In the Journals

Alternative preventive therapy, RDTs show promise against resistant malaria in pregnant women

As the prevalence of malaria resistant to sulfadoxine-pyrimethamine increases, alternative strategies — such as preventive artemisinin combination therapy containing dihydroartemisinin-piperaquine or rapid diagnostic test-and-treat — may provide pregnant women protection from infection, according to two recently published studies.

WHO guidance recommends preventive treatments of sulfadoxine-pyrimethamine (SP) at each antenatal clinic visit after the first trimester for pregnant women in malaria-endemic African countries. While SP has been shown to prevent peripheral parasitemia, maternal anemia and clinical malaria during pregnancy, and is also capable of reducing overall neonatal mortality, these benefits are becoming increasingly negated by developing resistance.

Grant Dorsey, MD, PhD

Grant Dorsey

“Resistance to SP has become widespread, especially in East and Southern Africa, and more recent studies have suggested that the effectiveness of [intermittent preventive treatment in pregnancy (IPTp)] with SP may be compromised,” Grant Dorsey, MD, PhD, professor of infectious diseases at the University of California, San Francisco, and colleagues wrote. “Thus, there is a need for the evaluation of alternatives to SP for IPTp.”

Early, frequent DP treatment improves protection

To evaluate the efficacy and safety of IPTp with an alternative regimen of dihydroartemisinin-piperaquine (DP), Dorsey and colleagues enrolled healthy pregnant women at 12 to 20 weeks gestational age living in Tororo, Uganda — an area with frequent transmission of SP-resistant malaria — into a double blind, randomized controlled trial.

The women were assigned either three doses of SP, three doses of DP or a dose of DP each month. In addition, all participants received a long-lasting insecticide-treated net, as well as medical examinations at a study clinic upon enrollment and every 4 weeks. Malaria diagnoses were made during these visits by clinical symptoms and thick blood smear. The women received an assessment at delivery, which included the collection of placental tissue, placental blood, cord blood and maternal blood, and continued to be monitored for 6 weeks after delivery.

The study’s primary outcome was the prevalence of placental malaria, as determined by histopathology. Other outcomes included the incidence of symptomatic malaria, parasitemia, adverse birth outcomes and drug tolerability.

Three hundred women were enrolled into the study between June and October 2014. Of these, 96.3% were followed through delivery, and 94% had placental tissue collected for histopathology. Upon enrollment, mean age of participants was 22 years, and 57% had malaria parasites detected by loop-mediated isothermal amplification (LAMP).

Compared with the 50% prevalence observed in the SP arm, placental malaria was lower among patients who received either three doses of DP (34.1%; P = .03) or monthly DP (27.1%; P = .001), the researchers wrote. Symptomatic malaria was more frequent within the SP arm than in the three dose DP arm (P = .001) and the monthly DP arm (P < .001). Similarly, parasite prevalence was greater in the SP arm compared with the three-dose SP arm (P < .001) and monthly DP arm (P < .001).

While no differences in individual birth outcomes were noted between treatment arms, the risk of any adverse birth was lower in the monthly DP group than in the three-dose (P = .02) or SP (P = .05) groups. Treatments were well-tolerated among all groups, and there were no differences in the incidence of adverse events except between the monthly and three-dose DP arms in regard to mild dysphagia.

The researchers wrote that the low efficacy of DP was unsurprising in light of previous studies detailing prevalent resistance to the preventive treatment in the region. In such circumstances, these data would support the implementation of an alternative DP regimen for malaria prevention.

“Increasing the dosing frequency of DP to every 4 weeks starting as early as 16 weeks gestational age provided more protection, in line with updated WHO policy recommendations that IPTp should be given at every antenatal clinic if at least 1 month apart,” Dorsey and colleagues wrote. “Additional and larger evaluations in different settings are needed to inform important questions of safety and potential risks for selection of drug-resistant parasites due to an increase in drug pressure.”

RDTs detect infection, enable prompt treatment

Sir Brian Greenwood, FMedSci, professor of clinical tropical medicine at the London School of Hygiene & Tropical Medicine, and colleagues demonstrated another tactic against SP failure involving the use of rapid diagnostic tests (RDTs) and treatment at antenatal visits.

In their recently published study, the researchers examined samples and data obtained from a large multicenter trial comparing preventive SP treatment to screening and treatment. Participating primigravidae and secundigravidae from four West African countries were screened with histidine-rich protein 2/parasite lactate dehydrogenase (HRP2/pLDH) RDT during multiple antenatal clinic visits, and treated with artemether-lumefantrine if positive. The researchers re-examined finger prick blood samples collected during each visit for malaria infection using microscopy and PCR assay, and compared these findings with RDT results reported during the primary study.

The overall sensitivity of the RDT was 87.4% (95% CI, 85.3-89.4), Greenwood and colleagues wrote, and 55.6% of all RDT detections occurred during the first visit to an antenatal clinic. Sensitivity ranged from 90.9% in Burkina Faso to 59.3% in The Gambia, which the researchers wrote may suggest a potential relationship between parasite density and RDT specificity. Among Ghanaian women alone, P. falciparum prevalence was highest at enrollment and RDT sensitivity was 88.8% at the first antenatal clinic, 83.7% at the second, 77.4% at the third and 48.6% at delivery. There was no association between RDT results and any measured birth outcomes, and the only identifiable risk factor of missed infection was pregnancy with a second child, as opposed to a first (OR = 1.85; 95% CI, 1-3.43).

In light of increasingly frequent SP treatment failures and the impracticality of blanket prevention regimens in areas with lower malaria prevalence, Greenwood and colleagues suggested RDT screening and treatment upon a pregnant woman’s first clinic visit as a cost-effective means to detect and treat many infections with no serious repercussions for the child. However, the diminished test accuracy in less affected regions is a major shortcoming in need of more investigation.

“The lowest sensitivity of the RDT seen in this study was at the site with the lowest transmission; it is not clear if this is a causal association due to lower average parasite densities but this is a possible explanation for this observation,” the researchers wrote. “It is also unclear if sensitivity would decline further over the course of pregnancy in lower transmission settings and this needs to be investigated. As the incidence of malaria falls in many previously highly endemic areas, new approaches to the control of malaria in pregnancy need to be developed and evaluated.” - by Dave Muoio

Reference:

Kakuru A, et al. New Engl J Med. 2016;doi:10.1056/NEJMoa1509150.

WHO. WHO Evidence Review Group: Intermittent Preventive Treatment of malaria in pregnancy with Sulfadoxine-Pyrimethamine. 2012. www.who.int/malaria/mpac/sep2012/iptp_sp_erg_meeting_report_july2012.pdf. Accessed March 8, 2016.

Williams JE, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ1198.

Disclosure: Dorsey, Charlebois and Havlir report receiving grants from the NIH. Greenwood and colleagues report no relevant financial disclosures.

As the prevalence of malaria resistant to sulfadoxine-pyrimethamine increases, alternative strategies — such as preventive artemisinin combination therapy containing dihydroartemisinin-piperaquine or rapid diagnostic test-and-treat — may provide pregnant women protection from infection, according to two recently published studies.

WHO guidance recommends preventive treatments of sulfadoxine-pyrimethamine (SP) at each antenatal clinic visit after the first trimester for pregnant women in malaria-endemic African countries. While SP has been shown to prevent peripheral parasitemia, maternal anemia and clinical malaria during pregnancy, and is also capable of reducing overall neonatal mortality, these benefits are becoming increasingly negated by developing resistance.

Grant Dorsey, MD, PhD

Grant Dorsey

“Resistance to SP has become widespread, especially in East and Southern Africa, and more recent studies have suggested that the effectiveness of [intermittent preventive treatment in pregnancy (IPTp)] with SP may be compromised,” Grant Dorsey, MD, PhD, professor of infectious diseases at the University of California, San Francisco, and colleagues wrote. “Thus, there is a need for the evaluation of alternatives to SP for IPTp.”

Early, frequent DP treatment improves protection

To evaluate the efficacy and safety of IPTp with an alternative regimen of dihydroartemisinin-piperaquine (DP), Dorsey and colleagues enrolled healthy pregnant women at 12 to 20 weeks gestational age living in Tororo, Uganda — an area with frequent transmission of SP-resistant malaria — into a double blind, randomized controlled trial.

The women were assigned either three doses of SP, three doses of DP or a dose of DP each month. In addition, all participants received a long-lasting insecticide-treated net, as well as medical examinations at a study clinic upon enrollment and every 4 weeks. Malaria diagnoses were made during these visits by clinical symptoms and thick blood smear. The women received an assessment at delivery, which included the collection of placental tissue, placental blood, cord blood and maternal blood, and continued to be monitored for 6 weeks after delivery.

The study’s primary outcome was the prevalence of placental malaria, as determined by histopathology. Other outcomes included the incidence of symptomatic malaria, parasitemia, adverse birth outcomes and drug tolerability.

Three hundred women were enrolled into the study between June and October 2014. Of these, 96.3% were followed through delivery, and 94% had placental tissue collected for histopathology. Upon enrollment, mean age of participants was 22 years, and 57% had malaria parasites detected by loop-mediated isothermal amplification (LAMP).

Compared with the 50% prevalence observed in the SP arm, placental malaria was lower among patients who received either three doses of DP (34.1%; P = .03) or monthly DP (27.1%; P = .001), the researchers wrote. Symptomatic malaria was more frequent within the SP arm than in the three dose DP arm (P = .001) and the monthly DP arm (P < .001). Similarly, parasite prevalence was greater in the SP arm compared with the three-dose SP arm (P < .001) and monthly DP arm (P < .001).

While no differences in individual birth outcomes were noted between treatment arms, the risk of any adverse birth was lower in the monthly DP group than in the three-dose (P = .02) or SP (P = .05) groups. Treatments were well-tolerated among all groups, and there were no differences in the incidence of adverse events except between the monthly and three-dose DP arms in regard to mild dysphagia.

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The researchers wrote that the low efficacy of DP was unsurprising in light of previous studies detailing prevalent resistance to the preventive treatment in the region. In such circumstances, these data would support the implementation of an alternative DP regimen for malaria prevention.

“Increasing the dosing frequency of DP to every 4 weeks starting as early as 16 weeks gestational age provided more protection, in line with updated WHO policy recommendations that IPTp should be given at every antenatal clinic if at least 1 month apart,” Dorsey and colleagues wrote. “Additional and larger evaluations in different settings are needed to inform important questions of safety and potential risks for selection of drug-resistant parasites due to an increase in drug pressure.”

RDTs detect infection, enable prompt treatment

Sir Brian Greenwood, FMedSci, professor of clinical tropical medicine at the London School of Hygiene & Tropical Medicine, and colleagues demonstrated another tactic against SP failure involving the use of rapid diagnostic tests (RDTs) and treatment at antenatal visits.

In their recently published study, the researchers examined samples and data obtained from a large multicenter trial comparing preventive SP treatment to screening and treatment. Participating primigravidae and secundigravidae from four West African countries were screened with histidine-rich protein 2/parasite lactate dehydrogenase (HRP2/pLDH) RDT during multiple antenatal clinic visits, and treated with artemether-lumefantrine if positive. The researchers re-examined finger prick blood samples collected during each visit for malaria infection using microscopy and PCR assay, and compared these findings with RDT results reported during the primary study.

The overall sensitivity of the RDT was 87.4% (95% CI, 85.3-89.4), Greenwood and colleagues wrote, and 55.6% of all RDT detections occurred during the first visit to an antenatal clinic. Sensitivity ranged from 90.9% in Burkina Faso to 59.3% in The Gambia, which the researchers wrote may suggest a potential relationship between parasite density and RDT specificity. Among Ghanaian women alone, P. falciparum prevalence was highest at enrollment and RDT sensitivity was 88.8% at the first antenatal clinic, 83.7% at the second, 77.4% at the third and 48.6% at delivery. There was no association between RDT results and any measured birth outcomes, and the only identifiable risk factor of missed infection was pregnancy with a second child, as opposed to a first (OR = 1.85; 95% CI, 1-3.43).

In light of increasingly frequent SP treatment failures and the impracticality of blanket prevention regimens in areas with lower malaria prevalence, Greenwood and colleagues suggested RDT screening and treatment upon a pregnant woman’s first clinic visit as a cost-effective means to detect and treat many infections with no serious repercussions for the child. However, the diminished test accuracy in less affected regions is a major shortcoming in need of more investigation.

“The lowest sensitivity of the RDT seen in this study was at the site with the lowest transmission; it is not clear if this is a causal association due to lower average parasite densities but this is a possible explanation for this observation,” the researchers wrote. “It is also unclear if sensitivity would decline further over the course of pregnancy in lower transmission settings and this needs to be investigated. As the incidence of malaria falls in many previously highly endemic areas, new approaches to the control of malaria in pregnancy need to be developed and evaluated.” - by Dave Muoio

Reference:

Kakuru A, et al. New Engl J Med. 2016;doi:10.1056/NEJMoa1509150.

WHO. WHO Evidence Review Group: Intermittent Preventive Treatment of malaria in pregnancy with Sulfadoxine-Pyrimethamine. 2012. www.who.int/malaria/mpac/sep2012/iptp_sp_erg_meeting_report_july2012.pdf. Accessed March 8, 2016.

Williams JE, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ1198.

Disclosure: Dorsey, Charlebois and Havlir report receiving grants from the NIH. Greenwood and colleagues report no relevant financial disclosures.