Pregnant women are a reservoir of malaria transmission in Blantyre, Malawi.

BACKGROUND: During pregnancy, women living in malaria-endemic regions are at increased risk of malaria infection and can harbour chronic placental infections. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPTp) is administered to reduce malaria morbidity. It was hypothesized that the presence of placental malaria infection and SP-IPTp use would increase the risk of peripheral blood gametocytes, the parasite stage that is transmissible to mosquitoes. This would suggest that pregnant women may be important reservoirs of malaria transmission. METHODS: Light microscopy was used to assess peripheral gametocytaemia in pregnant women enrolled in a longitudinal, observational study in Blantyre, Malawi to determine the association between placental malaria and maternal gametocytaemia. The relationship between SP-IPTp and gametocytaemia was also examined. RESULTS: 2,719 samples from 448 women were analysed and 32 episodes of microscopic gametocytaemia were detected in 27 women. At the time of enrolment 22 of 446 women (4.9%) had gametocytaemia and of the 341 women for whom there was sufficient sampling to analyse infection over the entire course of pregnancy, 27 (7.9%) were gametocytaemic at least once. Gametocytaemia at enrollment was associated with placental malaria, defined as malaria pigment or parasites detected by histology or qPCR, respectively (OR: 32.4, 95% CI: 4.2-250.2), but was not associated with adverse maternal or foetal outcomes. Administration of SP-IPTp did not affect gametocyte clearance or release into peripheral blood. CONCLUSIONS: Gametocytaemia is present in 5% of pregnant women at their first antenatal visit and associated with placental malaria. SP-IPTp does not alter the risk of gametocytaemia. These data suggest that pregnant women are a significant reservoir of gametocyte transmission and should not be overlooked in elimination efforts. Interventions targeting this population would benefit from reaching women prior to first antenatal visit.

Chloroquine-azithromycin combination antimalarial treatment decreases risk of respiratory- and gastrointestinal-tract infections in Malawian children.

BACKGROUND: Chloroquine-azithromycin is being evaluated as combination therapy for malaria. It may provide added benefit in treating or preventing bacterial infections that occur in children with malaria. OBJECTIVE: We aim to evaluate the effect of treating clinical malaria with chloroquine-azithromycin on the incidence of respiratory-tract and gastrointestinal-tract infections compared to treatment with chloroquine monotherapy. METHODS: We compared the incidence density and time to first events of respiratory-tract and gastrointestinal-tract infections among children assigned to receive chloroquine-azithromycin or chloroquine for all symptomatic malaria episodes over the course of 1 year in a randomized longitudinal trial in Blantyre, Malawi. RESULTS: The incidence density ratios of total respiratory-tract infections and gastrointestinal-tract infections comparing chloroquine-azithromycin to chloroquine monotherapy were 0.67 (95% confidence interval [CI], .48, .94) and 0.74 (95% CI, .55, .99), respectively. The time to first lower-respiratory-tract and gastrointestinal-tract infections were significantly longer in the chloroquine-azithromycin arm compared to the chloroquine arm (P = .04 and P = .02, respectively). CONCLUSIONS: Children treated routinely with chloroquine-azithromycin had fewer respiratory and gastrointestinal-tract infections than those treated with chloroquine alone. This antimalarial combination has the potential to reduce the burden of bacterial infections among children in malaria-endemic countries.

Timing of malaria infection during pregnancy has characteristic maternal, infant and placental outcomes.

We conducted a clinical study of pregnant women in Blantyre, Malawi to determine the effect of the timing of malaria infection during pregnancy on maternal, infant and placental outcomes. Women were enrolled in their first or second trimester of their first or second pregnancy and followed every four weeks until delivery. Three doses of sulfadoxine-pyrimethamine were given for intermittent preventive treatment for malaria, and all episodes of parasitemia were treated according to the national guidelines. Placentas were collected at delivery and examined for malaria parasites and pigment by histology. Pregnant women had 0.6 episodes of malaria per person year of follow up. Almost all episodes of malaria were detected at enrollment and malaria infection during the follow up period was rare. Malaria and anemia at the first antenatal visit were independently associated with an increased risk of placental malaria detected at delivery. When all episodes of malaria were treated with effective antimalarial medication, only peripheral malaria infection at the time of delivery was associated with adverse maternal and infant outcomes. One quarter of the analyzed placentas had evidence of malaria infection. Placental histology was 78% sensitive and 89% specific for peripheral malaria infection during pregnancy. This study suggests that in this setting of high antifolate drug resistance, three doses of sulfadoxine-pyrimethamine maintain some efficacy in suppressing microscopically detectable parasitemia, although placental infection remains frequent. Even in this urban setting, a large proportion of women have malaria infection at the time of their first antenatal care visit. Interventions to control malaria early and aggressive case detection are required to limit the detrimental effects of pregnancy-associated malaria.

A longitudinal trial comparing chloroquine as monotherapy or in combination with artesunate, azithromycin or atovaquone-proguanil to treat malaria.

BACKGROUND: The predominance of chloroquine-susceptible falciparum malaria in Malawi more than a decade after chloroquine's withdrawal permits contemplation of re-introducing chloroquine for targeted uses. We aimed to compare the ability of different partner drugs to preserve chloroquine efficacy and prevent the re-emergence of resistance. METHODOLOGY/PRINCIPAL FINDINGS: Children with uncomplicated malaria were enrolled at a government health center in Blantyre, Malawi. Participants were randomized to receive chloroquine alone or combined with artesunate, azithromycin or atovaquone-proguanil for all episodes of uncomplicated malaria for one year. The primary outcome was incidence of clinical malaria. Secondary endpoints included treatment efficacy, and incidence of the chloroquine resistance marker pfcrt T76 and of anemia. Of the 640 children enrolled, 628 were included in the intention-to-treat analysis. Malaria incidence (95% confidence interval) was 0.59 (.46-.74), .61 (.49-.76), .63 (.50-.79) and .68 (.54-.86) episodes/person-year for group randomized to receive chloroquine alone or in combination with artesunate, azithromycin or atovaquone-proguanil respectively and the differences were not statistically significant. Treatment efficacy for first episodes was 100% for chloroquine monotherapy and 97.9% for subsequent episodes of malaria. Similar results were seen in each of the chloroquine combination groups. The incidence of pfcrt T76 in pure form was 0%; mixed infections with both K76 and T76 were found in two out of 911 infections. Young children treated with chloroquine-azithromycin had higher hemoglobin concentrations at the study's end than did those in the chloroquine monotherapy group. CONCLUSION/SIGNIFICANCE: Sustained chloroquine efficacy with repeated treatment supports the eventual re-introduction of chloroquine combinations for targeted uses such as intermittent preventive treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00379821.

Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment.

BACKGROUND: Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. METHODS: Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998-2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. RESULTS: Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. CONCLUSIONS: The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.

Malaria treatment efficacy among people living with HIV: the role of host and parasite factors.

Identification of an effect of HIV-associated immunosuppression on response to antimalarial therapy would help guide management of malaria infection in areas of high HIV prevalence. Therefore, we conducted an observational study of people living with HIV infection in Blantyre, Malawi. Participants who developed malaria were treated with sulfadoxine-pyrimethamine (SP) and followed for 28 days. Molecular markers for SP resistance were measured. One hundred seventy-eight episodes of malaria were assessed. The 28-day cumulative treatment failure rate was 29.1%. In univariate analysis, CD4 cell count was not associated with treatment failure (hazard ratio 0.6, 95% confidence interval 0.3-1.2). Among children, the risk of treatment failure increased with infection with SP-resistant parasites and anemia. Decreased CD4 cell count was not associated with impaired response to antimalarial therapy or diminished ability to clear SP-resistant parasites, suggesting that acquired immunity to malaria is retained in the face of HIV-associated immunosuppression.

Pneumocystis pneumonia in HIV-positive adults, Malawi.

In a prospective study of 660 HIV-positive Malawian adults, we diagnosed Pneumocystis jirovecii pneumonia (PcP) using clinical features, induced sputum for immunofluorescent staining, real-time PCR, and posttreatment follow-up. PcP incidence was highest in patients with the lowest CD4 counts, but PcP is uncommon compared with incidences of pulmonary tuberculosis and bacterial pneumonia.

Return of chloroquine antimalarial efficacy in Malawi.

BACKGROUND: In 1993, Malawi became the first country in Africa to replace chloroquine with the combination of sulfadoxine and pyrimethamine for the treatment of malaria. At that time, the clinical efficacy of chloroquine was less than 50%. The molecular marker of chloroquine-resistant falciparum malaria subsequently declined in prevalence and was undetectable by 2001, suggesting that chloroquine might once again be effective in Malawi. METHODS: We conducted a randomized clinical trial involving 210 children with uncomplicated Plasmodium falciparum malaria in Blantyre, Malawi. The children were treated with either chloroquine or sulfadoxine\#8211;pyrimethamine and followed for 28 days to assess the antimalarial efficacy of the drug. RESULTS: In analyses conducted according to the study protocol, treatment failure occurred in 1 of 80 participants assigned to chloroquine, as compared with 71 of 87 participants assigned to sulfadoxine\#8211;pyrimethamine. The cumulative efficacy of chloroquine was 99% (95% confidence interval [CI], 93 to 100), and the efficacy of sulfadoxine\#8211;pyrimethamine was 21% (95% CI, 13 to 30). Among children treated with chloroquine, the mean time to parasite clearance was 2.6 days (95% CI, 2.5 to 2.8) and the mean time to the resolution of fever was 10.3 hours (95% CI, 8.1 to 12.6). No unexpected adverse events related to the study drugs occurred. CONCLUSIONS: Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi. (ClinicalTrials.gov number, NCT00125489 [ClinicalTrials.gov].).