• 1

    Nosten F, McGready R, Mutabingwa T, 2007. Case management of malaria in pregnancy. Lancet Infect Dis 7 :118–125.

  • 2

    Brockman A, Price RN, van Vugt M, Heppner DG, Walsh D, Sookto P, Wimonwattrawatee T, Looareesuwan S, White NJ, Nosten F, 2000. Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Med Hyg 94 :537–544.

    • Search Google Scholar
    • Export Citation
  • 3

    Dolan G, ter Kuile FO, Jacoutot V, White NJ, Luxemburger C, Malankirii L, Chongsuphajaisiddhi T, Nosten F, 1993. Bed nets for the prevention of malaria and anaemia in pregnancy. Trans R Soc Trop Med Hyg 87 :620–626.

    • Search Google Scholar
    • Export Citation
  • 4

    McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsay SW, 2001. Safety of the insect repellent N,N-diethyl-M-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 65 :285–289.

    • Search Google Scholar
    • Export Citation
  • 5

    McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, Looareesuwan S, White NJ, Nosten F, 2001. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 95 :651–656.

    • Search Google Scholar
    • Export Citation
  • 6

    McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F, 2006. The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol 62 :1021–1031.

    • Search Google Scholar
    • Export Citation
  • 7

    Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ, Nosten F, 2005. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 41 :425–432.

    • Search Google Scholar
    • Export Citation
  • 8

    Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, Talisuna AO, Greenhouse B, Nosten F, Rosenthal PJ, Wabwire-Mangen F, Dorsey G, 2007. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials 18 :e20.

    • Search Google Scholar
    • Export Citation
  • 9

    McGready R, Keo NK, Villegas L, White NJ, Looareesuwan S, Nosten F, 2003. Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Trans R Soc Trop Med Hyg 97 :592–594.

    • Search Google Scholar
    • Export Citation
  • 10

    Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, Leowattana W, Hutagalung R, Wilairatana P, Brockman A, Looareesuwan S, Nosten F, White NJ, 2004. Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis 190 :1773–1782.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Dihydroartemisinin—Piperaquine Rescue Treatment of Multidrug-resistant Plasmodium falciparum Malaria in Pregnancy: A Preliminary Report

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  • 1 Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Academic Medical Center, Amsterdam, The Netherlands; Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand; Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom

Dihydroartemisinin-piperaquine (DHA-PPQ) is a promising new artemisinin combination treatment. There are no published data on the intentional use of the drug in pregnancy. Between June 2006 and January 2007, 50 Karen pregnant women with recurrent P. falciparum infections, despite 7-day treatments with quinine or artesunate (+/−clindamycin) or both, were treated with DHA-PPQ. This rescue treatment was effective and well tolerated and there was no evidence of toxicity for the mothers or the fetus. The PCR adjusted cure rate by Kaplan Meier analysis at day 63 was 92.2% (95% CI: 76.9–97.4).

INTRODUCTION

Multidrug-resistant Plasmodium falciparum malaria during pregnancy is an increasing public health concern in the tropics. Malaria infection—even if confined to asymptomatic parasitemia—is harmful for the mother and the fetus.1 In the border areas of Thailand, P. falciparum has developed resistance to all antimalarial drugs except the artemisinin derivatives.2 Studies from the North-Western border of Thailand have failed to find a significantly effective preventive measure for pregnant women.3,4 Quinine in pregnancy is associated with high failure rates; 30% of patients have polymerase chain reaction (PCR) confirmed recrudescences. Although efficacy can be improved by combining quinine with clindamycin, frequent side effects and the need for a 7-day course of treatment result in poor adherence.5 The World Health Organization (WHO) recommends the use of artemisinin combination therapy (ACT) (short-course, 3-day treatments) in the second and third trimester of pregnancy; however, to date published trials on fixed-dose ACTs in pregnant women include only 13 women.6 Mefloquine has been associated with an increased risk of stillbirth in Thailand and Artemether-lumefantrine is not widely used in this area. The only ACT available to us was DHA-piperaquine.

Dihydroartemisinin-piperaquine (DHA-PPQ) is a new co-formulated ACT effective against multidrug-resistant falciparum malaria. Both of the individual components have been used extensively in pregnancy, although exposure to DHA has mainly been as the metabolite of artesunate, and data on piperaquine from China, where it was the first-line drug for malaria for 16 years, are limited. Recent randomized clinical trials in Asia and Africa indicate excellent tolerability and high cure rates with DHA-PPQ.7,8 This new ACT is being used increasingly in South-East Asia, is already part of national treatment recommendations in Cambodia and Vietnam, and is being used to treat pregnant women in West Papua. Piperaquine (PPQ) is a “chloroquine-like” bisquino-line drug with a long half life and a favorable animal reproductive toxicology profile. We conducted a retrospective evaluation of pregnant women with multiple recurrent P. falciparum episodes after 7-day regimens of quinine (± clindamycin), artesunate (± clindamycin), or both, who were then treated with dihydroartemisinin-piperaquine.

METHODS

Pregnant women in this case series attended the weekly antenatal care (ANC) of the Shoklo Malaria Research Unit (SMRU) on the North-Western border of Thailand. In this hilly forested area malaria transmission is low and seasonal. Acquired immunity is poorly protective and severe malaria is common at all ages, especially in pregnant women. At the start of the research program, maternal mortality due to malaria was high: 1,000 per 100,000 live births. Women are invited to come to the ANC as soon as they are aware of their pregnancy. All women attending the consultation are screened weekly for malaria as the only effective strategy to prevent maternal death. A PCR spot on filterpaper is done for each woman with P. falciparum malaria. Prophylactic ferrous sulphate (200 milligram/day), folic acid (5 mg/week), and vitamin B1 tablets (100 mg/day) are provided to all pregnant women on a weekly basis. Hematocrit levels are measured twice weekly and anemic women (hematocrit < 30%) are treated with ferrous sulphate (200 mg thrice daily) and folic acid (5 mg/day) and blood transfusion is given for symptomatic anemia (hematocrit < 20%).

Treatment with 3 days of DHA-PPQ (DHA 40 mg, PPQ 320 mg per tablet, Holley Pharm PRC) was offered to women with recurrence of P. falciparum after 7-day treatments with quinine (30 mg/kg/day, Government Pharmaceutical Organization) (± clindamycin [15 mg/kg/day, Siam Bheasach]), artesunate (2 mg/kg/day, Guilin, PRC) (± clindamycin), or both. Although every effort was made to follow the women closely, this was not a prospective study; therefore, there was no procedure other than the routine antenatal care common to all women following the ANC.

Treatment was based on weight categories with an approximated total dosing of 6.5 mg DHA/kg and 51.2 PPQ/kg over 3 days. Treatments were supervised and patients observed for vomiting for the first hour after treatment. Women had a daily malaria smear until negative and continued to be followed up in the routine ANC thereafter. All women were encouraged to deliver in the SMRU delivery unit and babies were examined as soon as possible after birth and at 1 month of age.

Definitions used in the analysis include: febrile—(aural) temperature > 37.5°C; hyperparasitemia—≥ 4% red blood cells infected; anemia—hematocrit < 30%; severe anemia hematocrit < 20%; prematurity—delivery before 37 weeks gestation; low birth weight—infants with a birth weight of less than 2,500 g. Gametocyte carriage was defined as the number of weeks in which blood slides were positive for gametocytes, divided by the total number of weeks of follow up, and expressed per 1,000 person weeks.

Statistical analysis.

Data were described using the statistical program SPSS for Windows (SPSS, Benelux Inc., Gorinchem, Netherlands) and Epi Info (Center for Disease Control and Prevention). The Kaplan Meier method was used to calculate parasitological efficacy.

RESULTS

In this retrospective analysis we report 50 Karen pregnant women with recurrent P. falciparum infections who were treated with DHA-PPQ between June 2006 and January 2007. The baseline demography of the women and total number of malaria episodes and treatments during pregnancy are summarized (Table 1). These 50 women had a total of 192 episodes of slide-confirmed malaria during their pregnancy: P. falciparum (N = 117), mixed (N = 13), and P. vivax (N = 62) malaria with a median [range] of 2 [2–8] episodes per pregnancy. Before the DHA-PPQ treatment 41 women received quinine (± clindamycin) and 14 artesunate (± clindamycin) treatments. Two women had an allergic reaction to quinine that necessitated a change to artesunate. The characteristics of the 62 episodes of malaria treated with DHA-PPQ are summarized (Table 2).

Safety and tolerability.

All 62 episodes of malaria in all 50 women were included for this part of the analysis. No women deteriorated under treatment and no serious adverse events were reported. No women vomited any dose of DHA-PPQ. Of the 8 women with fever on admission all were afebrile by day 2. Parasite clearance occurred at a median [range] of 2 [1–5] days. Anemia on admission was present in 53.2% (33/62) of the episodes (Table 2). There were four episodes with severe symptomatic anemia that required blood transfusion (i.e., 8% [4/50]) of women. The day 28 hematocrit was significantly higher than on admission: mean SD [range] 30.7 ± 3.2% [22–38.0], P = 0.001 (paired t test).

Parasitological efficacy.

Initial parasitological efficacy analysis was confined to the first rescue treatments in 47 women who completed the 3-dose course of DHA-PPQ. The 3 other women failed to complete treatment taking only a single dose. The median time to a negative smear was 2 [1–5] days. During 63-day follow-up there were 11 and 9 women who had P. falciparum and P. vivax reappearances at a median [range] of 49 [21–63] and 48 [35–63] days after starting treatment, respectively. PCR genotyping of recurrent P. falciparum infections identified 3 possible recrudescences: 1 definite identical genotype (day 21); 2 indeterminate (day 38 and 49), and 8 new infections. Thus assuming the indeterminate were in fact recrudescent infections (parasites can sequester in the placenta for months) the PCR-adjusted efficacy by day 63 was 92.2% (95% CI: 76.9–97.4).

In 26% (12/47) of the episodes gametocytes were detected on day 0. The gametocyte carriage in women who did not have admission gametocytemia was 11.7 (95% CI: 3.0–36.7) person-gametocyte-weeks (PGW) per 1,000 women weeks.

Pregnancy outcome.

Of the 50 women exposed to DHA-PPQ, 5 women left the area before the end of pregnancy and 45 had a known pregnancy outcome. All babies were live born and examined: 44 singletons and one set of twins. Of the singleton babies weighed within 3 days of birth the mean (±SD) [range] birth weight was 2816 (±397) gram [1930–3500]; 21.7% (5/21) had low birth weight and 4.4% of known deliveries (2/45) were premature. Two infants were reported to be abnormal at birth: one with a small umbilical hernia (exposed to treatment at 24.4 weeks) and one diagnosed clinically with Patau syndrome (trisomy 13) (exposed to treatment at 34.3 weeks). This infant died at 6 hours of age and the remaining infants were all seen at 1 month of age and found to be healthy.

DISCUSSION

In low-transmission settings, malaria is an important cause of morbidity and mortality in pregnancy. Over half the pregnant women in this retrospective series of acute uncomplicated P. falciparum malaria reported a history of fever or were febrile. There was a high rate of direct malaria-related adverse events: 8% of women had to be transfused in their second episode of P. falciparum malaria. Furthermore, 22% of babies were born with low birth weight, which increases the risk of death in the first weeks of life. This emphasizes the need for effective treatments in pregnancy. DHA-PPQ was used to rescue pregnant women with multiple recurrences of highly drug-resistant P. falciparum malaria. It proved effective and provided rapid fever and parasite clearance. Rapid resolution of symptoms reduces the risk of premature labor. Most recurrences were caused by new infections or by P. vivax. The PCR-confirmed cure rate and the median time to reappearance were slightly lower than previously published results at this site using the triple combination of atovaquone-proguanil-artesunate for rescue treatment in pregnant women.9 As expected, the cure rates in these pregnant women with multiple malaria infections also appear lower than those achieved in non-pregnant patients from the same area with primary infections.7,10

There were no serious adverse events related to the drug and the two abnormalities identified in the newborns are unlikely to be drug related. The pregnancy outcomes are similar to those of women treated for multiple infections with the combination of artesunate-atovaquone-proguanil.9 A notable result of this series was the fact that there was not a single dose of vomited drug—a significant benefit for pregnant women. Gametocyte carriage rates post-treatment were also low and similar to rates from non-pregnant patients treated with DHA-PPQ.7

An effective, short-course, relatively inexpensive, fixed artemisinin combination has never been available to pregnant women on the Thai-Burmese border and DHA-PPQ currently looks the most promising candidate.

Table 1

Demographic and malaria characteristics of 50 pregnant women treated for uncomplicated P. falciparum malaria with DHA-PPQ, Thai-Burmese border, 2006

Data are median [range] unless otherwise stated.
* Two women changed to artesunate due to quinine allergy.
† Unable to be traced for treatment.
‡ Parasitemia of mixed infection for P. falciparum trophozoites only.
Age (years)24 [16–39]
Proportion of women smoking (%) (n)32.0 (16/50)
Gravidity2 [1–12]
Parity1 [0–9]
Proportion of primigravida, % (n)26.0 (13/50)
Proportion of treatments by antimalarial used, % (n):
Quinine ± clindamycin21.4 (41)
Artesunate ± clindamycin*13.5 (26)
Chloroquine (for P. vivax)31.8 (61)
Coartemether0.5 (1)
Not treated (P. vivax)†0.5 (1)
DHA-PPQ32.3 (62)
Total antimalarial treatments100 (192)
Parasitaemia, geometric mean [range]/μL
P. falciparum (N = 117) and mixed infection‡ (N = 13)1,979 [12–251,189]
P. vivax (N = 62)295 [16–33,884]
Proportion of hyperparasitemic episodes1.5% (2/130)
Table 2

Malaria details of 62 P. falciparum episodes in 50 pregnant women treated with DHA-PPQ

* Parasitemia of mixed infection for P. falciparum trophozoites only.
Gestational age at DHA-PPQ treatment (weeks)23.7 ± 8.2 [9.2–39.1]
Weight (kilogram), mean (±SD) [range]48 ± 6 [36–60]
Proportion of women with a history of fever, % (n)53.2 (33/62)
Temperature °C, mean (±SD) [range]36.6 ± 1.0 [35.1–40.0]
Proportion of febrile women, % (n)12.9 (8/62)
Proportion of mixed (P. falciparum and P. vivax) infections, % (n)8.1 (5/62)
Parasitemia/μL, geometric mean* [range]1,951 [12–85,114]
Hematocrit (%), mean (±SD) [range]28.8 ± 4.3 [18–37]
Proportion of anemic women, % (n)53.2 (33/62)

*

Address correspondence to François Nosten, Shoklo Malaria Research Unit, PO Box 46, 63110 Mae Sot, Tak, Thailand. E-mail: SMRU@tropmedres.ac

All authors have no conflict of interest.

Authors’ addresses: Marcus J. Rijken, Rose McGready, Machteld E. Boel, Marion Barends, Stephane Proux, Mupawjay Pimanpanarak, and François Nosten, Shoklo Malaria Research Unit, PO Box 46, 63110 Mae Sot, Tak, Thailand, Tel: +66-55-545021, Fax: +66-55-545020, E-mail: SMRU@tropmedres.ac. Pratap Singhasivanon, Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchadewee, Bangkok 10400, Thailand, Tel: +66-2-354-9100, Fax: +66-2-354-9198.

Acknowledgments: The authors thank all the staff of the Shoklo Malaria Research Unit, especially Suleeporn Parnpeeya, Wimon, Supor Keereecharoen, Ratri Arunjerdja, Saw Oo Tan, Aung Pyae Phyo, Carit Ler Moo, Lay Lay, Candy Beau, Claudia Turner, Verena Carrara, Khin Maung Lwin, Anchalee Jaidee, Nathapon Laochan, Julian Zwang, Siam, and Carela. Dihyroartemisinin-piperaquine was kindly provided by Holley Cotec Pharmaceutical, Guangzhou, China.

Financial support: The Shoklo Malaria Research Unit is part of the Mahidol Oxford University Research Programme, funded by the Wellcome Trust of Great Britain.

REFERENCES

  • 1

    Nosten F, McGready R, Mutabingwa T, 2007. Case management of malaria in pregnancy. Lancet Infect Dis 7 :118–125.

  • 2

    Brockman A, Price RN, van Vugt M, Heppner DG, Walsh D, Sookto P, Wimonwattrawatee T, Looareesuwan S, White NJ, Nosten F, 2000. Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Med Hyg 94 :537–544.

    • Search Google Scholar
    • Export Citation
  • 3

    Dolan G, ter Kuile FO, Jacoutot V, White NJ, Luxemburger C, Malankirii L, Chongsuphajaisiddhi T, Nosten F, 1993. Bed nets for the prevention of malaria and anaemia in pregnancy. Trans R Soc Trop Med Hyg 87 :620–626.

    • Search Google Scholar
    • Export Citation
  • 4

    McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsay SW, 2001. Safety of the insect repellent N,N-diethyl-M-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 65 :285–289.

    • Search Google Scholar
    • Export Citation
  • 5

    McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, Looareesuwan S, White NJ, Nosten F, 2001. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 95 :651–656.

    • Search Google Scholar
    • Export Citation
  • 6

    McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F, 2006. The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol 62 :1021–1031.

    • Search Google Scholar
    • Export Citation
  • 7

    Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ, Nosten F, 2005. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 41 :425–432.

    • Search Google Scholar
    • Export Citation
  • 8

    Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, Talisuna AO, Greenhouse B, Nosten F, Rosenthal PJ, Wabwire-Mangen F, Dorsey G, 2007. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials 18 :e20.

    • Search Google Scholar
    • Export Citation
  • 9

    McGready R, Keo NK, Villegas L, White NJ, Looareesuwan S, Nosten F, 2003. Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Trans R Soc Trop Med Hyg 97 :592–594.

    • Search Google Scholar
    • Export Citation
  • 10

    Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, Leowattana W, Hutagalung R, Wilairatana P, Brockman A, Looareesuwan S, Nosten F, White NJ, 2004. Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis 190 :1773–1782.

    • Search Google Scholar
    • Export Citation
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