The Efficacy of Malaria Chemoprophylaxis

HSJ – HEALTH SCIENCE JOURNAL® VOLUME 2, ISSUE 1 (2008)

THE EFFICACY OF MALARIA CHEMOPROPHYLAXIS

Saridi Maria1, Pappa Vasiliki1, Saroglou George 2

1. Registered Nurse, MSc Clinical Nursing, National and Capodistrean University of Athens 2. Professor of Internal Medicine, National and Capodistrean University of Athens

Abstract

Introduction: Malaria is a highly contagious disease. According to W.H.O., its cases are expected to increase due to climate changes. Despite eradication efforts, malaria still remains one of the most significant causes of morbidity and mortality in tropical and subtropical regions. Many different antimalarial regimens are used; however resistance is emerging to many of them. Purpose: This critical review was conducted, in order to respond to the following questions. A) Which antimalarial regimen is the most effective? B) Which regimen is the safest for travelers in endemic regions? C) Which regimen is best tolerated? Methodology: The literature research was conducted through the Internet. The Medline and Cinahl databases were used, as well as the search engines google, altavista and lycos. The research included clinical trial articles. The studies were selected based on the aforementioned research questions and the chronological time limits. Results: Atovaquone/proguanil, tafenoquine, primaquine were the most effective regimens. Tafenoquine, as well as, primaquine were related to hemolytic incidents in individuals with G6PD deficiency, gastrointestinal disorders, backache and flu-like syndrome. Doxycycline and mefloquine were related to gastrointestinal and neurological disorders. Those were the less tolerated regimens. Conclusions: Atovaquone/proguanil, tafenoquine, primaquine were the most effective regimens. As far as safety is concerned, tafenoquine and primaquine should not be prescribed to individuals with G6PD deficiency. All the regimens were considered well tolerated, while most withdrawals due to adverse effects, took place in the doxycycline and mefloquine trials.

Keywords: malaria prophylaxis, malaria chemoprophylaxis, atovaquone - proguanil, tafenoquine, primaquine, doxycycline, mefloquinehe

Corresponding Author: Saridi Maria E-mail: [email protected]

Introduction

1 Malaria is a highly contagious disease . an infected female anopheline mosquito. Humans contract malaria through the bite of The responsible organism, is the Plasmodium

HSJ – HEALTH SCIENCE JOURNAL® VOLUME 2, ISSUE 1 (2008)

spp. There are 4 different plasmodium Unfortunately, the emerging resistance species, able to cause disease in humans. P. against the malaria chemoprophylactic drugs falciparum malaria is the most serious, as its Table 2 mortality may reach as high as 10%. Other more benign plasmodium species are P. vivax, P. malariae and P. ovale. (Table 1). P. f Table 1

renders many of them, inefficient. While, some of the new drugs can cause serious adverse effects and may be more expensive than former therapies. In order to tackle malaria, many regimens alciparum prevails in the sub-Saharan area, 5,6 Africa, East Asia, Oceania and the Amazon. are being employed. (Table 3, Appendix). It poses a serious threat to the residents and Drugs or drug combinations that are the travelers of these areas as well. currently suggested for malaria prophylaxis In the last decades, war, natural disasters, are chloroquine, atovaquone/proguanil, mefloquine, doxycycline and primaquine. unemployment and tourism have brought 7,8,9 many population changes in malaria endemic countries. Moreover, the emerging Resistance has been developed against most resistance of plasmodium species to of these drugs, especially in South East Asia, antimalarial drugs, dictate constant where doxycycline and perhaps primaquine vigilance, in order to avoid new cases or are the only efficient drugs. Unfortunately, epidemic outbreaks in malaria free they have been correlated with frequent countries. Despite all efforts, malaria still adverse effects. Thus, new, efficient and safe chemoprophylactic antimalarial remains one of the most important causes of 10,11,12 morbidity and mortality in tropical and sub- regimens are necessary. tropical areas. According to W.H.O., there The purpose of this critical review is to are 300 – 500 million cases of malaria conclude which regimen is best suited for annually and every year, approximately 1.5 - recommendation to travelers of malaria 2.7 million people die from the disease2,3. endemic areas. What’s more, malaria incidence is expected to increase due to climatological changes. Purpose: In the United States, the mean of imported This critical review has been conducted in malaria cases is 1300 patients annually order to address the following questions: (Table 2, appendix). The risk for travelers, 1. Which antimalarial regimens are who do not receive chemoprophylaxis varies more efficient? according to the destination, but lies among 2. Which regimens are safer for 24 / 1000 travelers per month in West travelers in endemic regions? Africa, 2.5 / 1000 travelers per month in 3. Which regimen is best tolerated by India and 0.5 / 1000 travelers per month in the travelers? South America4.

Table 3 Drug Usage Adult dose Pediatric dose Comments

Atovaquone/proguanil Prophylaxis in Adult tablets Paediatric Begin 1-2 days before travel contain 250 mg (Malarone™) areas with atovaquone and tablets contain to malarious areas. Take 100 mg chloroquine- 62.5 mg daily at the same time each proguanil resistant or hydrochloride. atovaquone and day while in the malarious

mefloquine- 1 adult tablet 25 mg proguanil area, and for 7 days after orally, daily resistant hydrochloride. leaving such areas.

Plasmodium 11-20 kg: 1 Contraindicated in persons

falciparum tablet with severe renal

21-30 kg: 2 impairment (creatinine

tablets clearance < 30mL/min).

31-40 kg: 3 Atovaquone/proguanil

tablets should be taken with food

41 kg or more: 1 or a milky drink. Not

adult tablet recommended for children <

daily 11 kg, pregnant women, and

women breastfeeding

infants weighing <11 kg.

Chloroquine Prophylaxis only 300 mg base 5 mg/kg base Begin 1-2 weeks before phosphate (Aralen™ in areas with (500 mg salt) (8.3 mg/kg salt) travel to malarious areas. and generic) chloroquine- orally, orally, Take weekly on the same

sensitive P. once/week once/week, up day of the week while in the

falciparum to maximum malarious areas and for 4

adult dose of weeks after leaving such

300mg base areas.

May exacerbate psoriasis

Drug Usage Adult dose Pediatric dose Comments

Doxycycline (Many Prophylaxis in 100 mg orally, 8 years of age Begin 1-2 days before travel brand names and areas with daily or more: 2 to malarious areas. Take generic) chloroquine- mg/kg up to daily at the same time each

resistant or adult dose of day while in the malarious

mefloquine- 100mg/day area and for 4 weeks after

resistant P. leaving such areas.

falciparum Contraindicated in children

< 8 years of age and

pregnant women.

Hydroxychloroquine An alternative to 310 mg base 5 mg/kg base Begin 1-2 weeks before sulfate (Plaquenil™) chloroquine for (400 mg salt) (6.5 mg/kg salt) travel to malarious areas.

primary orally, orally, Take weekly on the same

prophylaxis* only once/week once/week, up day of the week while in the

in areas with to maximum malarious areas and for 4

chloroquine- adult dose of weeks after leaving such

sensitive P. 310 mg base. areas.

falciparum May exacerbate psoriasis

Drug Usage Adult dose Pediatric dose Comments

Mefloquine (Lariam™ Prophylaxis in 228 mg base ≤9 kg: 4.6 Begin 1-2 weeks before mg/kg base (5 and generic) areas with (250 mg salt) mg/kg salt) travel to malarious areas. orally, chloroquine- orally, Take weekly on the same once/week resistant P. once/week day of the week while in the 10-19 kg: ¼ falciparum tablet malarious areas and for 4 once/week weeks after leaving such 20-30 kg: ½ tablet, areas. once/week Contraindicated in persons

31-45 kg: ¾ allergic to mefloquine or tablet once/week related compounds (e.g.

≥46 kg: 1 tablet, quinine and quinidine) and once/week in persons with active

depression, a recent history

of depression, generalized

anxiety disorder, psychosis,

schizophrenia, other major

psychiatric disorders, or

seizures. Use with caution

in persons with psychiatric

disturbances or a previous

history of depression. Not

recommended for persons

with cardiac conduction

abnormalities.

Primaquine An option for 30 mg base 0.5 mg/kg base Begin 1-2 days before travel

prophylaxis in (52.6 mg salt) (0.8 mg/kg salt) to malarious areas. Take

Drug Usage Adult dose Pediatric dose Comments

special orally, daily up to adult daily at the same time each

circumstances. dose, orally, day while in the malarious

Call Malaria daily area and for 7 days after

Hotline (770- leaving such areas.

488-7788) for Contraindicated in persons

additional with G6PD1 deficiency. Also

information. contraindicated during

pregnancy and lactation

unless the infant being

breast-fed has a

documented normal G6PD

level. Use in consultation

with malaria experts.

Primaquine Used for 30 mg base 0.5 mg/kg base Indicated for persons who (52.6 mg salt) presumptive orally, (0.8) mg/kg have had prolonged once/day for 14 anti-relapse salt) up to adult exposure to P. vivax and P. days after therapy departure from dose orally, ovale or both. the malarious (terminal area. once/day for 14 Contraindicated in persons

prophylaxis) to days after with G6PD (1) deficiency.

decrease the departure from Also contraindicated during

risk of relapses the malarious pregnancy and lactation

of P. vivax and area. unless the infant being

P. ovale. breast-fed has a

documented normal G6PD

level.

Methodology: Furthermore, as the authors point out, the The literature research for this critical participants were all residents of a highly review included the Internet and the library endemic region and they might have of the Department of Health Sciences of the developed stronger immunity against National and Capodistrean University of malaria compared to the general population, Athens. The Medline and Cinahl databases therefore they might not be a representative have been used, as well as the search sample. engines google, altavista and lycos. Data The study of Alper Sonmez, et.al, with the were also found in the sites of W.H.O. and title, “The Efficacy and Tolerability of C.D.C. Doxycycline and Mefloquine in Malaria The articles researched, were clinical trials Prophylaxis of the ISAF Troops in studies. Afghanistan”. Keywords were: malaria prophylaxis, malaria This study took place in Afghanistan, one of chemoprophylaxis, atovaquone/proguanil, the endemic regions for chloroquine tafenoquine, primaquine, doxycycline, resistant P. falciparum. Mefloquine and mefloquine doxycycline are recommended for The time frame involved articles, which chemoprophylaxis. The purpose of the study were published between the years 1999 and was to compare the efficacy and tolerability 2006. The chosen articles were clinical of the regimens in Turkish soldiers in Kabul, trials, which were not conducted on Afghanistan. pregnant women or children. Articles The duration of the chemoprophylaxis was written prior to 1999, in languages other approximately 12 weeks for each soldier. than English and abstracts only, were The side effects and the compliance were excluded. evaluated with questionnaires in the 2nd and In the end, 8 articles remained. 8th week of the chemoprophylaxis. The SPSS 10 for windows was used for the Results: statistical analysis. The comparisons The study of Dennis Shanks, et.al, with the between groups used the x2 test and the title, “A New Primaquine Analogue, Fischer exact x2 test. Only alpha values Tafenoquine (WR 238605), for Prophylaxis <0.05 were considered statistically against Plasmodium falciparum Malaria significant. (2001)”. However, it is undetermined whether the This study assessed the ability of results should be considered statistically tafenoquine (WR 238605) to prevent malaria significant. The sample is purposive and the in a P. falciparum holoendemic area. It is a authors do not clarify whether the size has double–blind,placebo–controlled, been selected based on the statistical randomized clinical trial in West Kenya. power, although there is a significance The study population included healthy male level. Moreover, there was a large subject and female volunteers, aged between 18 withdrawal and there was no control group. and 55. They were all residents of a highly Additionally, we are not certain if the malarious area, in West Kenya. In the questionnaires used in order to evaluate the statistical analysis, failure of prophylaxis compliance and the adverse effects, have rates were compared by calculating point been estimated for their reliability. Finally, estimates ant 95% Confidence Intervals for as the authors indicated, the region was the protective efficacy of each tafenoquine malarious hypoendemic and therefore, the dose relative to placebo. prophylactic efficacy may not be as high as However, despite the 95% Confidence estimated. Intervals, the researchers do not explain The study of Bertrand Lell, et. al., with whether the sample size has been selected the title, “Malaria chemoprophylaxis with based on statistical power or significance tafenoquine: a randomised study”. level. Thus, it is uncertain, whether the The authors conducted a randomized, results are statistically significant. double blind study, where they evaluated

the prophylactic efficacy and the safety of factors have a negative effect in the internal tafenoquine in different doses. The study validity of the trial. took place between February and July, The study of J. Kevin Baird, et.al., with 1999, in Gabon, a region highly endemic for the title, “Randomized, Parallel Placebo- P. falciparum malaria. Individuals, aged Controlled Trial of Primaquine for Malaria between 12 – 20 years old, were invited, Prophylaxis in Papua, Indonesia”. from 3 different secondary schools. This study is a randomized, parallel placebo- The 95% C.I. for protective efficacy were controlled trial. The efficacy of primaquine calculated as the ratio of two Poisson for malaria protection was compared to the variables. The reported data were obtained placebo. The participants were residents of by per protocol analysis. The pair Student’s three villages in the northeastern Papua. t test for continuous laboratory data was Their age was between 12 and 65 years old, used for the statistical analysis. The x2 test their weight was >40 kg and they lived in was used in order to calculate differences in Papua for a period between 3 and 26 the number of individuals reporting adverse months. All the participants had lived in effects. malaria free areas for more than 2 years. This study had a good external, as well as They provided written informed consent. internal validity. However, there was a large The researchers used a randomization code subject withdrawal. Furthermore, the assigning sequential numbers to either participants had increased immunity due to inclusion or exclusion for the trial in a 3:1 the highly endemic region, they resided. ratio. The study of J. Dirk van der Berg, et.al, The statistical analysis was carried out using with the title, “Safety and Efficacy of the statistical package SPSS 9.0 and Epi Info Atovaquone and Proguanil Hydrochloride (version 6.04 Center for Disease Control and for the Prophylaxis of Plasmodium Prevention). The differences in means were falciparum Malaria in South Africa”. assesed using the paired or unpaired The aim of this study was to determine the Student’s t test or Mantel Haenszel test. P safety and efficacy of the atovaquone and values ≤ 0.05 were considered proguanil hydrochloride combination therapy significant.The integral validity of the study for the prophylaxis of P. falciparum malaria. was adequate. It is not clear whether the The trial took place in South Africa during sample size was chosen size based on the main season of malaria transmission, statistical power, although there was a February through July. The participants significance level. Thus the results should were 175 healthy, non immune volunteers. not be considered statistically significant. They were all South African National Moreover, the sample may not be Defense Force personnel, male and female, representative, because all the participants aged between 16 and 65 years old and they were residents of the area. had a risk for malaria infection. A written The study of Judith Ling, et.al., with the informed consent was provided. The mean title, “Randomized, Placebo-Controlled duration of exposure to the drug was 8.9 Trial of Atovaquone/ Proguanil for the weeks. The proportion of prophylactic Prevention of Plasmodium falciparum or success was summarized using a 95% Plasmodium vivax Malaria among Migrants Confidence Interval. to Papua, Indonesia”. The study was not randomized, thus the This is a randomized double- blind study on results can not be applied to the general 297 individuals from a non endemic area in population. Furthermore, it is not clear, Indonesia, who migrated to Papua, where whether the sample size was selected based malaria is endemic. Atovaquone/ proguanil on statistical power or significance level. is compared to the placebo in order to Nevertheless, there was a 95% Confidence determine the prophylactic efficacy of the Interval. Therefore, the results should not regimen for P. falciparum and P. vivax be considered statistically significant. infection. The age of the volunteers was Moreover, there was no control group and between 12 and 65 years old and their the subject withdrawal was large. These weight was over 40 kg. They had migrated

from a non endemic area during a period of The authors conducted a randomized, 3 to 26 months. Every participant signed a double–blind, placebo-controlled study, in written informed consent. Subjects were order to determine the efficacy and safety randomized in a 3:1 ratio to continue or of Malarone (250 mg atovaquone/ 100 mg discontinue the study. The 95% Confidence proguanil hydrochloride per tablet) for Interval was calculated from the binomial malaria chemoprophylaxis and especially P. distribution. The Yates’s corrected x2 test falciparum malaria in Zambia. was used in the statistical analysis. The study population included healthy male Apart from the participant withdrawal in the and female volunteers, aged between 18–65 control group, mainly due to infection, the years old, who resided in a highly malarious trial had adequate internal and external endemic region in Zambia All the validity. participants provided written informed The study of Eli Schwartz and Gili Regev- consent forms and the research protocol was Yochay, with the title “Primaquine as approved by the Zambia’s Institute of Prophylaxis for Malaria for Non immune Tropical Diseases. Travelers: A Comparison with Mefloquine The prophylactic efficacy for the two groups and Doxycycline”. were compared by considering the 2 * 2 This is a comparative study among frequency table and performing a Fisher’s primaquine, mefloquine and doxycycline for exact test. The mean difference was their ability to prevent malaria. It is a estimated with Hodges-Lehmann and there retrospective study during 1995 -1998. The was 95% C.I. for the biochemical and travelers joined rafting trips to Ethiopia. hematological factors. The study population consisted of 158 The study had good internal and external Israelis who joined rafting trips to the river validity. Omo in Ethiopia, for a duration of 12 to 20 days. The trips took place during 1995 – Research Results: 1998. All travelers were followed up in The prophylactic efficacy of atovaquone/ different clinics for malaria symptoms and proguanil was 97% against P. falciparum. their compliance was assessed. In addition, Two more studies showed that the 50 participants who took primaquine filled prophylactic efficacy of the regimen against out questionnaires on side effects. all Plasmodium spp. is 95% and 93% with 95% The binomial distribution with correction for C.I. continuity was used for the comparison of The prophylactic efficacy of tafenoquine efficacy of primaquine with that of the against P. falciparum was 68% with a 400mg/ other drugs. The x2 test and the Fisher exact day for 3 days, 86% with 200mg / day for 3 test were used for the statistical analysis. days and consequently 200 mg weekly and The sample of the study was not randomized 89% with 400 mg/ day for 3 days and and we do not know if the size was consequently 400mg weekly. In another estimated based on statistical power or study, none of the participants who received significance level. Therefore the results 250 mg tafenoquine daily for 3 days should not be considered statistically contracted malaria. significant Furthermore, it is not clarified The prophylactic efficacy of primaquine whether the reliability of the questionnaires against malaria was 93% for all Plasmodium was estimated. Finally, the internal validity spp.. One study simply refers to the regimen of the study is threatened because there as more efficient compared to mefloquine was no control group. and doxycycline. Finally, in one trial none of The study of T. Y. Sukwa, et.al., with the the participants who received mefloquine or title “A Randomized, Double-Blind, doxycycline contracted malaria. Placebo-Controlled Field Trial to As far as the safety of the regimens is Determine the Efficacy and Safety of concerned, tafenoquine has been related to Malarone, (Atovaquone/ Proguanil) for the hemolytic incidences in patients with G6PD Prophylaxis of Malaria in Zambia”. deficiency and mild gastrointestinal disorders. Primaquine was related to

hemolytic incidences, toxinemia, This review leads to the following directions gastrointestinal disorders, headache, cough, for future research: sore throat, malaise, dizziness and back • More trials should be conducted, on pains. The complains for the atovaquone/ non-immune individuals. proguanil regimen regarded stomatitis, • Safer regimens have to be employed headache, gastrointestinal disorders, back for high risk groups such as children pain, flue like syndrome and exfoliative skin and pregnant women. rash. Doxycycline was related to An appropriate antimalarial drug should be gastrointestinal disorders, rash, malaise, demonstrated, in order to reduce the risk of headache, insomnia, and neurological emerging resistant Plasmodium spp disorders. Finally, mefloquine was associated with gastrointestinal and neurological disorders. As far as the tolerance of the regimen is concerned, in one trial 2 out of 223 Bibliography participants discontinued tafenoquine use, due to toxinemia and hemolysis. In a study 1. World Health Organization, 1990. of 158 travelers one had to discontinue Practical Chemotherapy of Malaria. primaquine prophylaxis due to World Health Organ Tech Rep Ser 805: 1– gastrointestinal disorders and another one 141. doxycycline prophylaxis due to a rash. In 2. WHO, 1996. Investing in Health Research another trial, 12.5 % and 4.6% of the and Development: Report of the Ad Hoc participants withdrew from doxycycline and Committee on Health Research Relating mefloquine use, respectively, due to adverse to Future Intervention Options. Geneva, effects. Furthermore, in a study on 175 Switzerland: World Health Organization. participants, 3 discontinued atovaquone/ TDR/Gen/96.1. proguanil treatment due to headache and 3. WHO, 1993. Implementation of the dizziness, while in another one, 4 out of 150 global malaria control strategy—Report participants had to withdraw due to of a WHO study group on the abdominal pain and exfoliative skin rash. implementation of the global plan of action for malaria control 1993–2000. Conclusions Geneva, Switzerland: World Health The most efficient regimens were Organization. WHO Technical Report atovaquone/ proguanil, tafenoquine and Series 839. primaquine, while mefloquine and 4. Neal R. Gross, Court reporters and doxycycline were less efficient. As for the transcribers,1323 Rhode Island Ave., safety, tafenoquine and primaquine should N.W.(202) 234-4433 Washington, D.C. not be prescribed to patients with G6DP 2005 deficiency, due to the risk of hemolysis. All 5. Hoffman SL, 1992. Diagnosis, treatment, the regimens were well tolerated and most and prevention of malaria. Med Clin withdrawals were, due to adverse effects in North Am 76: 1327–1355. patients on doxycycline and mefloquine. 6. http://www.cdc.gov/travel. However, we should be cautious with these 7. National Center for Infectious Diseases, results. Apart from the trials on Division of Global Migration and atovaquone/ proguanil, by Judith Ling et.al. Quarantine,2006 and T. Y. Sukwa et al., and that on 8. WHO, 1995. Model Prescribing tafenoquine, by Bertrand Lell et.al, all the Information: Drugs Used in Parasitic other studies faced methodological Diseases. Geneva, Switzerland: World inconsistencies. Thus, more reliable studies Health Organization. have to be conducted, in order to provide 9. Bradley DJ, Bannister B on behalf of the valid results for the protection and the Advisory Committee on Malaria safety of the travellers. Prevention for UK Travellers. Guidelines Directions for malaria prevention in travellers from

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Appendix

STUDY RESEARCHERS- DATE

A New Primaquine Analogue, G. Dennis Shanks,, Aggrey J. Oloo,, Gladys M. et.al, Tafenoquine (WR 238605), for Prophylaxis 2001 against Plasmodium falciparum Malaria

The efficacy and tolerability of doxycycline and Alper Sonmeza,*, Ali Harlakb, Selim Kilicc et.al, mefloquine in malaria prophylaxis of the ISAF 2000? troops in Afghanistan

Malaria chemoprophylaxis with tafenoquine: a Bertrand Lell, Jean-Franηois Faucher, Michel randomised study) Anoumou Missinou, et.al., 2000

Safety and Efficacy of Atovaquone and Proguanil J. Dirk van der Berg, MBChB,l Cornelia S. J. Duvenage, Hydrochloride for the Prophylaxis of Plasmodium et.al, 2000? falciparum Malaria in South Africa

Randomized, Parallel Placebo-Controlled Trial of J. Kevin Baird,1 Mark D. Lacy,1 Hasan Basri , et.al, Primaquine for Malaria Prophylaxis in Papua, 2001 Indonesia Randomized, Placebo-Controlled Trial of Judith Ling,1,5,a J. Kevin Baird,1 David J. Fryauff, Atovaquone/Proguanil for the Prevention of et.al, 2002 Plasmodium falciparum or Plasmodium vivax Malaria among Migrants to Papua, Indonesia

Primaquine as Prophylaxis for Malaria for Eli Schwartz and Gili Regev-Yochay, 1999 Nonimmune Travelers: A Comparison with Mefloquine and Doxycycline A Randomized, Double-Blind, Placebo-Controlled T. Y. SUKWA, M. MULENGA, N. CHISDAKA, N. S. Field Trial to Determine the Efficacy and Safety ROSKELL, AND T. R. SCOTT, 1999 of Malarone, (Atovaquone/ Proguanil) for the Prophylaxis of Malaria in Zambia