographic characteristics. For example, among people who use mefloquine, more women report adverse events than men. Because in general women weigh less than men and have a smaller vascular volume, a fixed dose tablet of an antimalarial may result in higher plasma levels of the drug in people of lower weight (women) than in people of heavier weight (men). Some studies have shown that adverse events are related to the concentration of drug in the blood (Schwartz et al., 2001), not to the absolute dose of drug delivered. Therefore, if the target of drug delivery was for a specific plasma level across all adult users, then the drug would have to be dosed on a mg/kg basis. Since the goal of prophylaxis is protection against malaria, the fixed dose was determined based on the pharmacokinetic studies of a dose that offers the best combination of protection and tolerability and that was easy to mass produce.