Malaria prophylaxis

Malaria prophylaxis is a preventative treatment of malaria.

Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity (resistance); the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Several malaria vaccines are under development.

• Awareness of risk;
• Bite prevention - Travelers to malarious areas are advised to wear long clothes that cover as much of the skin as possible. Exposed parts of the body should be treated with insect repellent. When sleeping, insecticide-impregnated bed nets should be used. See also: Indoor residual spraying
• Chemoprophylaxis; and
• rapid diagnosis and treatment.

Recent improvements in malaria prevention strategies have further enhanced its effectiveness in combating areas highly infected with the malaria parasite. Additional bite prevention measures include mosquito and insect repellents that can be directly applied to skin. This form of mosquito repellent is slowly replacing indoor residual spraying, which is shown to have high levels of toxicity by WHO (World Health Organization). Further additions to preventative care are sanctions on blood transfusions. Once the malaria parasite enters the erythorocytic stage, it can adversely affect blood cells, making it possible to contract the parasite through infected blood.

Chloroquine may be used where the parasite is still sensitive.^[1] However due to resistance one of three medications: mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride (Malarone) is frequently needed.^[1] Doxycycline and the atovaquone and proguanil combination are the best tolerated with mefloquine associated with higher rates of neurological and psychiatric symptoms.^[1]

Medications

In choosing the agent, it is important to weigh the risk of infection against the risks and side effects associated with the medications.^[2]

Suppressive prophylaxis

Chloroquine, proguanil, mefloquine, and doxycycline are suppressive prophylactics. This means that they are only effective at killing the malaria parasite once it has entered the erythrocytic stage (blood stage) of its life cycle, and therefore have no effect until the liver stage is complete. That is why these prophylactics must continue to be taken for four weeks after leaving the area of risk.

Causal prophylaxis

Causal prophylactics target not only the blood stages of malaria, but the initial liver stage as well. This means that the user can stop taking the drug seven days after leaving the area of risk. Malarone and primaquine are the only causal prophylactics in current use.

Regimens

Specific regimens are recommended by the WHO,^[3] UK HPA^[4] and CDC^[5] for prevention of P. falciparum infection. HPA and WHO advice are broadly in line with each other (although there are some differences). CDC guidance frequently contradicts HPA and WHO guidance.

These regiments include:

• doxycycline 100 mg once daily (started one day before travel, and continued for four weeks after returning);
• mefloquine 228 to 250 mg once weekly (started two-and-a-half weeks before travel, and continued for four weeks after returning);
• atovaquone/proguanil (Malarone) 1 tablet daily (started one day before travel, and continued for 1 week after returning).

In areas where chloroquine remains effective:

• chloroquine 300 to 310 mg once weekly, and proguanil 200 mg once daily (started one week before travel, and continued for four weeks after returning);

What regimen is appropriate depends on the person who is to take the medication as well as the country or region travelled to. This information is available from the UK HPA, WHO or CDC (links are given below). Doses depend also on what is available (e.g., in the US, mefloquine tablets contain 228 mg base, but 250 mg base in the UK). The data is constantly changing and no general advice is possible.

Doses given are appropriate for adults and children aged 12 and over.

Other chemoprophylactic regimens that have been used on occasion:

• Dapsone 100 mg and pyrimethamine 12.5 mg once weekly (available as a combination tablet called Maloprim or Deltaprim): this combination is not routinely recommended because of the risk of agranulocytosis;
• Primaquine 30 mg once daily (started the day before travel, and continuing for seven days after returning): this regimen is not routinely recommended because of the need for G-6-PD testing prior to starting primaquine (see the article on primaquine for more information).
• Quinine sulfate 300 to 325 mg once daily: this regimen is effective but not routinely used because of the unpleasant side effects of quinine.

Prophylaxis against Plasmodium vivax requires a different approach given the long liver stage of this parasite^[6]. This is a highly specialist area.

Vaccines

In October 2011, preliminary findings from the Phase III trials of an experimental malaria vaccine known as RTS,S reported that it could protect approximately 50% of inoculated infants and children. The RTS,S vaccine was engineered using genes from the outer protein of Plasmodium falciparum malaria parasite and a portion of a hepatitis B virus and a chemical adjuvant to boost the immune system response.^[7] It is being developed by PATH and GlaxoSmithKline (GSK), which has spent about $300 million on the project, plus about $200 million more from the Bill and Melinda Gates Foundation^[8]

History

Malaria is one of the oldest known pathogens, and began having a major impact on human survival about 10,000 years ago with the birth of agriculture. The development of virulence in the parasite has been demonstrated using genomic mapping of samples from this period, confirming the emergence of genes conferring a reduced risk of developing the malaria infection. References to the disease can be found in manuscripts from ancient Egypt, India and China, illustrating its wide geographical distribution. The first treatment identified is thought to be Quinine, one of four alkaloids from the bark of the Cinchona tree. Originally it was used by the tribes of Ecuador and Peru for treating fevers. Its role in treating malaria was recognised and recorded first by an Augustine monk from Lima, Peru in 1633. Seven years later the drug had reached Europe and was being used widely with the name ‘the Jesuit's bark’. From this point onwards the use of Quinine and the public interest in malaria increased, although the compound was not isolated and identified as the active ingredient until 1820. By the mid-1880’s the Dutch had grown vast plantations of cinchona trees and monopolised the world market.

Quinine remained the only available treatment for malaria until the early 1920’s. During the First World War German scientists developed the first synthetic antimalarial compound – Atabrin and this was followed by Resochin and Sontochin derived from 4-aminoquinoline compounds. American troops, on capturing Tunisia during the Second World War, acquired, then altered the drugs to produce Chloroquine.

The development of new antimalarial drugs spurred the World Health Organization in 1955 to attempt a global malaria eradication program. This was successful in much of Brazil, the US and Egypt but ultimately failed elsewhere. Efforts to control malaria are still continuing, with the development of drug-resistant parasites presenting increasingly difficult problems.

References

1. ^ ^{a b c} Jacquerioz FA, Croft AM (2009). "Drugs for preventing malaria in travellers". Cochrane Database Syst Rev (4): CD006491. doi:10.1002/14651858.CD006491.pub2. PMID 19821371. 
2. ^ Julia A. McMillan; Ralph D. Feigin; Catherine DeAngelis; M. Douglas Jones (1 April 2006). Oski's pediatrics: principles & practice. Lippincott Williams & Wilkins. pp. 1348. ISBN 9780781738941. http://books.google.com/books?id=VbjFQiz8aR0C&pg=RA1-PA1348. Retrieved 13 November 2010. 
3. ^ The World Health Organisation provides country-specific advice on malaria prevention.
4. ^ 2007 guidelines are available from the UK Health Protection Agency website as a PDF file and includes detailed country-specific information for UK travellers.
5. ^ the Centers for Disease Control and Prevention website hosts constantly updated country-specific information on malaria. The advice on this website is less detailed, is very cautious and may not be appropriate for all areas within a given country. This is the preferred site for travellers from the US.
6. ^ Schwartz E, Parise M, Kozarsky P, Cetron M (October 2003). "Delayed onset of malaria--implications for chemoprophylaxis in travelers". N. Engl. J. Med. 349 (16): 1510–6. doi:10.1056/NEJMoa021592. PMID 14561793. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=14561793&promo=ONFLNS19. 
7. ^ "First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children". New England Journal of Medicine. 2011. doi:10.1056/NEJMoa1102287. PMID 22007715.  edit
8. ^ Stein, R. Experimental malaria vaccine protects many children, study shows. Washington Post 18 October 2011.