Malaria Update from the Annual Meeting of the American Society of Tropical Medicine and Hygiene

Special Report by Lin H. Chen, MD

Synopsis: At the 52nd Annual Meeting of the American Society of Tropical Medicine and Hygiene, Dr. Monica Parise from the Centers for Disease Control and Prevention presented her annual update on prevention and treatment of malaria. The CDC Malaria Branch held an expert meeting on malaria chemoprophylaxis in January 2003 with input from the Division of Global Migration and Quarantine, during which the experts reviewed more than 1700 references.

Six drugs were examined in detail: chloroquine, hydroxychloroquine, mefloquine, doxycycline, atovaquone/proguanil, and primaquine. Experts discussed several questions about each drug, including the indications, dosing (how much before trip, loading dose, split dose), efficacy, adverse drug reactions, contraindications, precautions regarding cardiovascular disease, fine motor skills, drivers, drug interactions, and safety in pregnancy, breast-feeding, and children.

Overall recommendations are in agreement with existing policy. For areas with chloroquine-resistant Plasmodium falciparum (CRPF), options for chemoprophylaxis will be simply alphabetized. Primaquine is added as a second-line chemoprophylaxis agent. Chloroquine-proguanil is eliminated as an option in areas of CRPF prevalence. For chloroquine-sensitive P falciparum (CSPF) areas, recommendations will explicitly state that mefloquine, doxycycline, and atovaquone/proguanil might be used. In order to assess tolerance, the medication could be started as early as 3-4 weeks before exposure. A statement will be made about avoiding the purchasing of medications overseas due to potentially suboptimal drug quality. In addition, information on adverse drug reactions will be disseminated and the importance of antimalarials communicated. Rates of mild/moderate and severe adverse drug reactions are needed.

Regarding chloroquine (CQ) and hydroxychloroquine (HCQ), CQ remains the first choice for CSPF because there are more data. No eye exam is required due to very low risk of retinitis, even with long-term use. Twice-weekly dosing remains an option. No glucose-6-phosphatase deficiency (G6PD) screening is necessary prior to using either CQ or HCQ. Further discussion should explore tolerance of CQ vs HCQ and long-term use of HCQ in children.

The literature reviews reveal that doxycycline does not interfere with oral contraceptive efficacy. Doxycycline is preferred over minocycline for malaria prophylaxis on the basis of efficacy, experience, and potential side effects. However, long-term use of doxycycline needs to be further discussed. The dose of primaquine for terminal prophylaxis should increase to 30 mg base/d × 14 days for all areas. Primaquine should be avoided for primary or terminal prophylaxis in G6PD deficiency. No new insights emerged regarding candidates for terminal prophylaxis. Concerns regarding myelosuppression and the use in young children need to be addressed.

Atovaquone/proguanil efficacy is adequate as first-line malaria chemoprophylaxis. Efficacy is adequate against P vivax to recommend it in areas with P vivax predominance, but terminal prophylaxis is still recommended. Safety in children weighing 5-11 kg remains to be assessed.

Members of the expert panel recognize that mefloquine has become difficult to prescribe because of its potential side effects. There is no good explanation for long-term neuropsychiatric adverse drug reactions. However, gender differences exist, since women are more likely to experience adverse events than males. Adverse drug reactions may last weeks because of mefloquine’s long half-life. The panel concluded that it is acceptable to use mefloquine for persons with a prior history of febrile seizures. No statement was felt necessary regarding the concurrent use of alcohol and mefloquine. It is also acceptable in persons needing fine motor skills, but the course may start 3-4 weeks early. Permissive language regarding loading doses will be added. Questions remain regarding split-dose prophylaxis, monitoring of liver function tests, and the use during pregnancy.

Primaquine is approved as a second-line drug for primary prophylaxis. Efficacy in recent trials was 88-94% against P falciparum and 85-92% against P vivax. The drug is well tolerated. Gastrointestinal upset is the most common adverse drug reaction. The most serious side effect is hemolysis in patients with G6PD deficiency; therefore, G6PD needs to be tested before this medication is used. Methemoglobinemia is also fairly common. Primaquine is well tolerated up to 1 year.

Finally, sulfadoxine-pyrimethamine is no longer recommended for self-treatment. Atovaquone/proguanil is now the drug of choice. Statements will specifically recommend avoidance of halofantrine. A summary report will be provided in the near future.

Abstract Summaries

Additional interesting reports on malaria from the Supplement to the American Journal of Tropical Medicine and Hygiene (2003;69[3]) are as follows:

Many of the studies presented had examined malaria epidemiology. MacLean et al reported an analysis of malaria surveillance data obtained at the McGill University Centre for Tropical Diseases. Data showed an increase in malaria cases from 1981 to 2002, with a dramatic increase in incidence between 1996 and 1998 attributed to P vivax acquired in India, where a malaria epidemic was identified concurrently. The study is an illustration of the potential of travelers to act as sentinels for infectious disease outbreaks and changing epidemiology (Abstract #58). Alger et al studied the prevalence, incidence, and recurrence of malaria in northern Honduras. Study subjects were examined with malaria smears in December 1998, August 1999, December 1999, and September 2000. The baseline prevalence of malaria was 7.1% (range, 9.8-21.5%), with a 4.3% prevalence of P falciparum (range, 3.4-10.0%). The incidence of P vivax infection was higher in children up to 14 years old, whereas the incidence of P falciparum was greater in older persons (Abstract #256). Maguire et al evaluated residents for malaria at select locations of the Sanma and Shefa provinces of the Republic of Vanuatu. Malaria smears indicated a mean malaria prevalence of 22% (range, 4-33%), predominantly P falciparum (73%), followed by P vivax (25%). The gametocyte rate among persons with P falciparum was 54%. Primaquine was apparently removed from the national malaria treatment guidelines in 1991, which may explain the finding of a high gametocyte rate (Abstract #277). MacArthur et al investigated 3 autochthonous cases of P vivax malaria in Loudoun Country, Va; 2 presented in August 2002 and 1 in March 2003. Entomologic vector investigation showed Anopheles quadrimaculatus and A punctipennis. Parasite DNA analysis suggested a single source in spite of the long lag time for the third case. Although uncommon, autochthonous cases of malaria continue to occur within the continental United States (Abstract #279).

Several aspects of malaria immune response were reported. Njama et al assessed the prevalence of asymptomatic parasitemia and its association with symptomatic malaria in Ugandan children between the ages of 6 months and 5 years living in Kampala. A total of 283 subjects had routine blood smears done at enrollment and approximately every 30 days. The risk of developing symptomatic malaria within 30 days was 50% in the subjects with a positive routine smear compared to 9% in those with a negative smear. Six percent of the subjects had asymptomatic parasitemia that was preceded and followed by a negative routine smear. Njama et al conclude that asymptomatic parasitemia should be treated and that a reduction of transmission intensity may reduce symptomatic malaria (Abstract #6). Similarly, Diemert et al used monthly malaria smears to evaluate the association of symptomatic malaria episodes following asymptomatic parasitemia in 2 Malian villages. Diemert et al also found that routine monthly assessment of parasitemia correlated with subsequent clinical malaria (Abstract #15). Legorreta-Herrera et al used a mouse model to study the effect of early treatment of malaria in modification of cross protection for further infections. They evaluated 5 groups of mice infected with P chabaudi, in which each group was treated once with pyrimethamine on day 0, 5, 7, or 9, or no treatment (control group). Each group was divided further 8 weeks later and infected with P chabaudi, P yoelii 17XL (lethal), or a mixture of the 2 parasites. Mice with early treatment (day 0 or 5) died, whereas mice with later treatment (day 7 or 9) or no treatment survived. This study in mice showed that infection with P chabaudi induces immunity against the same parasite. The study also showed that infection with P chabaudi produces cross protection against P yoelii 17XL and that early treatment of the first infection reduced the cross protection effect (Abstract #665).

Data on malaria medication efficacy included a report by De Boever et al on the efficacy of Malaroneä (atovaquone and proguanil hydrochloride) in a post-marketing surveillance. An estimated 1.28 million people had been prescribed atovaquone/proguanil as of April 2003, with most prescriptions written for malaria prophylaxis. Up to that point, 48 post-marketing prophylaxis failures and 15 falciparum malaria treatment failures were reported. Five cases of clinical failure have been documented to have a genetic mutation in codon 268 of cytochrome-b gene, which results in a reduced parasite binding affinity of atovaquone. The countries from which failure has been confirmed include Nigeria, Mali, Cameroon, Ivory Coast, Kenya, and Gabon (Abstract #245). Filler et al investigated reported malaria chemoprophylactic failure among travelers in a US university exchange program. A post-travel questionnaire was used to evaluate cases of malaria reported among a group of American University staff and students who traveled to Ghana. Twenty-five of the 33 travelers completed the questionnaire. Twenty-four of the 25 took a chemoprophylactic drug recommended by the CDC (atovaquone/proguanil 15, mefloquine 6, doxycycline 3), but only 14 (56%) reported complete compliance. Twenty reported symptoms consistent with possible malaria during the trip, and 13 were evaluated medically. Six were diagnosed with malaria and were treated with antimalarial drugs, in spite of appropriate chemoprophylaxis in 3 of these travelers. Some of the travelers in the group decided to discontinue chemoprophylaxis because of the impression that the drugs were ineffective. Upon return, 5 travelers with a reported microscopic diagnosis of malaria were tested for anti-Plasmodium antibodies and all were negative. Filler et al documented the frequency of misdiagnosis occurring in malaria-endemic countries, misconceptions regarding efficacy, and poor compliance with chemoprophylaxis, drug resistance, safety issues resulting from misdiagnosis, and unnecessary treatment for malaria (Abstract #57).

Smith et al examined responses to treatment of P falciparum in HIV-infected and HIV-uninfected individuals in Siaya, Kenya. Febrile adults found to be parasitemic with P falciparum were recruited and were tested for HIV, molecular analysis of P falciparum resistance, and sulfa drug levels. Subjects represented 3 groups: HIV-positive CD4 < 200 (n = 43), HIV-positive CD4 > 200 (n = 79), and HIV-negative (51). All subjects were treated with SP (national guidelines) and followed for 28 days. Parasite density on day 0 was 4 times higher in HIV-positive CD4 < 200 subjects than the other 2 groups, and there were significant differences between the baseline parasitemias of the 3 groups. Twenty-one of the 28 failures (6 early treatment failures and 22 late parasitologic failures) were among the HIV positives, which suggested a negative effect of HIV on treatment of P falciparum malaria (Abstract #273).

A number of combination therapies for malaria treatment were presented. Sihuincha et al studied the efficacy of artesunate-mefloquine in treating uncomplicated P falciparum malaria in patients detected by the national malaria program in Loreto, Peru. P falciparum parasites have been increasingly resistant to CQ and sulfadoxine-pyrimethamine (SP) in Amazonian Peru. Peru included mefloquine plus artesunate as standard treatment in the National Malaria Control Program beginning in November 2001. Efficacy of the regimen using artesunate (4 mg/kg/d for 3 days) and mefloquine (12.5 mg/kg/d for 2 days starting on day 2 of treatment) was studied among 143 patients. Ninety-two percent of patients cleared parasitemia within 24 hours; another 8% cleared parasitemia by 48 hours. A total of 89% of patients defervesced within 24 hours and another 11% within 48 hours (Abstract #262). Pitmang et al compared the efficacy of combination SP + CQ to that of SP alone in treating uncomplicated P falciparum malaria in Nigerian patients. A total of 120 patients were treated with the combination, while 116 were treated with SP alone. The combination group cleared their parasitemia more quickly (75% vs 42% by day 3) and had greater clinical improvement by day 14 (95% vs 72%). RI, RII, and RIII resistance was lower in the combination group compared to the SP group (7.9%, 3.5%, 1.8% vs 23%, 17%, 5%, respectively). Although parasite resistance to SP and CQ is well established, the combination of SP + CQ for malaria appears to be more effective than monotherapy and may lead to a longer use of these drugs (Abstract #442). In contrast, a randomized trial by Obonyo et al compared treatment of P falciparum with either SP alone or in combination with artesunate for 1 (As1) or 3 days (As3) in Kenya. Treatment failure by day 14 was highest in the SP group (26%), compared to 16% in SP + As1, and 9.4% in SP + As3. Failure rates by day 28 were 46%, 38%, and 26%, respectively. The study demonstrated high resistance to SP and inadequate efficacy of the combination of SP + As in Kenya (Abstract #791).

Interest in herbal therapies was also evident at the meetings. Aderounmu et al reported on the antimalarial activity of 4 commonly used medicinal plants in Nigeria. Four plants, Enantia chlorantha, Azadirachta indica, Morinda lucida, and Cymbopogon giganteus, were evaluated for their activity against P falciparum in vitro. The crude extracts of these plants inhibited parasite growth. E chlorantha inhibited parasite growth by 68.9% and appears to be a promising anti-malarial (Abstract #639). Waters et al evaluated in vitro anti-malarial activity of traditional herbal remedies from Kenyan plants. The genera Erythrina and Millettia contained anti-malarial compounds that appeared to kill both drug-sensitive and drug-resistant parasites (Abstract #643). Given the development of Plasmodium parasite resistance, potentially useful plants or compounds should continue to be identified and further explored.

Lin H. Chen, MD, Clinical Instructor, Harvard Medical School Director, Travel Resource Center, Mt. Auburn Hospital, Cambridge, Mass