Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria in Papua New Guinea.

BACKGROUND: In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy. METHODS: Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined. RESULTS: A total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54). CONCLUSIONS: AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.

Iron deficiency during pregnancy is associated with a reduced risk of adverse birth outcomes in a malaria-endemic area in a longitudinal cohort study.

BACKGROUND: Low birth weight (LBW) and preterm birth (PTB) are major contributors to infant mortality and chronic childhood morbidity. Understanding factors that contribute to or protect against these adverse birth outcomes is an important global health priority. Anaemia and iron deficiency are common in malaria-endemic regions, but there are concerns regarding the value of iron supplementation among pregnant women in malaria-endemic areas due to reports that iron supplementation may increase the risk of malaria. There is a lack of evidence on the impact of iron deficiency on pregnancy outcomes in malaria-endemic regions. METHODS: We determined iron deficiency in a cohort of 279 pregnant women in a malaria-endemic area of Papua New Guinea. Associations with birth weight, LBW and PTB were estimated using linear and logistic regression. A causal model using sequential mediation analyses was constructed to assess the association between iron deficiency and LBW, either independently or mediated through malaria and/or anaemia. RESULTS: Iron deficiency in pregnant women was common (71% at enrolment) and associated with higher mean birth weights (230 g; 95% confidence interval, CI 118, 514; p < 0.001), and reduced odds of LBW (adjusted odds ratio, aOR = 0.32; 95% CI 0.16, 0.64; p = 0.001) and PTB (aOR = 0.57; 95% CI 0.30, 1.09; p = 0.089). Magnitudes of effect were greatest in primigravidae (birth weight 351 g; 95% CI 188, 514; p < 0.001; LBW aOR 0.26; 95% CI 0.10, 0.66; p = 0.005; PTB aOR = 0.39, 95% CI 0.16, 0.97; p = 0.042). Sequential mediation analyses indicated that the protective association of iron deficiency on LBW was mainly mediated through mechanisms independent of malaria or anaemia. CONCLUSIONS: Iron deficiency was associated with substantially reduced odds of LBW predominantly through malaria-independent protective mechanisms, which has substantial implications for understanding risks for poor pregnancy outcomes and evaluating the benefit of iron supplementation in pregnancy. This study is the first longitudinal study to demonstrate a temporal relationship between antenatal iron deficiency and improved birth outcomes. These findings suggest that iron supplementation needs to be integrated with other strategies to prevent or treat infections and undernutrition in pregnancy to achieve substantial improvements in birth outcomes.

Hemoglobin Levels and the Risk of Malaria in Papua New Guinean Infants: A Nested Cohort Study.

Studies are available that assess the risk of malaria in accordance to the body's iron store and the systematic iron supplementation of preschool children. However, only a few studies evaluated the temporal association between hemoglobin and malaria and their results are opposing. A total of 1,650 3-month-old Papua New Guinean infants were enrolled in this study and followed-up for 12 months. The risk of malaria was assessed in all children every 3 months and with each episode of fever. The incidence of clinical malaria between 3 and 15 months of age was 249 cases per 1,000 infants per year. After adjustment for potential confounding factors, a decrease of 1 g/dL of hemoglobin was associated with a nonsignificant increase of 11% for risk of malaria infection (hazard ratio, 1.11, 95% confidence interval; CI, 0.99-1.25, P = 0.076). Only children with severe anemia (hemoglobin < 8.0 g/dL) at baseline were at higher risk of malaria infection (hazard ratio, 1.72, 95% CI, 1.08-2.76, P = 0.023) during the follow-up year compared with the control group (Hemoglobin > 10.0 g/dL). This association was not statistically significant if only clinical malaria episodes were taken into account (hazard ratio, 1.42, 95% CI, 0.77-2.61, P = 0.26). Our study suggests that infants with lower hemoglobin levels are not protected against malaria infection. Further research that examines the risk of malaria in relation to both hemoglobin and iron store levels would be important to better understand this complex interaction.

Impact of intermittent preventive treatment in pregnancy with azithromycin-containing regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.

Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P<0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P=0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P=0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P=0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation.

Severe anemia in Papua New Guinean children from a malaria-endemic area: a case-control etiologic study.

BACKGROUND: There are few detailed etiologic studies of severe anemia in children from malaria-endemic areas and none in those countries with holoendemic transmission of multiple Plasmodium species. METHODOLOGY/PRINCIPAL FINDINGS: We examined associates of severe anemia in 143 well-characterized Papua New Guinean (PNG) children aged 0.5-10 years with hemoglobin concentration <50 g/L (median [inter-quartile range] 39 [33]-[44] g/L) and 120 matched healthy children (113 [107-119] g/L) in a case-control cross-sectional study. A range of socio-demographic, behavioural, anthropometric, clinical and laboratory (including genetic) variables were incorporated in multivariate models with severe anemia as dependent variable. Consistent with a likely trophic effect of chloroquine or amodiaquine on parvovirus B19 (B19V) replication, B19V PCR/IgM positivity had the highest odds ratio (95% confidence interval) of 75.8 (15.4-526), followed by P. falciparum infection (19.4 (6.7-62.6)), vitamin A deficiency (13.5 (5.4-37.7)), body mass index-for-age z-score <2.0 (8.4 (2.7-27.0)) and incomplete vaccination (2.94 (1.3-7.2)). P. vivax infection was inversely associated (0.12 (0.02-0.47), reflecting early acquisition of immunity and/or a lack of reticulocytes for parasite invasion. After imputation of missing data, iron deficiency was a weak positive predictor (6.4% of population attributable risk). CONCLUSIONS/SIGNIFICANCE: These data show that severe anemia is multifactorial in PNG children, strongly associated with under-nutrition and certain common infections, and potentially preventable through vitamin A supplementation and improved nutrition, completion of vaccination schedules, and intermittent preventive antimalarial treatment using non-chloroquine/amodiaquine-based regimens.

Increasing chloramphenicol resistance in Streptococcus pneumoniae isolates from Papua New Guinean children with acute bacterial meningitis.

In Papua New Guinean (PNG) children with acute bacterial meningitis (ABM), all Haemophilus influenzae isolates were resistant to chloramphenicol. Although Streptococcus pneumoniae isolates had a median chloramphenicol MIC of 3 µg/ml, it was ≥4 µg/ml in 42.8%, and the likelihood of an area under the 24-hour concentration-time curve/MIC ratio of >100 h at a MIC of ≥4 µg/ml was approximately 50%. All isolates were ceftriaxone sensitive. These data support ceftriaxone rather than conventional chloramphenicol for all PNG children with suspected ABM.

Treatment with coartem (artemether-lumefantrine) in Papua New Guinea.

A recent drug efficacy trial reported Coartem (artemether-lumefantrine) to be highly effective against Plasmodium falciparum in children less than 5 years of age in Papua New Guinea (PNG). In contrast, we have observed high levels of treatment failures in non-trial conditions in a longitudinal cohort study in the same age group in PNG. Recrudescences were confirmed by genotyping of three different marker genes to provide optimal discrimination power between parasite clones. After excluding genetic host factors by genotyping potentially relevant cytochrome P450 loci, the high number of treatment failures in our study is best explained by poor adherence to complex dosing regimens in combination with insufficient fat supplementation, which are both crucial parameters for the outcome of Coartem treatment. In contrast to the situation in classic drug trials with ideal treatment conditions, our field survey highlights potential problems with unsupervised usage of Coartem in routine clinical practice and under program conditions.

A review of the current state of malaria among pregnant women in Papua New Guinea.

Besides young children, pregnant women are at high risk of malaria in highly endemic countries. This paper reviews evidence from studies conducted in Papua New Guinea (PNG) in the last 20 years on the burden and prevention of malaria in pregnancy and highlights gaps in our knowledge of malaria in pregnancy in PNG. Overall, primigravidae were found to be at higher risk than multigravidae, with up to 40% of primigravidae but only 10-25% of multigravidae infected with Plasmodium falciparum at delivery. Such infections were found to be associated with a 128-145 g decrease in birthweight. Mean birthweights reported between 1980 and 2003 range from 2.58 to 2.72 kg in primigravidae and 2.84 to 3.09 kg in multigravidae, with 21% to 48% and 9% to 19% of babies born to primigravidae and multigravidae, respectively, of low birthweight (<2500 g). The negative impact of malaria in pregnancy is compounded by relatively low rates of antenatal coverage. The current PNG national treatment policy which prescribes a treatment course of first-line antimalarial treatment (currently chloroquine and sulphadoxine-pyrimethamine) at first antenatal clinic contact, followed by weekly chloroquine prophylaxis and iron and folate supplementation, may no longer be effective given the high levels of resistance to chloroquine in PNG and poor compliance. In order to reduce the burden of malaria in pregnancy in PNG, alternative methods of control such as insecticide-treated nets and intermittent preventive treatment in pregnancy (IPTp), as well as improved modes of delivery of maternal health interventions, are urgently needed.

Rectal administration of artemisinin derivatives for the treatment of malaria.

CONTEXT: Rectal administration of artemisinin derivatives is a potentially lifesaving emergency treatment of severe malaria. Many different preparations are marketed in tropical countries, but their pharmacokinetic disposition and clinical efficacy may vary. OBJECTIVE: To review the pharmacokinetics, efficacy, and safety of rectally administered artesunate, artemisinin, dihydroartemisinin, and artemether. DATA SOURCES: We searched the MEDLINE, EMBASE, Cochrane Database of Clinical Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006, along with reviewing unpublished data from conference proceedings, pharmaceutical companies, and regulatory applications. Studies in languages other than English were translated. STUDY SELECTION: Studies were included involving rectal administration of an artemisinin derivative to healthy volunteers or patients with measurement of plasma drug concentrations or rates of initial parasite clearance. Both single-arm and comparative trials were included. DATA EXTRACTION: Forty-five studies were identified, of which 39 eligible studies were included in the review. Primary efficacy outcome measures included parasite density as a percentage of baseline at 12 and 24 hours following the first dose. Pharmacokinetic variables included maximum plasma concentration (C(max)), time to C(max) (T(max)), and area under the plasma concentration-time curve. Weighted means were calculated from available data. DATA SYNTHESIS: Thirty-two studies provided valid clinical efficacy data: 19 of artesunate, 10 of artemisinin, 2 of dihydroartemisinin, and 1 of artemether. All demonstrated prompt parasite clearance, with evidence of a dose-dependent effect for artesunate. Mortality rates in severe malaria (weighted means, 0%-13%) were consistent with those expected. Eight studies compared rectal artemisinin with conventional parenteral treatment (quinine, artemether, or artesunate) for severe malaria. Despite similar clinical outcomes, rectal artemisinin derivatives initiated parasite clearance more rapidly than parenteral treatment (percentage of baseline at 12 hours, < or =27% vs > or =56%, respectively). Eighteen pharmacokinetic studies were identified, including 13 of artesunate. There was marked interindividual variability in most pharmacokinetic variables, but artesunate achieved an earlier T(max) and higher C(max) and area under the plasma concentration-time curve than other artemisinin derivatives. CONCLUSIONS: Available rectal preparations of artemisinin derivatives differ in their pharmacokinetic disposition. Most available evidence pertains to artesunate and artemisinin. Despite marked interindividual variability in bioavailability, rectal preparations appear to have acceptable therapeutic efficacy, including in severe illness.