Recent Advances In The Treatment Of Malaria

Medical and Health Science Project and Seminar Material

Recent Advances In The Treatment Of Malaria


Abstract


Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans (a group of single-celled microorganisms) belonging to the genus Plasmodium (WHO, 2014). The majority of malaria-endemic countries have adopted intravenously (i.v.) administered artesunates as first-line therapy for uncomplicated falciparum malaria, following establishment of a correct diagnosis of malaria by rapid diagnostic tests. In endemic areas, malaria should be suspected, and tested for, in any unwell person who has been in an area where malaria is enmeshed. Treatment involves antimalarial drugs and supportive measures preferably after parasitological confirmation by expert microscopy or, in most cases, following a rapid diagnostic immunochromatographic antigen detection test. In non-malaria malarias, P. vivax and P. knowlesi also carry the risk of severe and life-threatening illness. Malaria chemotherapy remains a dynamic field, with novel drugs and drug combinations continue to emerge in order to outpace the development of large-scale drug resistance against the currently most important drug class, the arteses.


Table of Contents


Preliminary Page(s)

  • Title page
  • Certification page
  • Dedication
  • Acknowledgement
  • Abstract
  • Table of content

Chapter One

1.0 Introduction

  • 1.1 Malaria
  • 1.2 Signs and symptoms of malaria chapter two
  • 1.3 Epidemiology

Chapter Two

2.0 Causes, Pathophysiology and Diagnosis

  • 2.1 Causes of malaria
  • 2.2 Pathophysiology of malaria
  • 2.3 Diagnosis of malaria

Chapter Three

3.0 Prevention and Treatment of Malaria

  • 3.1 Prevention of malaria
  • 3.2 Treatment of malaria

Chapter Four

4.0 Recent Advances in the Treatment of Malaria

  • 4.1 Treatment of uncomplicated plasmodium falciparum malaria
  • 4.2 Treatment of severe malaria
  • 4.3 Treatment of non-falciparum malaria
  • 4.4 Treatment of malaria in pregnancy
  • 4.5 Treatment of malaria in children
  • 4.6 Treatment of malaria as an imported condition
  • 4.7 Conclusion
  • References

Chapter One


1.0 Introduction

1.1 Malaria

Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans (a group of single-celled microorganisms) belonging to the genus Plasmodium (WHO, 2014). Malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases it can cause yellow skin, seizures, coma or death (Caraballo et al., 2014).The disease is transmitted by the biting of mosquitos, and the symptoms usually begin ten to fifteen days after being bitten. If not properly treated, people may have recurrences of the disease months later (WHO, 2014). In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria(Caraballo et al., 2014).The disease is most commonly transmitted by an infected female Anopheles mosquito. The mosquito bite introduces the parasites from the mosquito’s saliva into a person’s blood (WHO, 2014). The parasites travel to the liver where they mature and reproduce. Five species of Plasmodium can infect and be spread by humans (Caraballo et al., 2014).Most deaths are caused by P. falciparum because P. vivax, P. ovale, and P. malariae generally cause a milder form of malaria (WHO, 2014; Caraballo et al., 2014).The species P. knowlesi rarely causes disease in humans (WHO, 2014). Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests (Caraballo et al., 2014).Methods that use the polymerase chain reaction to detect the parasite’s DNA have been developed, but are not widely used in areas where malaria is common due to their cost and complexity (Nadjm and Behrens, 2012).

The risk of disease can be reduced by preventing mosquito bites by using mosquito nets and insect repellents, or with mosquito-control measures such as spraying insecticides and draining standing water (Caraballo et al., 2014).Several medications are available to prevent malaria in travellers to areas where the disease is common. Occasional doses of the medication sulfadoxine/pyrimethamine are recommended in infants and after the first trimester of pregnancy in areas with high rates of malaria. Despite a need, no effective vaccine exists, although efforts to develop one are ongoing (WHO, 2014). The recommended treatment for malaria is a combination of antimalarial medications that includes an artemisinin (WHO, 2014; Caraballo et al., 2014).The second medication may be either mefloquine, lumefantrine, or sulfadoxine/pyrimethamine (WHO, 2010). Quinine along with doxycycline may be used if an artemisinin is not available (WHO, 2010). It is recommended that in areas where the disease is common, malaria is confirmed if possible before treatment is started due to concerns of increasing drug resistance. Resistance among the parasites has developed to several antimalarial medications; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and resistance to artemisinin has become a problem in some parts of Southeast Asia (WHO, 2014).


1.2 Signs and Symptoms of Malaria

The signs and symptoms of malaria typically begin 8–25 days following infection;[11] however, symptoms may occur later in those who have taken antimalarial medications as prevention (Nadjm and Behrens, 2012). Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms, (Bartoloni A, Zammarchi, 2012)and can resemble other conditions such as sepsis, gastroenteritis, and viral diseases (Nadjm and Behrens, 2012). The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions (Beare et al., 2006).

The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae. P. falciparum infection can cause recurrent fever every 36–48 hours, or a less pronounced and almost continuous fever (Ferri, 2009).

Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection (Bartoloni and Zammarchi, 2012). Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.


1.3 Epidemiology

The WHO estimates that in 2010 there were 219 million cases of malaria resulting in 660,000 deaths (Nadjm and Behrens, 2012). Others have estimated the number of cases at between 350 and 550 million for falciparum malaria (Olupot-Olupot and, Maitland, 2013) and deaths in 2010 at 1.24 million (Murray et al., 2012) up from 1.0 million deaths in 1990 (Murray et al., 2012). The majority of cases (65%) occur in children under 15 years old (Murray et al., 2012). About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly (Hartman et al., 2010). There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States (Taylor et al., 2012). About 900 people died from the disease in Europe between 1993 and 2003 (Kajfasz, 2009). Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO and UNICEF, deaths attributable to malaria in 2015 were reduced by 60% from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies (Howitt et al., 2012). In 2012, there were 207 million cases of malaria. That year, the disease is estimated to have killed between 473,000 and 789,000 people, many of whom were children in Africa (WHO, 2014). Efforts at decreasing the disease in Africa since the turn of millennium have been partially effective, with rates of the disease dropping by an estimated forty percent on the continent (Bhatt et al., 2015).

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur (Layne, 2007). An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66) (Provost, 2011). A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali (Murray et al., 2012). The Malaria Atlas Project aims to map global endemic levels of malaria, providing a means with which to determine the global spatial limits of the disease and to assess disease burden (Guerra et al., 2007). This effort led to the publication of a map of P. falciparumendemicity in 2010 (Gething et al., 2011). As of 2010, about 100 countries have endemic malaria. Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease (Kajfasz, 2009).

The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other (Greenwood and Mutabingwa, 2002). Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, providing them with the environment they need for continuous breeding (Jamieson et al., 2006). In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall (Abeku, 2007). Malaria is more common in rural areas than in cities.


Chapter Four


4.0 Recent Advances in the Treatment of Malaria

4.1 Treatment of Uncomplicated Plasmodium Falciparum Malaria

The causative species, the severity of signs and symptoms as well as patient age, immunity status and other risk determining factors (acute or chronic conditions, pregnancy and/or immune impairment) direct the choice of the most appropriate therapy. In addition, drug therapy should be in conjunction with relevant treatment guidelines and subject to local availability of drugs.

Much evidence from RCTs and meta-analyses is available on the treatment of uncomplicated P. falciparum malaria (Zwang et al., 2012).

To overcome the threat of drug resistance of P. falciparum, and to augment treatment efficacy, most malaria-endemic countries have endorsed the World Health Organization (WHO) recommendation and adopted ACTs as first-line therapy for uncomplicated falciparum malaria (WHO, 2010), following establishment of a correct diagnosis of malaria by rapid diagnostic tests. The history of artesunates from ‘household remedy’ against malarial fevers on the Chinese peninsula of Hainan to the modern-day backbone class of antimalarials has been summarized (Cui et al., 2009). The artesunate derivate components in combination treatments are active against all stages of the asexual malaria parasites and lead to significantly shorter parasite clearance time than other antimalarials (Fehintola et al., 2008). Moreover, they exhibit some effect on gametocytes, thus reducing the risk of life cycle perpetuation in post-therapeutic patients, which is important when it comes to optimizing malaria control/pre-elimination efforts in malaria-endemic areas (Douglas et al., 2013). The rationale of administering an ACT, usually over 3 days in total, is twofold; first, administering two or more blood schizontocidal drugs with different modes of action and targets is most often more effective compared to a single drug. In the event that resistance conferring polymorphisms preexist, or arise from de novo mutations during treatment to one of the drugs, the mutant and resistant parasite will be probably killed by the still effective other drug. Secondly, artemisininderivates should be given in combination since they exhibit an extremely short half-life. Recrudescence may result if given as monotherapy for too short. Artemisinins do have a favorable adverse effects profile (Medh et al., 2009).

Several artemisininderivates are available — with no regimen having been unequivocally demonstrated to be superior over the others — including artesunate (water-soluble: for oral, rectal, intramuscular or parenteral use) and artemether (lipid-soluble: for oral, rectal or intramuscular use). These agents are converted to the active agent dihydroartemisinin (DHA), which itself can also be administered directly as in the DHA-piperaquine combination. These drugs differ in their pharmacokinetic and dynamic properties such as stability, bioavailability, metabolism, absorption and excretion.

Serious side effects of ACTs have not been reported in humans, although neurotoxicity has been reported in animal studies (Gordi and Lepist, 2004) ACTs are generally not recommended in the first trimester of pregnancy, on the ground of lack of safety data.

ACT options now recommended for treatment of uncomplicated P. falciparum malaria in any order are: artemether + lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine and DHA + piperaquine (PIP). A wealth of clinical trials have been performed to evaluate the efficacy and safety of artemether-lumefantrine (AL) (Ogutu, 2013). This combination is well tolerated and regularly yielded cure rates of > 95% for P. falciparum malaria in several trials (Juma et al., 2008; Abuaku et al., 2012).

Recently, the combination artesunate-amodiaquine showed a significantly higher unadjusted adequate clinical and parasitological response compared to AL (58.4 vs 46.1%) at day 28 (Tinto et al., 2014).

The efficacy of the combination of fosmidomycin and clindamycin has been investigated in several trials (Borrmann et al., 2004; Ruangweerayut et al., 2008) and has been considered as a promising antimalarial combination as alternative to artemisinins. However, results are conflicting and a recent trial conducted showed inadequate efficacy of a new formulation of fosmidomycinclindamycin combination treatment (Lanaspa et al., 2012).


4.2 Treatment of Severe Malaria

With the increasing availability of injectable artesunates in Good Manufacturing Practice (GMP) quality – while availability seems to remain an issue in and outside endemic areas (Amuasi et al., 2012), there is widespread acceptance of the SEAQUAMAT (Dondorp et al., 2005) and AQUAMAT (Dondorp et al., 2010) multicenter trial results that subsequently led to a WHO policy change from intravenously (i.v.) administered quinine to i.v.artesunate(followed by an oral single drug or drug combination as first-line treatment of complicated malaria). Notwithstanding open detail questions, SEAQUAMAT (Dondorp et al., 2005) in adult patients from India and across Southeast Asia and AQUAMAT (Dondorp et al., 2010) in children across sub-Saharan Africa established the superiority of artesunate not alone with regard to statistically significant mortality reductions, but also in terms of easier handling (e.g., no rate-controlled infusion, no continuous cardiac monitoring, no frequent plasma glucose monitoring required) and an overall favorable adverse events profile (with regard to neurological consequences of severe malaria, no significant differences between both drugs have been observed). That notwithstanding, i.v. administered quinine remains an option for the treatment of severe malaria particularly if artesunate availability in adequate quality is not warranted yet, or in future, should emergence of resistance arise on a large scale before other alternatives become available. However, while artesunate resistance is not a major issue in practice to date, duration of treatment, a disadvantageous adverse events profile with cinchonism, induction of hypoglycemia and pharmacokinetical properties requiring skilled administration from loading dose to dose adaptation in due course facilitated fairly swift acceptance of a shift from quinine to artesunate as backbone drug against severe falciparum malaria (Sheehy and, Angus, 2011). Intramuscular administration of an oily emulsion of artemether is feasible (Hien et al., 2004; Karunajeewa et al., 2006) but where possible, preference is given to i.v. administrable artesunate. The intramuscular use of oily artemether might increase risk of neurotoxicity, although the current regimen dosing duration appears to be safe (Li and Hickman, 2011). Although there are no major safety issues with parenteral artesunate, there are some concerns regarding risk of prolonged and/or late hemolysis after high-dose artesunate treatment. Over the past years, up to 25% of patients from several cohorts treated with i.v.artesunate for severe falciparum malaria from Africa (children/malaria-endemic area: Gabon) and Europe (mainly adults, imported malaria) developed in some cases profound delayed hemolytic anemia 7 – 31 days after treatment (Jarvis et al., 2013).Up to date, the pathophysiology, causality and dimension of the problem remain to be fully elucidated.
Rectal administration of artesunate prior to referral to/arrival at an appropriately equipped health-care referral unit (Gomes et al., 2009) has been proven to be potentially lifesaving, and all practical problems notwithstanding, repeated rectal administration have been suggested to further improving pre-referral outcomes in cases of suspected malaria (Grobusch, 2009; Okebe and Eisenhut, 2014). in settings where prompt adequate diagnosis and treatment may not be at hand.


4.3 Treatment of Non-Falciparum Malaria

Non-falciparum malaria refers to disease due to infection with Plasmodium spp. other than P. falciparum; namely P. vivax, P. ovale subspecies curtisi and wallikeri, P. malariae and P. knowlesi. Although the cause of nearly all of the deaths due to malaria is due to P. falciparum, non-falciparum malarias (P. vivax and P. knowlesi) also carry the risk of severe and life-threatening illness. Plasmodium knowlesi, a parasite of macaque monkeys in Southeast Asia, has been identified as the cause of uncomplicated as well as severe and fatal malaria in Southeast Asia (Cox-Singh et al., 2008; Singh and Daneshvar, 2013). Severe malaria in P. malariae and P. ovale is extremely rare. Of the non-falciparum species, P. vivax has the largest geographic distribution and burden of disease in terms of health, longevity and socioeconomic development, and accounts for 40% of malaria cases worldwide (Douglas et al., 2010). The other two human malaria Plasmodium species P. malariae and P. ovale are normally less prevalent, but they are distributed widely across malaria-endemic areas.


4.4 Treatment Of Malaria in Pregnancy

Pregnant women are at increased risk of acquiring malaria and are susceptible to more severe disease. The treatment of malaria in pregnant women poses particular challenges, as the theoretical risks of teratogenicity of antimalarial drugs need to be weighed against the risk of undertreatment (Kayentao et al., 2013). In addition, safety and efficacy data from clinical trials are limited. Knowledge about adequate drug levels in pregnant women is scarce. More pharmacodynamic and pharmacokinetic data are needed to be able to adjust dosages according to body weight and not according to age groups, which allow a large deviation in exact therapeutic drug levels. For pregnant women, there is a need to adapt pharmacokinetic models and safety data need to be collected in a systemic way.
Commonly, the newer the antimalarial drug, the more effective it is (to a certain extent due to the lack of time for drug resistance to emerge). However, less information will be at hand on safety and efficacy in pregnancy, in particular the first trimester, in the early years of usage of a drug/drug combination, as data will only accumulate on inadvertent use particularly in early, on time point of treatment initiation unrecognized pregnancy. Therefore, physicians should base their management on the clinical state of the pregnant patient, geographical data, resistance patterns, national guidelines, experience (of colleagues) and published data concerning safety of the drug in pregnancy. The safety of the mother should always prevail over that of the unborn child. Treatment involves antimalarial drugs and supportive measures preferably after parasitological confirmation by expert microscopy or, in the majority of settings in endemic areas, following a rapid diagnostic immunochromatographic antigen detection test. This will reduce the unnecessary exposure to antimalarials of both the mother and the unborn child. Prevention of malaria during pregnancy involves chemoprophylaxis ‘Intermittent Preventive Treatment in pregnancy (IPTp)’ (Bardaji et al., 2012; Kayentao et al., 2013) and preventing mosquito bites, for example, with insecticide-treated bednets, are discussed elsewhere (Hill et al., 2013).


4.5 Treatment of Malaria in Children

Malaria is, on a global scale, a pediatric disease (White et al., 2014). Very much different from many other diseases, almost all clinical drug development trials have been performed in children in endemic areas, with treatment outcomes being extrapolated from those trials to inform treatment strategies for adults in malaria-endemic areas, as well as for children and adults exporting malaria to non-endemic, affluent countries. That notwithstanding, the most appropriate choice of combination therapy needs to take age and age-specific pharmacokinetic and dynamic factors, body weight and specific pediatric risk factors (e.g., among others, the problems of administering tetracyclines to younger children) into account. AL is the ACT most commonly used for the treatment of uncomplicated malaria in children. AL has been demonstrated to be safe when compared with other antimalarials such as quinine, sulphadoxine-pyrimethamine and chloroquine (Egunsola and Oshikoya, 2013). Several combinations have been investigated. Firstly, AL has been compared with dihydroartemisinin-piperaquine in 11 studies (Zongo et al., 2007; Kamya et al., 2007), involving 5958 children. No drug-related deaths were identified, and the risk of serious adverse events for AL was not significantly different for DHA + PP (Egunsola and Oshikoya, 2013).
Other trials compared AL with artesunate-amodiaquine (13 studies, 6018 children) (Martensson et al., 2005; Mutabingwa et al., 2005), with chlorproguanil-dapsone-artesunate (three studies, 3366 children) (Premji et al., 2999), with artesunate-mefloquine (two studies, 476 children) and with artesunate-azithromycin (one study, 261 children) (Mutabingwa et al., 2005).

Regarding the safety and tolerability of AL, the authors of a recent systematic review (Egunsola and Oshikoya, 2013). demonstrate cough as the most common adverse event in children treated with AL. Other frequently reported adverse effects are gastrointestinal symptoms such as vomiting, abdominal pain and diarrhea. Headache and anemia were also described as common adverse events.


4.6 Treatment of Malaria as an Imported Condition

Whereas most cases of malaria remain to be pediatric in endemic countries, most imported cases are in adults – yet our treatment strategies are everywhere based on data predominantly obtained from clinical trials conducted in young children in Africa. There is a wealth of national guidelines in place in the various countries where malaria is regularly encountered as an imported condition. Whereas those vary in some detail, atovaquone-proguanil, mefloquine and ACTs, with AL dominating and DHA-PIP now entering the Northern, affluent markets, are regularly featuring in various order of appearance with regard to preference (Lalloo and Hill, 2008). InEurope, atovaquone-proguanil ranges high in many nonendemic countries among the preferred therapies for uncomplicated falciparum malaria (Bouchaud et al., 2012), despite the fact that the slow action inherent to this drug combination, with comparably long parasite and fever clearance times, regularly leads to misperceptions about possible resistance, and to prolonged disease episodes compared to ACTs. Special recommendations for the treatment of children/pregnant women apply throughout all guidelines. A recently introduced black box warning regarding mefloquine use for the therapy of uncomplicated falciparum malaria (Bouchaud et al., 2012) will reduce its use as treatment for uncomplicated malaria further. However, for some indications (high-risk groups, such as long-term travelers, VFR travelers and families with small children), there is currently no replacement for mefloquine available or in the pipeline (Schlagenhauf et al., 2010). In our view, ACTs should most consequently be used for the treatment of uncomplicated imported falciparum malaria in view of its favorable adverse events profile as well as the rapid schizontocidal action.

There is also an increasing debate on whether to continue with non-ACTs (chloroquine in the first place, mostly followed by primaquine administration in non-G6PDdeficient individuals) for non-falciparum species (except for P. knowlesi) therapy as far as susceptibility is assumed. In some non-endemic countries, first shifts away from chloroquine for vivax and ovale malaria treatment toward ACTs on basis of good tolerance and swift clinical improvement due to quick parasite and fever clearance times can be observed (Schlagenhauf et al., 2010), mainly based on data from malaria-endemic countries and based on expert opinion, as controlled trials being tedious to carry out at least in non-endemic countries.

With the prospects of increased availability of GMP conform artesunates in non-malaria-endemic countries improving, there is an increasing shift toward adopting i.v.artesunate in place of i.v. quinine as chemotherapeutic backbone for the treatment of severe falciparum malaria. While controlled trials on the scale of the trials in Asia and Africa are not possible due to small patient numbers (Schlagenhauf et al., 2010), there is evidence from small case series as well as growing expert opinion in favor of parenteral artesunate use (Cramer et al., 2011).


4.7 Conclusion

Malaria chemotherapy remains a dynamic field, with noveldrugs and drug combinations continue to emerge in order tooutpace the development of large-scale drug resistance againstthe currently most important drug class, the artesunates. Continuousinvestment into malaria drug development is a vital contribution to combat artemisinin resistance and successfullyimprove malaria control toward the ultimate elimination goal.


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