In recent years, increasing drug resistance has caused many countries to change their policies for treatment of uncomplicated Plasmodium falciparum malaria from traditional mono-therapies to artemisinin-based combination therapy, as recommended by the World Health Organization.1 In November 2001, Peru changed the first-line treatment for uncomplicated P. falciparum malaria in the Departments of Tumbes and Piura on its northern Pacific coast from sulfadoxine-pyrimethamine (SP) alone to a combination of oral SP (25 mg/kg based on the sulfadoxine component) as a single dose plus oral artesunate (AS), 4 mg/kg/day for three days. SP-AS therapy was implemented after an initial safety and efficacy study of 94 patients showed no severe adverse events (SAEs), but mild adverse reactions were more common in the SP-AS group than in SP alone group.2 Although tolerability of this drug combination was supported by studies from Africa and Asia where no SAEs had been documented,3–5 there was concern regarding the applicability of those findings to malaria in the Americas where Peru was the first country in the region to adopt SP-AS. Therefore, we designed a study to investigate the incidence of serious, unknown, or infrequent adverse reactions to SP-AS therapy in the northern coast region of Peru.
Surveillance for adverse reactions was conducted in the Departments of Piura and Tumbes on the northern Pacific Coast of Peru where the patient population is of mestizo background (Figure 1). We selected 27 of the 386 health centers in the region that had reported the highest number of P. falciparum malaria cases during the preceding two years. The study protocol was reviewed and approved by Naval Medical Research Center Institutional Review Board (Protocol no. 31564) and the Instituto Nacional de Salud Ethics Committee (INS-CE-No. 026-2001).
A total of 1,658 patients with a microscopically confirmed, uncomplicated P. falciparum malaria infection sought treatment at one of the 27 health facilities from June 2002 through June 2004. Of these patients, 1,552 with P. falciparum malaria who had received SP-AS were enrolled. These patients represent 65.5% (1,552 of 2,369) of all SP-AS treatments dispensed in the Departments of Piura and Tumbes during that two-year period. The remaining 106 P. falciparum patients received some other antimalarial therapy, usually quinine plus clindamycin. We excluded 25 women from the study who were pregnant. Pregnancy tests are not routine in the health clinics prior to administration of antimalarial therapy but according to the Peruvian national treatment policy for malaria, pregnant women who have been diagnosed with P. falciparum malaria are mandated to receive quinine and clindamycin. Table 1 provides detailed information on 1,265 of the 1,552 patients enrolled in the study population with regards to age, sex, and nature of malaria episode.
Patients were treated with SP-AS under direct observation on days 0, 1, and 2, and were asked to return for follow up on days 7 and 14. During each visit, trained health care workers asked the patients about new or worsening symptoms after initiation of SP-AS therapy. Patients who reported that they had experienced complications provided a written informed consent and answered questions about additional symptoms. Known or potentially serious illnesses or conditions and/or any hospitalization occurring after initiation of SP-AS therapy were classified as a possible SAE. All unusual health related complaints or symptoms signifying possible SAEs were investigated intensively by a study physician, including detailed histories, physical examinations, and laboratory and pertinent imaging studies, with appropriate specialty referrals. We did not determine drug efficacy of this combination therapy during this study because it had been determined.2
One hundred thirty-seven patients (8.8%) complained of new or worsening symptoms, most of which were mild, did not require discontinuation of SP-AS therapy, and resolved without additional treatment. Fifty-five (3.5%) reported vomiting, 47 (3.0%) nausea, 39 (2.5%) headache, 27 (1.7%) abdominal pain, 27 (1.7%) dizziness or ataxia, 16 (1.0%) fever, 14 (0.9%) malaise, and 10 (0.6%) other signs or symptoms. There were no deaths during follow up. Three patients were admitted to a hospital after beginning treatment with SP-AS and were classified as having possible SAEs. One patient had a syncopal episode with and a chest radiograph indicated signs of congestive heart failure. Further discussion with the patient found that she had dyspnea on exertion for and peripheral edema for 2–4 months before contracting malaria. The second patient was diagnosed with acute pyelonephritis as determined by a positive urine culture. The third patient had a severe case of acute otitis media as indicated by high fever, nausea and vomiting, and bloody right ear discharge. All three patients had symptoms and evidence of other conditions before or at the time diagnosis of malaria was made and each recovered after appropriate treatment. None of their illnesses were considered to be related to SP-AS therapy.
The percentage of adverse reactions seen in this study (8.8%) is less than that reported during drug efficacy trials among children in Gambia where Doherty and others3 and von Seidlein and others6 reported a prevalence of AEs of 30% and 55.2%, respectively. In Uganda, Dorsey and others reported malaise in 38% of children receiving SP alone or SP-AS,4 and Obonyo and others reported significantly more AEs among children in Kenya receiving SP-AS (76%) than those receiving SP alone (61%).7 Our results are similar to previous reports from Indonesia (8.6%),5 several places in Sudan (10–14.9%),8–10 and our earlier therapeutic efficacy trial of SP-AS (8.9%) in Peru.2 Many of the most commonly reported symptoms in this study (nausea, vomiting, headache, dizziness, and fever) could have been caused by the patients’ underlying malaria infection. Although cutaneous reactions to SP are well known,11 only 10 patients had such reactions in this study. We did not observe any severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, which are more frequent when SP is used as prophylaxis.12
No neurologic symptoms other than dizziness or ataxia in 27 patients (1.7%) were reported. Animal studies have demonstrated limited symptomatic and pathologic evidence of neurotoxicity after parenteral administration of high doses of the oil-based artemisinin derivatives artemether and ar-teether.11 In contrast, postmortem studies of patients who died of severe malaria while receiving treatment with artemether failed to show neuropathologic changes.13 There are several case reports of tremors and ataxia in patients receiving oral artemisinins,14,15 but these symptoms could be related to malaria16 or its sequelae. In addition, 1,100 patients in Thailand have had full neurologic examinations after treatment with an artemisinin drug and no specific pattern of neurologic abnormalities was seen.17 We did not complete neurologic tests in our patients.
Although the total number of patients followed up in this study was relatively small, it does represent two-thirds of all uncomplicated cases of P. falciparum malaria treated with SP-AS on the northern coast of Peru over a two-year period. Treatmewnt with SP-AS was associated with a low frequency of mild, self-limited adverse reactions in Peru, but we did not find any SAE directly associated with treatment. Consequently, we believe that SP-AS is suitable alternative for treatment of uncomplicated malaria in areas of the Americas where the efficacy of SP is still high.
Demographics of the study population from which surveillance for severe adverse effects was conducted
| Adverse reactions, no. (%) | |||
|---|---|---|---|
| Characteristic | No. (%) | Yes | No |
| * Only 1,265 patients records of 1,552 patients enrolled were available for analysis. | |||
| † < = 40 parasites in 100 high-power fields (HPFs); +/2 = 40–60 parasites in 100 HPFs; | |||
| 1+ = 1 parasite per field in 100 HPFs; 2+ = 2–20 parasites per field in 100 HPFs: 3+ = | |||
| 21–200 parasites per field in 100 HPFs; 4+ = > 200 parasites per field in 100 HPFs. | |||
| Total | 1,265* (100) | 137 (29) | 1,128 (71) |
| Female | 520 (41) | 72 (14 | 448 (86) |
| Male | 745 (59) | 65 (9) | 680 (91) |
| Age, years | |||
| ≤ 5 | 33 (3) | 3 (9) | 30 (91) |
| ≥ 6 | 1,230 (97) | 134 (11) | 1,096 (89) |
| Unknown | 2 (0) | 0 | 2 (100) |
| Parasite count† | |||
| < 40 | 247 (20) | 26 (11) | 221 (89) |
| +/2 | 225 (18) | 23 (10) | 202 (90) |
| 1+ | 343 (27) | 21 (6) | 322 (94) |
| 2+ | 396 (31) | 58 (14) | 338 (86) |
| 3+ | 47 (4) | 9 (19) | 38 (81) |
| 4+ | 1 (0) | 0 | 1 (100) |
| Missing data | 6 (0) | 0 | 6 (100) |
Map of the northern coastal region of Peru showing the departments where the 27 health facilities are located.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 1; 10.4269/ajtmh.2008.79.42
Map of the northern coastal region of Peru showing the departments where the 27 health facilities are located.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 1; 10.4269/ajtmh.2008.79.42
Map of the northern coastal region of Peru showing the departments where the 27 health facilities are located.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 1; 10.4269/ajtmh.2008.79.42
Address correspondence to David J. Bacon, Navy Environmental and Preventative Medicine Unit-2, 1887 Powhatan St., Norfolk, VA 23511-3394. E-mail: david.bacon@med.navy.mil
Authors’ addresses: Javier Cairo and Salomón Durand, Naval Medical Research Center Detachment, Unit 3800, APO AA 34031, Tel: 203-751-1615, E-mails: javier.cairolavado@yale.edu and salomondurand@gmail.com. Wilmer Marquiño, National Institute of Health Lima, Peru. César Cabezas, National Institute of Health Lima, Peru, E-mail: ccabezas@ins.gob.pe. Arnaldo Lachira, Fernando Quintana, and Walter Vegas, Dirección Regional de Salud Piura, Ministerio de Salud Piura, Peru, E-mail: alachira@yahoo.com. Trenton K. Ruebush II, U.S. Agency for International Development Bureau for Global Health, 1300 Pennsylvania Avenue, NW, Washington, D.C. 20523-4600, E-mail: truebush@usaid.gov. Gregory Utz, Infectious Diseases and Internal Medicine, 34800 Bob Wilson Drive, Suite 110 San Diego, CA 92134, E-mail: greg.utz@med.navy.mil. David J. Bacon, Navy Environmental and Preventative Medicine Unit-2, 1887 Powhatan St., Norvolk, VA 23511-3394, Tel: 757-953-6571, Fax: 757-953-7212, E-mail: david.bacon@med.navy.mil.
Financial support: This study was supported by the Department of Defense–Global Emerging Infectious System under the unit number 847705.82000.256B,B0016, and by the U.S. Agency for International Development–Government of Peru VIGIA Project addressing Threats of Emerging and Re-Emerging Infectious Diseases (Activity 527-0391).
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of the Navy, Department of Defense, nor the U.S. government. Some of the authors are military service members. This work was prepared as part of our official duties. Title 17 U.S.C. §105 provide that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
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