Effect of dihydroartemisinin/piperaquine for malaria intermittent preventive treatment on dolutegravir exposure in pregnant women living with HIV.

BACKGROUND: In sub-Saharan Africa, the burdens of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PLWH) require both ART and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin/piperaquine has been identified as a promising alternative to sulfadoxine/pyrimethamine for IPTp. However, another antimalarial drug, artesunate/amodiaquine, similar to dihydroartemisinin/piperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults. OBJECTIVES: To investigate the effect of dihydroartemisinin/piperaquine on dolutegravir plasma exposure in pregnant women on dolutegravir-based ART. METHODS: We conducted an open-label, non-randomized, fixed-sequence, pharmacokinetic study in PLWH in Malawi. Dolutegravir concentrations were measured over a 24 h period, before and after the recommended 3 day treatment dose of dihydroartemisinin/piperaquine in 12 pregnant women in their second or third trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% CIs were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods. RESULTS: Co-administration of dihydroartemisinin/piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24) and Cmax by 30% (GMR 1.30; 90% CI 1.11-1.52) and 31% (GMR 1.31; 90% CI 1.13-1.51), respectively. The dolutegravir trough (C24) concentration increased by 42% (GMR 1.42; 90% CI 1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed. CONCLUSIONS: Dihydroartemisinin/piperaquine may be administered with dolutegravir-based ART in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, ensures its efficacy without any clinically significant adverse events observed in this small study.

Malaria preventive therapy in pregnancy and its potential impact on immunity to malaria in an area of declining transmission.

BACKGROUND: Regular anti-malarial therapy in pregnancy, a pillar of malaria control, may affect malaria immunity, with therapeutic implications in regions of reducing transmission. METHODS: Plasma antibodies to leading vaccine candidate merozoite antigens and opsonizing antibodies to endothelial-binding and placental-binding infected erythrocytes were quantified in pregnant Melanesian women receiving sulfadoxine-pyrimethamine (SP) with chloroquine taken once, or three courses of SP with azithromycin. RESULTS: Malaria prevalence was low. Between enrolment and delivery, antibodies to recombinant antigens declined in both groups (p<0.0001). In contrast, median levels of opsonizing antibodies did not change, although levels for some individuals changed significantly. In multivariate analysis, the malaria prevention regimen did not influence antibody levels. CONCLUSION: Different preventive anti-malarial chemotherapy regimens used during pregnancy had limited impact on malarial-immunity in a low-transmission region of Papua New Guinea. TRIAL REGISTRATIONS: NCT01136850.

The association between malaria and iron status or supplementation in pregnancy: a systematic review and meta-analysis.

INTRODUCTION: Malaria prevention and iron supplementation are associated with improved maternal and infant outcomes. However, evidence from studies in children suggests iron may adversely modify the risk of malaria. We reviewed the evidence in pregnancy of the association between malaria and markers of iron status, iron supplementation or parenteral treatment. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, and the Malaria in Pregnancy library to identify studies that investigated the association between iron status, iron treatment or supplementation during pregnancy and malaria. Thirty one studies contributed to the analysis; 3 experimental and 28 observational studies. Iron supplementation was not associated with an increased risk of P. falciparum malaria during pregnancy or delivery in Africa (summary Relative Risk = 0.89, 95% Confidence Interval (CI) 0.66-1.20, I(2) = 78.8%, 5 studies). One study in Asia reported an increased risk of P. vivax within 30 days of iron supplementation (e.g. adjusted Hazard Ratio = 1.75, 95% CI 1.14-2.70 for 1-15 days), but not after 60 days. Iron deficiency (based on ferritin and C-reactive protein) was associated with lower odds for malaria infection (summary Odds Ratio = 0.35, 0.24-0.51, I(2) = 59.2%, 5 studies). With the exception of the acute phase protein ferritin, biomarkers of iron deficiency were generally not associated with malaria infection. CONCLUSIONS: Iron supplementation was associated with a temporal increase in P vivax, but not with an increased risk of P. falciparum; however, data are insufficient to rule out the potential for an increased risk of P. falciparum. Iron deficiency was associated with a decreased malaria risk in pregnancy only when measured with ferritin. Until there is more evidence, it is prudent to provide iron in combination with malaria prevention during pregnancy.

Sulfadoxine-pyrimethamine-based intermittent preventive treatment, bed net use, and antenatal care during pregnancy: demographic trends and impact on the health of newborns in the Kassena Nankana District, northeastern Ghana.

Demographics and health practices of 2,232 pregnant women in rural northeastern Ghana and characteristics of their 2,279 newborns were analyzed to determine benefits associated with intermittent preventive treatment (IPTp), antenatal care, and/or bed net use during pregnancy. More than half reported bed net use, 90% reported at least two antenatal care visits, and > 82% took at least one IPTp dose of sulfadoxine-pyrimethamine. Most used a bed net and IPTp (45%) or IPTp alone (38%). Low birth weight (< 2,500 grams) characterized 18.3% of the newborns and was significantly associated with female sex, Nankam ethnicity, first-born status, and multiple births. Among newborns of primigravidae, IPTp was associated with a significantly greater birth weight, significantly fewer low birth weight newborns, improved hemoglobin levels, and less anemia. Babies of multigravidae derived no benefit to birth weight or hemoglobin level from single or multiple doses of sulfadoxine-pyrimethamine during pregnancy. No differences or benefits were seen when a bed net was the only protective factor.

The safety of amodiaquine use in pregnant women.

Few antimalarial drugs have been evaluated extensively in pregnancy because of fears over toxicity. However, increasing Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine makes finding alternative antimalarials that are safe and effective in pregnancy a priority. There is a renewed interest in amodiaquine as a potential candidate, particularly as a partner drug in artemisinin-based combination therapy. The available data suggest that, at standard dosages, amodiaquine is not teratogenic and that the adverse events associated with taking amodiaquine in pregnancy are not greater than those associated with falciparum malaria in pregnancy. Thus, amodiaquine in combination with other antimalarial drugs may be useful for malaria treatment in pregnancy, but inadequate data on its safety and pharmacokinetics in pregnancy limits its deployment for intermittent preventive treatment in pregnancy.

Preliminary evaluation of maternotoxic effect of Ascaris extract in mice.

Administration intraperitoneally of the Ascaris suum extract--ASE-(0.6-1.4 g of Ascaris proteins/kg/day) at a late stage of organogenesis (8-12 days of gestation) disturbed course of mouse pregnancy. It has been found that injections of higher doses of ASE to pregnant mice caused the symptoms manifesting maternal toxicity (decreased body weight gain/p < 0.001/as compared to control, intrauterine resorption of litter, vaginal hemorrhages, female mortality and altered behaviour). There is a linear interrelationship between the logarithm of the dose of ASE and mortality of pregnant mice. The DL50 value of Ascaris proteins for pregnant mice was 1.02 g/kg/day (confidence interval 0.97-1.07 g/kg/day). ASE exerted embryotoxic effects: significantly decreased the number of surviving fetuses per litter and the mean body weight of fetuses, increased the number of fetal resorptions.

Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy.

Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit > 30% (hazard ratio = 1.5, 95% CI 1.2-2, P = 0.001) and recent (< or = 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P = 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy.

Comparison of the effect of Ascaris trypsin inhibitor in various periods of mouse pregnancy.

Trypsin inhibitor isolated from Ascaris suum and injected into pregnant BALB/c mice (five times, in doses: 300 or 400 mg/kg/day) in various periods of pregnancy (early and late organogenesis) disturbed the development of fetuses. The nature and intensity of prenatal disturbances are determined by the inhibitor dose and time of injection. It has been found that administration of the inhibitor from 5-th until 9-th day of gestation did not delay or prevent implantation, but caused a high rate of intrauterine deaths and also specific congenital malformations (exnencephaly and hydrocephalus). Additionally, other types of defects were noted in fetuses after injection of the inhibitor between 8-th and 12-th day of pregnancy (cleft palate, fusion of ribs). Independent of the time of injection during gestation the inhibitor exhibited embriotoxic effects (e.g. decreased the number of live fetuses per litter and mean fetal weight).

Preliminary evaluation of maternotoxic effect of Ascaris alpha-chymotrypsin inhibitor in mice.

Administration intraperitoneally of the Ascaris alpha-chymotrypsin inhibitor (40-300 mg/kg/day) at a late stage of organogenesis (8-12 days of gestation) disturbed course of mouse pregnancy. The low doses of alpha-chymotrypsin inhibitor (40-80 mg/kg/day) significantly decreased the number of live fetuses per litter, increased the number of fetal resorptions. The symptoms of maternal toxicity that occurred after administration of the highest doses of the inhibitor (80-300 mg/kg/day) to pregnant mice included: decreased body weight gain as compared to control, vaginal hemorrhage, intrauterine resorption of litters, abortions, altered behaviour of animals immediately after injection and death. There is a linear interrelationship between the logarithm of the doses of the inhibitor and mortality of pregnant mice. The DL50 value of the inhibitor for female was 116 mg/kg/day (confidence interval: 95.5-140.0 mg/kg/day).

Protozoal causes of reproductive failure in domestic ruminants.

Protozoan parasites are a significant cause of abortion and infertility in domestic ruminants. Toxoplasma gondii, a widespread cause of abortion in sheep and goats, and Sarcocystis spp., which cause a common, frequently asymptomatic infection of domestic ruminants, both have a two-host life cycle. Carnivorous definitive hosts spread the infection through their feces and domestic ruminants are intermediate hosts. A similar, recently recognized protozoa, Neospora sp., has emerged as an important cause of reproductive disease, especially as an abortifacient in dairy cattle. Neospora is presumed to also have a two-host life cycle, although the definitive host(s) has not been identified. The venereally transmitted Tritrichomonas foetus is an important cause of pregnancy loss in naturally bred cattle throughout the world. In the absence of effective methods for vaccination or treatment, control of these parasites is based on management procedures to reduce infection and transmission.