The Potential of Intermittent Screening and Treatment with Dihydroartemisinin-Piperaquine for the control of malaria in pregnancy in areas with high sulphadoxine-pyrimethamine resistance

Importance: In Africa most P. falciparum malaria infections during pregnancy remain asymptomatic yet are associated with maternal anaemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy during the second and third trimester with Sulphadoxine-Pyrimethamine (IPTp-SP). However, SP efficacy is threatened by high-level parasite resistance. Thesis objectives: The objectives of this thesis were three fold: Efficacy and safety of ISTp-DP To evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with Dihydroartemisinin-piperaquine (ISTp-DP) as an alternative strategy to IPTp-SP in an area of high malaria transmission and SP resistance. Effect of asymptomatic malaria infections To investigate the effect of asymptomatic malaria infections, specifically evaluating the role of asymptomatic infections missed by a malaria rapid diagnostic test (mRDT) on pregnancy and birth outcomes. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria To determine the sensitivity of an mRDT to detect active malaria infection sequestered in the placenta. Design, setting, and participants: This was an open-label two-arm individually randomised superiority trial in 3 sites with high SP resistance in Malawi. Between July 2011 and March 2013, 1873 HIV-seronegative women at 16-28 weeks of gestation were recruited (1155 primigravidae and secundigravidae [paucigravidae], 718 multigravidae). Interventions: IST and IPTp-SP were administered at 3 or 4 scheduled visits in the 2nd and 3rd trimester, 4 to 6 weeks apart. The IPTp-SP arm received SP at each visit. The ISTp-DP arm were screened for malaria at every visit and treated with DP if RDT-positive. Main outcomes and measures: Efficacy and safety The primary outcomes of interest to evaluate the efficacy and safety of ISTp-DP were gravidity dependent. Amongst paucigravidae these were any adverse live birth outcome (composite of small-for-gestation age, low birthweight or preterm birth) whilst amongst multigravidae, any P. falciparum infection at delivery was of primary interest. Analysis was by modified intention to treat. Effect of asymptomatic malaria infections Outcomes of interest in this analysis were composite adverse live birth outcome, individual adverse live birth outcomes (small for gestational age, preterm birth and low birthweight) and maternal anaemia. Analysis was restricted to only women in the IST arm fulfilling the modified intention to treat criteria. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria The diagnostic sensitivity of mRDT on peripheral maternal venous blood at delivery for active placental malaria against placental histology as the gold standard was the primary outcome of interest. Analysis included women from both trial arms at delivery. Results: Efficacy and safety The prevalence of adverse birth outcome was similar in both arms: ISTp-DP=29.9%, IPTp-SP=28.8%, Risk-Difference: 1.08%, 95% confidence interval (CI): -3.25 to 5.41; Relative Risk (RR) =1.04 (0.90-1.20), p=0.625, (paucigravidae: RR=1.10 [0.92-1.31], p=0.282; multi-gravidae RR=0.92 [0.71-1.20], p=0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% vs 40.8%): Risk-Difference=7.85 (3.07-12.63); RR=1.19 (1.07-1.33), p=0.007 (paucigravidae: RR=1.16 [1.04-1.31], p=0.011; multi-gravidae: RR=1.29 [1.02-1.63], p=0.037). Foetal loss was more common with ISTp-DP (2.6% vs 1.3%; RR=2.06 [1.01-4.21], p=0.046) and highest among non DP-recipients (3.1%) in the ISTp-DP arm. Effect of asymptomatic malaria infections by RDT 46.2% of women had malaria infection by either RDT or PCR at their first antenatal visit. The prevalence of sub-RDT infection was consistently higher in multigravidae than paucigravidae throughout pregnancy. The risk for any placental malaria was higher with asymptomatic missed RDT parasitaemia than never having had any detected parasitaemia at study visits: 38.8% vs 20.4%; RR= 1.90; 95% CI 1.28, 2.82; p=0.002. This was consistent when stratified by gravidity. Missed infections were also associated with higher risk for composite any adverse live birth outcome (26.5% vs 12.8%; RR=2.06; 95%CI 1.23, 3.42; p=0.005) which was driven by the strong association with preterm birth: 19.1% vs 4.1%; RR=4.7; 95% CI 2, 11.1; p<0.001. Asymptomatic patent RDT infections were associated with increased risk for maternal anaemia, placental malaria, composite adverse live birth outcome, preterm birth and low birth weight. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria Peripheral blood RDTs at delivery were 48% sensitive (95% C.I 39.6, 56.4%) to diagnose active placental malaria infection. This was lower than PCR (64% vs 48%; difference=16.4%; 95% CI 8.4, 24.5%; p<0.001) but higher than LM (48% vs 16%; difference=31.5%; 95% CI 22.4, 40.6%; p<0.001). The sensitivity of RDTs on placental blood to diagnose active placental infection was lower than in peripheral blood: 34% vs 48%; difference=-13.7%; 95% CI -21.1, -6.3%, p<0.001. Peripheral blood RDT had a low diagnostic sensitivity at 70% (95% CI 47.1, 86.8%) in detecting an active placental infection density of above 100parasites/500 RBCs, associated with an increased risk of low birth weight. Conclusion and relevance: Scheduled screening for malaria parasites with RDTs provided 3 to 4 times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in a setting of high SP resistance, being associated with higher foetal loss and more malaria at delivery. This may be attributable to the effect of asymptomatic parasitaemia that are left to persists in the peripheral blood without treatment due to low rate of detection of infection by RDTs through subsequent antenatal visits, and/ or the low sensitivity to detect active infection sequestered in the placenta. As such, in areas with high SP resistance, ISTp-DP is not a viable option. There remains an urgent need to identify alternative drugs that can replace SP for antenatal malaria prevention

Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi.

BACKGROUND: Malaria in pregnancy is a major cause of adverse maternal and fetal outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) is one of the control strategies promoted by WHO. In response to mounting resistance to SP, intermittent screening and treatment (ISTp) has been proposed as an alternative. The objective of this study was to explore the acceptability of ISTp for health workers and pregnant women. METHODS: Semi-structured interviews of ten health workers and five focus group discussions of 38 women enrolled in an ongoing trial comparing IPTp-SP and ISTp with dihydroartemisinin-piperaquine (DP) were conducted at two antenatal clinics in rural Malawi. All transcripts were coded and themes were identified using a content analysis approach. RESULTS: Amongst health workers, there were contrasting opinions on the preference of blood sampling methods, and the influence of method on reliability of diagnosis. The perceived greater effectiveness of DP compared to SP was appreciated, however concerns of user compliance with the full dose of DP in non-trial settings were raised. Despite the discomfort of repeated finger pricks, pregnant women were generally accepting of ISTp, particularly the chance for regular blood tests to check for infections and the perceived greater effectiveness with fewer side effects of DP compared to SP. CONCLUSION: In the trial context, pregnant women tended to prefer ISTp-DP over IPTp-SP. Health workers were also accepting of ISTp-DP as an alternative to IPTp-SP in light of increasing SP resistance. However, reliability of stock, adherence to malaria test results and user adherence to the full course of DP may present barriers to successful routine implementation. Effective communication with health workers and between health workers, pregnant women and their communities will be essential for the acceptability of focused antenatal care, including the best malaria control measures available

Interactions between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium falciparum parasites and delivery outcomes in Malawi.

BACKGROUND Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP-recipients. METHODS We measured SP-resistance allele frequencies in Malawian women participating in a trial (www.isrctn.com/ISRCTN69800930) comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped PCR-detected parasites using deep sequencing of SP-resistance alleles. RESULTS Among 125 placental infections, A581G-bearing parasites were associated with reduced birthweight (mean difference[MD]:252g, 95% CI:46,457, p=0.017). Relative to ISTp, IPTp-SP was associated with higher birthweights in women with wildtype parasites (MD:116g, 95% CI:-40,272; p=0.142) and lower birthweights in women with A581G-bearing parasites (MD:192g, 95% CI:-264,648; p=0.385) (pinteraction=0.033). Similar associations were noted on gestational age (pinteraction=0.075). Amongst only IPTp-SP recipients, relative to women who last received SP >4 weeks before delivery, recent SP receipt was associated with lower birthweight in women with wildtype parasites (MD:118g, 95% CI:-376,139; p=0.361) and higher birthweight in women with A581G-bearing parasites (MD:783g, 95% CI:-20,1586; p=0.054) (pinteraction=0.005). CONCLUSIONS The effectiveness on birthweight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP

Impact of Maternal HIV Infection and Placental Malaria on the Transplacental Transfer of Influenza Antibodies in Mother-Infant Pairs in Malawi, 2013-2014

Background: Maternal influenza vaccination protects infants against influenza virus infection. Impaired transplacental transfer of influenza antibodies may reduce this protection. Methods: We conducted a cross-sectional study of influenza vaccine–naïve pregnant women recruited at delivery from Blantyre (urban, low malaria transmission) and Chikwawa (rural, high malaria transmission) in Southern Malawi. HIV-infected mothers were excluded in Chikwawa. Maternal and cord blood antibodies against circulating influenza strains A/California/7/2009, A/Victoria/361/2011, B/Brisbane/60/2008, and B/Wisconsin/1/2010 were measured by hemagglutination inhibition (HAI). We studied the impact of maternal HIV infection and placental malaria on influenza antibody levels in mother–infant pairs in Blantyre and Chikwawa, respectively. Results: We included 454 mother–infant pairs (Blantyre, n = 253; Chikwawa, n = 201). HIV-infected mothers and their infants had lower seropositivity (HAI titer ≥1:40) against influenza A(H1N1)pdm09 (mothers, 24.3 vs 45.4%; P = .02; infants, 24.3 vs 50.5%; P = .003) and A(H3N2) (mothers, 37.8% vs 63.9%; P = .003; infants, 43.2 vs 64.8%; P = .01), whereas placental malaria had an inconsistent effect on maternal and infant seropositivity. In multivariable analyses, maternal HIV infection was associated with reduced infant seropositivity (A(H1N1)pdm09: adjusted odds ratio [aOR], 0.34; 95% confidence interval [CI], 0.15–0.79; A(H3N2): aOR, 0.43; 95% CI, 0.21–0.89). Transplacental transfer was not impaired by maternal HIV or placental malaria. Conclusions: Maternal HIV infection influenced maternal antibody response to influenza A virus infection, and thereby antibody levels in newborns, but did not affect transplacental antibody transfer

Intermittent preventive treatment with sulphadoxine-pyrimethamine but not dihydroartemisinin-piperaquine modulates the relationship between inflammatory markers and adverse pregnancy outcomes in Malawi

Women in malaria-endemic areas receive sulphadoxine-pyrimethamine (SP) as Intermittent Preventive Treatment in Pregnancy (IPTp) to reduce malaria. While dihydroartemisinin-piperaquine (DP) has superior antimalarial properties as IPTp, SP is associated with superior fetal growth. As maternal inflammation influences fetal growth, we investigated whether SP alters the relationship between inflammation and birth outcomes. We measured C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP) at enrollment (16–28 gestation weeks (gw)), visit 3 (24–36 gw) and delivery in 1319 Malawian women randomized to receive monthly SP, DP, or DP and single-dose azithromycin (AZ) in the IMPROVE trial (NCT03208179). Logistic regression was used to assess the relationship between adverse outcomes, inflammation, and treatment arm. Elevated AGP at enrollment was associated with adverse birth outcome (aRR 1.40, 95% CI: 1.15, 1.70), with similar associations observed across treatment arms, exceptions being that elevated AGP was associated with low maternal weight gain in SP recipients (aRR 1.94, 95% CI: 1.36, 2.76) and with small for gestational age in DP+AZ recepients (aRR 1.49, 95% CI 1.02, 2.17). At visit 3 there were few associations between inflammation andoutcomes. At delivery, women with elevated AGP receiving either DP or DP+AZ had an increased risk of adverse birth outcomes (aRR 1.60, 95% CI: 1.28, 2.00), including low birth weight, pre-term birth and foetal loss, this was not seen in women receiving SP (aRR 0.82, 95% CI: 0.54, 1.26). The risk of an association between elevated AGP and adverse birth outcome was higher in those receiving DP or DP+AZ compared to those receiving SP (aRR 1.95, 95% CI: 1.21, 3.13). No clear associations between CRP and adverse outcomes were observed. AGP identified women at risk of adverse pregnancy outcomes. SP modifies the relationship between inflammatory biomarkers and adverse outcomes. Our findings provide insights into potential mechanisms by which SP may improve pregnancy outcomes

Research Article (New England Journal of Medicine) Four artemisinin-based treatments in African pregnant women with malaria

Background: Information regarding the safety and efficacy of artemisinin  combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa.Methods: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether–lumefantrine, amodiaquine–artesunate, mefloquine–artesunate, or dihydroartemisinin– piperaquine. The primary end points were the polymerase-chain-reaction (PCR)–adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes.Results: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether–lumefantrine group, 98.5% in the amodiaquine– artesunate group, 99.2% in the dihydroartemisinin–piperaquine group, and 96.8% in the mefloquine–artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine–artesunate group, dihydroartemisinin–piperaquine group, and the mefloquine–artesunate group. The cure rate in the artemether–lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the  post-treatment prophylactic effect, were significantly lower in the artemether–lumefantrine group (52.5%) than in groups that received amodiaquine–artesunate (82.3%), dihydroartemisinin–piperaquine (86.9%), or mefloquine–artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine–artesunate group (50.6%) and the amodiaquine–artesunate group (48.5%) than in the dihydroartemisinin–piperaquine group (20.6%) and the artemether–lumefantrine group (11.5%) (P&lt;0.001 for comparison among the four groups).Conclusions: Artemether–lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin–piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.

Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns

Introduction: Identification of low birthweight and small for gestational age is pivotal in clinical management and many research studies, but in low‐income countries, birthweight is often unavailable within 24 h of birth. Newborn weights measured within days after birth and knowledge of the growth patterns in the first week of life can help estimate the weight at birth retrospectively. This study aimed to generate sex‐specific prediction maps and weight reference charts for the retrospective estimation of birthweight for exclusively breastfed newborns in a low‐resource setting. Material and methods: This was a prospective cohort study nested in a clinical trial of intermittent preventive treatment in pregnancy for malaria with either dihydroartemisinin–piperaquine with/without azithromycin or sulfadoxine–pyrimethamine in Korogwe District, north‐eastern Tanzania (Clinicaltrials.gov: NCT03208179). Newborns were weighed at birth or in the immediate hours after birth and then daily for 1 week. Reference charts, nadir, time to regain weight, and prediction maps were generated using nonlinear mixed‐effects models fitted to the longitudinal data, incorporating interindividual variation as random effects. Predictions and prediction standard deviations were computed using a linear approximation approach. Results: Between March and December 2019, 513 live newborns with birthweights measured within 24 h of delivery were weighed daily for 1 week. Complete datasets were available from 476 exclusively breastfed newborns. There was a rapid decline in weight shortly after delivery. The average weight loss, time of nadir, and time to regain weight were 4.3% (95% confidence interval [CI] 3.8–4.9) at 27 h (95% CI 24–30) and 105 h (95% CI 91–120) in boys and 4.9% (95% CI 4.2–5.6) at 28 h (95% CI 23–33) and 114 h (95% CI 93–136) in girls, respectively. The data were used to generate prediction maps with 1‐h time intervals and 0.05 kg weight increments showing the predicted birthweights and weight‐for‐age and weight‐change‐for‐age reference charts depicting variation in weight loss from 10%. Conclusions: The prediction maps and reference charts can be used by researchers in low‐resource settings to retrospectively estimate birthweights using weights collected up to 168 h after delivery, thereby maximizing data utilization. Clinical practitioners can also use the prediction maps to retrospectively classify newborns as low birthweight or small for gestational age

Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial.

The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV. We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713. From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups. Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy

Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific.

PURPOSE: The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. PARTICIPANTS: Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. FINDINGS TO DATE: Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. FUTURE PLANS: This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective

Impact of Dolutegravir-Based Antiretroviral Therapy on Piperaquine Exposure following Dihydroartemisinin-Piperaquine Intermittent Preventive Treatment of Malaria in Pregnant Women Living with HIV

Dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, has been identified as a promising agent for intermittent preventive treatment of malaria in pregnancy. However, in pregnant women living with HIV (PLWH), efavirenz-based antiretroviral therapy (ART) significantly reduces the plasma exposure of piperaquine. In an open-label, nonrandomized, fixed-sequence, pharmacokinetic study, we compared piperaquine plasma concentrations in 13 pregnant women during a 3-day treatment course of dihydroartemisinin-piperaquine when coadministered with efavirenz-based versus dolutegravir-based ART in the second or third trimester of pregnancy. Piperaquine concentrations were measured over a 28-day period, while on efavirenz-based ART and after switching to dolutegravir-based ART. Noncompartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare piperaquine pharmacokinetic parameters between these two treatment periods. Compared with efavirenz-based ART, coadministration of dihydroartemisinin-piperaquine and dolutegravir-based ART resulted in a 57% higher overall piperaquine exposure (area under the concentration-time curve from 0 to 672 h [AUC0-672 h]) (GMR, 1.57; 90% CI, 1.28 to 1.93). Piperaquine's day 7 concentrations were also 63% higher (GMR, 1.63; 90% CI, 1.29 to 2.11), while day 28 concentrations were nearly three times higher (GMR, 2.96; 90% CI, 2.25 to 4.07). However, the maximum piperaquine concentration (Cmax) remained similar (GMR, 1.09; 90% CI, 0.79 to 1.49). Dihydroartemisinin-piperaquine was well tolerated, with no medication-related serious adverse events observed in this small study. Compared with efavirenz-based ART, a known inducer of piperaquine metabolism, dolutegravir-based ART resulted in increased overall piperaquine exposure with pharmacokinetic parameter values that were similar to those published previously for pregnant and nonpregnant women. Our findings suggest that the efficacy of dihydroartemisinin-piperaquine will be retained in pregnant women on dolutegravir. (The study was registered on PACTR.samrc.ac.za [PACTR201910580840196].). Erratum: In Fig.2 and Fig. S1, the first value on the y axis should read as “1” instead of “0.