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Background: Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax., Methods: In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections., Results: The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample., Conclusion: Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study observation period. The only in vivo malaria drug efficacy trial thus far published from the Republic of Vanuatu showed chloroquine/sulphadoxine-pyrimethamine combination therapy for P. falciparum and chloroquine alone for P. vivax to be highly efficacious. Although the chloroquine-resistant pfcrt allele was present in all P. falciparum isolates, mutant alleles in the dhfr and dhps genes do not yet occur to the extent required to confer sulphadoxine-pyrimethamine resistance in this population.

Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua, Indonesia. Subjects were randomized to treatment with standard chloroquine therapy (25 mg/kg in 3 doses over the course of 48 hours) with 30 mg primaquine administered daily for 28 days (n = 25) or a placebo of primaquine (n = 28). The 14-day cumulative incidence of therapeutic failure was 56% with primaquine and 79% with placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1-1.3; P = 0.08). Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14, but not at day 7 (20% versus 36%; OR, 0.2; 95% CI, 0.1-1.8; P = 0.2) or day 28 (82% versus 93%; OR, 0.31; 95% Cl, 0.04-2.1; P = 0.23). This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum.

Combination therapy is one method of overcoming the global challenge of drug-resistant Plasmodium falciparum malaria. We conducted a hospital-based 28-day in vivo test comparing chloroquine/doxycycline to chloroquine or doxycycline alone for treating P. falciparum and Plasmodium vivax malaria in Irian Jaya, Indonesia. Eighty-nine patients with uncomplicated falciparum malaria were randomized to standard dose chloroquine (n = 30), doxycycline (100 mg every 12 hours [7 days], n = 20), or chloroquine with doxycycline (n = 39); corresponding numbers for vivax malaria (n = 63) were 23, 16, 24. Endpoints were parasite sensitivity (S) or resistance (RI/RII/RIII). Of the 105 evaluable patients, chloroquine/doxycycline cured (S) 20/22 (90.9% [95% CI 78.9-100%]) patients with P. falciparum malaria; 2/22 (9.1% [0-21%]) were RIII resistant. Doxycycline cured 11/17 (64.7% [42.0-87.4%]) patients, and chloroquine 4/20 (20% [2.5-37.5%]). Against P. vivax, chloroquine/doxycycline cured (S) 12/17 (70.6% [48.9-92.2%]) patients, doxycycline 4/12 (33.3% [6.6-59.9%]), and chloroquine 5/17 (29.4% [7.7-51.1%]). Chloroquine/doxycycline was effective against P. falciparum but only modestly effective against P. vivax. These findings support the use of chloroquine/doxycycline as an inexpensive alternative to mefloquine for treating chloroquine-resistant P. falciparum but not chloroquine-resistant P. vivax in this setting.

Comparative results of baseline and endpoint screening for intestinal parasites are reported from Javanese men enrolled in a year-long, placebo-controlled malaria prophylaxis trial in Irian Jaya. The objective was to detect nontarget qualitative changes that may have resulted from prolonged chloroquine (300 mg base weekly) or primaquine (0.5 mg base/kg daily) prophylaxis. Fresh fecal specimens were examined (blinded trial) for parasites and ova using a modified Kato-Katz thick smear method. More than 88% (94/106) of the baseline population was infected by 1 or more parasite species of which hookworm and Blastocystis hominis were dominant. Paired comparison between baseline and endpoint revealed no significant changes within the primaquine or chloroquine groups with regard to the variety of species found, the mean number of species or ova/subject, the relative proportion of infections caused by these species, or the occurrence of parasite-free, single, and multiple infections. Relative to placebo, there was a significantly greater proportion of infections by Entamoeba histolytica/dispar and a lower mean hookworm egg count in the chloroquine group. The endpoint proportion of new or increased infections in the primaquine group was significantly lower than that of the chloroquine group but comparable to that of the placebo. Despite the dosage employed, the frequency and duration of use, and excretion primarily through the bowels as the active parent compound, primaquine appeared to have little or no significant effect against a variety of common intestinal parasites. These largely negative results lend support for the safety and acceptability of primaquine as a daily malaria prophylactic in a population frequently at risk of intestinal helminth infections.

In February 1995 we surveyed to chloroquine among patients with Plasmodium vivax malaria at Nias Island, in the Indian Ocean near north-western Sumatra, Indonesa. The subjects, 21 indigenous males and females (6-50 years old) infected with > 40 asexual blood stage parasites of P. vivax per microliter of blood, had mild symptoms or none at all. Seven of these patients had > 100 ng/mL whole blood chloroquine levels before the first supervised dose of chloroquine (3 doses of 10 mg/kg, 10 mg/kg, 5 mg/kg of base given at 24 h intervals). Whole blood chloroquine levels on the last day of dosing confirmed normal absorption (range 413-3248, mean 1141, SD 616 ng/mL). Blood films were examined on days 0, 2, 4, 7, 11, 14, 18, 21 and 28 after initiating therapy. Three patients had recurrent asexual P. vivax parasitaemias between days 14 and 18, despite effective levels of chloroquine in whole blood (> or = 100 ng/mL) at the time of recurrence. Resistance to standard chloroquine therapy by P. vivax appeared in 14% of infections among residents of Nias.

Optimal therapy for infection by chloroquine-resistant Plasmodium vivax has not been established. From 1992 to 1994 during three separate studies, 147 Javanese residents of Irian Jaya infected by P. vivax were treated with either chloroquine (25 mg of base/kg during 3 days or 10 mg of base/kg in one dose) plus primaquine (10 mg/kg during 28 days or 2.5 mg/kg during 3 days) (n = 78), chloroquine plus placebo (n = 50), or halofantrine (24 mg base/kg in 12 h; n = 19). There was no difference in tolerance to or side effects of any of the regimens. Within 14 days of starting therapy, therapeutic failure among these patients was 44% for chloroquine, 5% for chloroquine plus primaquine (P < .001), and 0 for halofantrine (P < .001). After 28 days, therapeutic failure was 78%, 15%, and 6%, respectively. Thus, chloroquine plus primaquine in combination and halofantrine alone are effective therapies for chloroquine-resistant P. vivax.

A comparison of primaquine versus chloroquine for prophylaxis among nonimmune transmigrants from Java and Bali in the hyperendemic Arso region of Irian Jaya, Indonesia was conducted. Forty-five subjects received 0.5 mg of primaquine base/kg of body weight every other day, and 54 people in the same village received weekly 5 mg of chloroquine base/kg for 16-19 weeks beginning in December 1992. Plasmodium falciparum accounted for 18 of 30 infections with chloroquine, and four of five infections among subjects receiving primaquine. Plasmodium vivax was found in 12 people taking chloroquine but in just one person taking primaquine. The risk of malaria among people taking chloroquine relative to that among subjects taking primaquine was 3.96 (P = 0.014) for P. falciparum and 10.56 (P = 0.012) for P. vivax. Primaquine was better tolerated than chloroquine. The minimal protective efficacy for primaquine prophylaxis was 74% against P. falciparum and 90% against P. vivax among nonimmune children and adults living in Irian Jaya. These findings require confirmation with randomized, double-blinded, and placebo-controlled trials.

Chloroquine has been the treatment of choice for vivax malaria for more than 40 years. Lately, several case-reports have suggested the emergence of resistance to chloroquine in Plasmodium vivax in Papua New Guinea and Indonesia. We undertook prospective treatment and prophylaxis trials of chloroquine in children and adults with vivax malaria living in Irian Jaya (Indonesia New Guinea). 46 villagers with P vivax parasitaemia were treated with chloroquine by mouth (25 mg base/kg body weight divided over 3 days) and followed up for 14 days. Parasitaemia cleared initially but recurred within 14 days in 10 (22%) subjects. All recurrences were in children younger than 11 years, 7 of whom were younger than 4 years; the failure rate among children under 4 was 70%. 7 of the patients with recurrences were given a second course of chloroquine. In all, the infections initially cleared but recurrent parasitaemia developed in 5 (71%) within 14 days. Whole-blood chloroquine concentrations were consistently above those previously shown to cure P vivax blood infections (90 micrograms/L whole blood). Subjects whose initial infections cleared and who had no parasitaemia on day 14 received weekly prophylaxis with chloroquine. Despite the presence of expected blood chloroquine concentrations, P vivax parasitaemia developed in 9 of 17 subjects receiving prophylaxis during 8 weeks of follow-up (median time to parasitaemia 5.3 weeks). Chloroquine can no longer be relied upon for effective treatment or chemoprophylaxis of P vivax blood infections acquired in this part of New Guinea.

Between 1987 and 1990, susceptibility of Plasmodium falciparum to chloroquine and to Fansidar was measured in vivo in 151 volunteers using the standard 7-day test. All volunteers lived in Arso PIR, Irian Jaya. A 25 mg/kg dose of chloroquine base was administered over a three-day period to 92 volunteers positive for P. falciparum rings (greater than 10 rings/200 white blood cells). Fifty volunteers (54%) showed results consistent with resistance. Twenty-nine were classified RII, and 21 RIII. In November 1989, a single curative dose of Fansidar was administered to 59 volunteers divided among three groups with 18 months, four years, and life-long exposure to endemic malaria. The proportion of volunteers in each group still positive for P. falciparum on day 7 of followup was 54%, 0%, and 14%, respectively. Thus, immune status profoundly effected clinically response to Fansidar. Standard in vitro microtests were also performed on parasites from 11 volunteers against chloroquine, amodiaquine, quinine, pyrimethamine/sulfadoxine, and and mefloquine. Nine of ten isolates showed in vitro growth consistent with resistance to chloroquine. Tests with other drugs showed few isolates with results considered indicative of susceptibility. Arso PIR has a severe drug resistance problem.

Evidence of emerging resistance to chloroquine by Plasmodium vivax is described from Irian Jaya (Indonesian New Guinea). Sixteen of 24 residents in the village of Arso PIR II taking supervised weekly chloroquine prophylaxis (5 mg base/kg) had asexual parasitemia with P. vivax at least once during eight weeks of surveillance. An American working in the same village developed symptomatic P. vivax parasitemia despite chloroquine prophylaxis. Five days after therapy with 600 mg chloroquine base, the asexual parasitemia in the American increased 40-fold, but cleared after treatment with 1,500 mg chloroquine base. Serum samples were not available from many of the cases, but six local residents and the American had serum levels of chloroquine in excess of the ordinarily suppressive 15 ng/ml at the time of their asexual parasitemias (16-70 ng/ml). The weekly 300 mg base tablet of chloroquine, which has been the standard for prophylaxis against malaria for more than 40 years, was not effective against P. vivax in Arso PIR, Irian Jaya.