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Rigor-Reviewed Manuscript

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.

Name: Kaimen Rigor review — 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.
Item: 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.
Rating: 100
Author: Alpha1

Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO

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Kaimen Rigor review — 4★ (Strong), 0 critical, 0 high issues for “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.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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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.

Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO

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DOI

10.1016/S0140-6736(23)02631-4

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

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.

Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO

Paper source

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

4 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 46 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the incidence of Plasmodium infection detected by PCR, microscopy, RDT, or placental histology, which is a surrogate for clinical benefit. The paper does not demonstrate target engagement at the tested dose (no PK/PD data linking the dose to protective piperaquine concentrations in this population) and does not cite validated evidence linking the surrogate to clinical outcomes such as reduced adverse pregnancy outcomes. In fact, the trial found no significant difference in adverse pregnancy outcomes, and the authors acknowledge the study was not powered for these outcomes.
“The primary endpoint was the incidence of at least one 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…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in malaria infection incidence (RR 0.45, IRR 0.32), but this is a surrogate outcome. The effect size is not anchored to a clinically meaningful threshold for the surrogate, and the trial found no significant improvement in hard clinical outcomes (adverse pregnancy outcomes, maternal anaemia). The authors state the study was not powered for these outcomes, so the clinical meaningfulness of the surrogate reduction is not established.
“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,…”
Find in source

Findings by category

01ArithmeticNone found 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit1 minor suggestion

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted and transparently reported phase 3 randomised controlled trial. The design is rigorous, statistical analysis is sound, and ethical approvals and data sharing are adequately documented. Minor reporting gaps include lack of explicit CONSORT and Declaration of Helsinki statements, and a typo in a table footnote.

Both reviewers classified the study as interventional, and I adopted that. The evaluation covered all eight dimensions; several sub-criteria were marked not applicable for a human drug trial (e.g., cell line authentication, housing conditions). The statistics verification covered only a subset of reported tests (those with test statistics/df or effect estimates with CIs); threshold-only p-values and resampling-based p-values were not machine-verified. The citation check found no retracted or unresolved references.

Numerical inconsistencies

None found

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Checked — nothing surfaced.

Recomputed 16 tests: 16 consistent, 0 inconsistent; 6 recomputed directly from the reported test statistics, 10 via agent-written checks.

Overstated conclusions

2 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

6 major claims checked against the paper's own evidence: all adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior trials of IPTp with mefloquine and the Ugandan pilot study with dihydroartemisinin-piperaquine, acknowledging their limitations (poor tolerability, drug-drug interactions, inconclusive results). The rationale linking the premise to the study objectives is explicit, and the study addresses prior limitations by using dolutegravir-based cART and a larger, adequately powered design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study clearly establishes the scientific premise, citing prior research on the threat of antifolate resistance and the need for alternative IPTp, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraphs 2-4]

“Two trials that added IPTp with mefloquine to daily co-trimoxazole in areas with high sulfadoxine-pyrimethamine resistance in women living with HIV on nevirapine-based or efavirenz-based combined antiretroviral therapy (cART) showed the superiority of the combination in reducing clinical malaria and placental malaria compared with daily co-trimoxazole alone.”

paraphrase[Introduction, final paragraph]

“We present the results of a trial designed to determine whether addition of monthly IPTp with dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria than the standard of care with daily co-trimoxazole alone in women receiving dolutegravir-based cART in areas with high sulfadoxine-pyrimethamine resistance.”

paraphrase[Introduction, paragraphs 3-4]

“The study was inconclusive. The combination of daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine was well tolerated, but no reduction in Plasmodium infections was achieved, likely because of reduced malaria transmission in the study area after the introduction of indoor residual spraying, and a clinically relevant drug-drug interaction between dihydroartemisinin-piperaquine and efavirenz resulting in a 27% reduction in exposure to dihydroartemisinin and 38% reduction in exposure to piperaquine.”

PASSReviewer 2· 95% conf

The study clearly establishes the scientific premise, citing prior research on the threat of antifolate resistance and the need for alternative IPTp, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraphs 2-4]

paraphrase[Introduction, final paragraph]

paraphrase[Introduction, paragraph 4]

“Unlike efavirenz, no clinically relevant drug-drug interactions have been seen between dihydroartemisinin-piperaquine and dolutegravir in pregnancy.”

Randomisation used computer-generated permuted blocks, stratified by site and HIV status, with allocation concealment via sealed envelopes. Blinding was comprehensive (participants, investigators, laboratory staff, data analysts). The sample size calculation is reported (80% power, 50% reduction, 898 participants). Inclusion/exclusion criteria are detailed. The modified ITT and safety populations are defined, and missing data handling (non-responder imputation) is described. As a human RCT, replicate_distinction, controls, and independent_replication are not applicable.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous: individually randomised, double-blind, placebo-controlled, with adequate sample size, pre-specified inclusion/exclusion criteria, and a clear primary analysis population.

Evidence

“Balanced randomisation was done using computer-generated permuted block randomisation stratified by site and HIV status (women diagnosed with HIV before enrolment as documented in their existing health records [ie, known positive] vs newly diagnosed).”

MethodsFind in source

“All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“The study was designed to achieve 80% power to detect a 50% reduction in the cumulative incidence of Plasmodium infection from 12% in the co-trimoxazole plus placebo group to 6% in the co-trimoxazole plus dihydroartemisinin-piperaquine group (risk ratio [RR] 0·50, two-sided α=0·05), which required 898 participants (449 per group), allowing for 20% loss to follow-up.”

PASSReviewer 2· 95% conf

The trial design is rigorous: individually randomised, double-blind, placebo-controlled, with computer-generated block randomisation, stratification, masking, a pre-specified power calculation, and clear inclusion/exclusion criteria.

Evidence

“Balanced randomisation was done using computer-generated permuted block randomisation stratified by site and HIV status”

MethodsFind in source

“All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“The study was designed to achieve 80% power to detect a 50% reduction in the cumulative incidence of Plasmodium infection from 12% in the co-trimoxazole plus placebo group to 6% in the co-trimoxazole plus dihydroartemisinin-piperaquine group (risk ratio [RR] 0.50, two-sided α=0.05), which required 898 participants (449 per group), allowing for 20% loss to follow-up.”

Sex is reported (all pregnant women). Age, weight, height, BMI, and health status (HIV status, viral load) are reported. Demographics include residence, marital status, education, and socioeconomic status. Since both sexes are not applicable (all female), sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables relevant to a human trial are well reported: sex (all female), age, weight, health status, and demographics are provided in baseline tables.

Evidence

paraphrase[Methods, Study design and participants]

“Eligible women were those living with HIV, eligible for (or on) daily cART consisting of tenofovir, lamivudine, and dolutegravir, had ultrasound-confirmed viable singleton pregnancies between 16 weeks' and 28 weeks' gestation”

paraphrase[Table 1]

“Maternal age (years) | 29·2 (5·6) | 29·2 (5·7) | | Weight (kg) | 63 (10·8) | 62 (10·1)”

paraphrase[Table 1]

“Residence | Rural | 330/448 (74%) | 338/456 (74%) | | Semi-urban or urban | 118/448 (26%) | 118/456 (26%)”

PASSReviewer 2· 90% conf

Biological variables are well reported: sex (all female), age, weight, height, and other maternal characteristics are provided in Table 1. Demographics are comprehensive.

Evidence

paraphrase[Table 1]

“Maternal age (years) | 29.2 (5.6) | 29.2 (5.7)”

paraphrase[Table 1]

“Residence | Rural | 330/448 (74%) | 338/456 (74%)”

The paper names the ethics committees (KEMRI, College of Medicine in Malawi, Liverpool School of Tropical Medicine) and states they approved the study. The CDC approved via reliance agreement. Informed consent is described as written. Regulatory compliance is implied by adherence to ethical standards, though not explicitly named (e.g., Declaration of Helsinki), but the named approvals are sufficient.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly documented: named ethics committees approved the study, and written informed consent was obtained from all participants.

Evidence

“Ethics committees of the Kenya Medical Research Institute (KEMRI), the College of Medicine in Malawi, and the Liverpool School of Tropical Medicine approved the study.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

paraphrase[Methods, Study design and participants]

“The study was approved by multiple ethics committees, indicating compliance with ethical regulations.”

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented: named ethics committees approved the study, and written informed consent was obtained from all participants.

Evidence

“Ethics committees of the Kenya Medical Research Institute (KEMRI), the College of Medicine in Malawi, and the Liverpool School of Tropical Medicine approved the study.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

As a drug trial, the key resources are the investigational products. Co-trimoxazole is identified as Sulfran-DS (Universal Corporation, Nairobi, Kenya) with dose. Dihydroartemisinin-piperaquine is identified as D-Artepp (Fosun Pharma, Shanghai, China) with dose. Placebo was provided by Fosun Pharma. Statistical software (Stata version 17) is identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (co-trimoxazole and dihydroartemisinin-piperaquine) are identified with manufacturer and dose, and statistical software is named.

Evidence

paraphrase[Methods, Procedures]

“Daily co-trimoxazole consisted of one double-strength tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim (Sulfran-DS, Universal Corporation, Nairobi, Kenya). Each monthly dihydroartemisinin-piperaquine course consisted of a fixed dose of three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine (D-Artepp, Fosun Pharma, Shanghai, China) given daily for 3 days until delivery.”

“Statistical analyses were done with Stata version 17.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational products (co-trimoxazole and dihydroartemisinin-piperaquine) are named with manufacturers, and statistical software is identified.

Evidence

paraphrase[Methods, Procedures]

“Statistical analyses were done with Stata version 17.”

Statistical analysisFind in source

Tests are named (log-binomial, Poisson, linear regression). Assumptions are handled by design (e.g., modified Poisson for non-convergence). Exact p-values are reported (e.g., p=0·0001). Effect sizes with 95% CIs are reported throughout. Software is identified. Data presentation includes per-group n and appropriate figures. Mathematical plausibility checks were performed on key percentages and found consistent.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well described, with exact p-values and effect sizes with confidence intervals reported; no arithmetic inconsistencies were found.

Evidence

paraphrase[Methods, Statistical analysis]

“Log-binomial regression was used for dichotomous endpoints to obtain RRs and corresponding 95% CIs and modified Poisson regression in case of non-convergence.”

paraphrase[Results, paragraph 3]

“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).”

paraphrase[Results, paragraph 3]

“The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the cotrimoxazole 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).”

PASSReviewer 2· 90% conf

Statistical analysis is rigorous: tests are named, effect sizes with confidence intervals are reported, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

paraphrase[Methods, Statistical analysis]

“Log-binomial regression was used for dichotomous endpoints to obtain RRs and corresponding 95% CIs and modified Poisson regression in case of non-convergence.”

paraphrase[Results, paragraph 3]

“risk ratio 0.45, 95% CI 0.30-0.67; p=0.0001”

paraphrase[Results, paragraph 3]

“incidence rate ratio 0.32, 95% CI 0.22-0.47, p<0.0001”

The data availability statement specifies that individual participant data will be available from the WWARN repository approximately 3 months after publication. This is a concrete access route. Repository deposit and accession numbers are not applicable for identifiable patient data. Code sharing is not applicable as no bespoke code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A data availability statement is present, naming a concrete repository (WWARN) with a timeframe, which is adequate for individual patient data.

Evidence

“Individual participant data will be available from the Worldwide Antimalarial Resistance Network (WWARN) repository approximately 3 months after publication.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately addressed: individual participant data will be available from the WWARN repository, a concrete managed-access route.

Evidence

“Individual participant data will be available from the Worldwide Antimalarial Resistance Network (WWARN) repository approximately 3 months after publication.”

Data availabilityFind in source

Trial registration number (NCT04158713) is provided. Methods are comprehensive. Limitations are explicitly discussed (e.g., not powered for birth outcomes, potential social desirability bias, multiple secondary endpoints). Conclusions are appropriately cautious, noting the need for larger studies for birth outcomes. Funding and COI statements are present.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is transparent: trial registration is provided, methods are detailed, limitations are discussed, and conclusions are proportional to the evidence.

Evidence

“This trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT04158713 (https://clinicaltrials.gov/ct2/show/NCT04158713) .”

Statistical analysisFind in source

“A limitation is that this study was done in sites with high-grade antifolate resistance but where the prevalence of parasites with the highly resistant sextuple pfdhfr/pfdhps haplotype containing the pfdhps Ala581Gly mutation is still fairly uncommon (11% in western Kenya and 8% in southern Malawi), limiting our ability to assess potential effect modification by antifolate resistance level.”

Discussion ¶8Find in source

paraphrase[Discussion, final paragraph]

“Addition of monthly treatment courses with dihydroartemisinin-piperaquine to daily co-trimoxazole should be considered for the chemoprevention of malaria in pregnancy in women living with HIV on dolutegravir-based antiretroviral drugs.”

PASSReviewer 2· 95% conf

Reporting is transparent: trial is registered, methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are declared.

Evidence

“This trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT04158713”

Statistical analysisFind in source

Discussion ¶8Find in source

paraphrase[Funding and Declaration of interests]

“This study received financial support from the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme under Horizon 2020; ... We declare no competing interests.”

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 33 references by DOI: 1 verified — 32 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

1 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 1 minor suggestion below.

1 copyedit issue flagged: mostly typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and methodologically sound. An informed reader should weigh the minor reporting gaps (missing explicit CONSORT and Declaration of Helsinki statements) and the typo in Table 3 footnote, but none of these undermine the validity of the findings. No erratum is warranted for the typo, though the authors may consider a correction for completeness.

1.
MEDIUMreporting
Add an explicit statement in the Methods (or Acknowledgements) that the trial was reported in accordance with the CONSORT guideline.
Both reviewers noted the reporting guideline is not explicitly mentioned; adding this strengthens transparency and aligns with journal expectations.
2.
MEDIUMethics
Add a sentence in the Methods stating that the study was conducted in accordance with the Declaration of Helsinki.
Reviewer 2 flagged regulatory_compliance as inadequate because the ethical framework is not explicitly named; this is a simple fix.
3.
MEDIUMcopyedit
Correct the typo in Table 3 footnote: change 'n=4l6' to 'n=416'.
The copyedit pass identified this typographical error; it should be fixed to avoid confusion.
4.
LOWdata code
Consider adding a link to the statistical analysis plan or protocol in the data sharing section.
Reviewer 2 suggested this to enhance transparency and reproducibility.
5.
LOWreporting
Consider reporting exact p-values for all secondary endpoints in the text, as some are only reported as thresholds in tables.
Reviewer 1 noted that some secondary endpoints only report p<0.0001; providing exact values would improve precision.
6.
LOWdata code
Clarify the data access procedure for the WWARN repository, including any conditions for access.
Reviewer 1 suggested this to fully meet the data availability criterion.

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Read alongside

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.

Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO

Read full text (PMC)

DOI

10.1016/S0140-6736(23)02631-4

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Record fingerprint

888c6f374bf9a91f541650f0b6de842aa6d30fc47f6bb08e08294d0f5268ca63

Verify via API

Issued Aug 16, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

4 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 46 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is the incidence of Plasmodium infection detected by PCR, microscopy, RDT, or placental histology, which is a surrogate for clinical benefit. The paper does not demonstrate target engagement at the tested dose (no PK/PD data linking the dose to protective piperaquine concentrations in this population) and does not cite validated evidence linking the surrogate to clinical outcomes such as reduced adverse pregnancy outcomes. In fact, the trial found no significant difference in adverse pregnancy outcomes, and the authors acknowledge the study was not powered for these outcomes.
“The primary endpoint was the incidence of at least one 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…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a reduction in malaria infection incidence (RR 0.45, IRR 0.32), but this is a surrogate outcome. The effect size is not anchored to a clinically meaningful threshold for the surrogate, and the trial found no significant improvement in hard clinical outcomes (adverse pregnancy outcomes, maternal anaemia). The authors state the study was not powered for these outcomes, so the clinical meaningfulness of the surrogate reduction is not established.
“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,…”
Find in source

Findings by category

01ArithmeticNone found 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit1 minor suggestion

Numerical inconsistencies

None found

Checked — nothing surfaced.

Recomputed 16 tests: 16 consistent, 0 inconsistent; 6 recomputed directly from the reported test statistics, 10 via agent-written checks.

Overstated conclusions

2 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

6 major claims checked against the paper's own evidence: all adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study clearly establishes the scientific premise, citing prior research on the threat of antifolate resistance and the need for alternative IPTp, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraphs 2-4]

paraphrase[Introduction, final paragraph]

paraphrase[Introduction, paragraphs 3-4]

PASSReviewer 2· 95% conf

The study clearly establishes the scientific premise, citing prior research on the threat of antifolate resistance and the need for alternative IPTp, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraphs 2-4]

paraphrase[Introduction, final paragraph]

paraphrase[Introduction, paragraph 4]

“Unlike efavirenz, no clinically relevant drug-drug interactions have been seen between dihydroartemisinin-piperaquine and dolutegravir in pregnancy.”

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

MethodsFind in source

“All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

PASSReviewer 2· 95% conf

Evidence

“Balanced randomisation was done using computer-generated permuted block randomisation stratified by site and HIV status”

MethodsFind in source

“All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“The study was designed to achieve 80% power to detect a 50% reduction in the cumulative incidence of Plasmodium infection from 12% in the co-trimoxazole plus placebo group to 6% in the co-trimoxazole plus dihydroartemisinin-piperaquine group (risk ratio [RR] 0.50, two-sided α=0.05), which required 898 participants (449 per group), allowing for 20% loss to follow-up.”

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables relevant to a human trial are well reported: sex (all female), age, weight, health status, and demographics are provided in baseline tables.

Evidence

paraphrase[Methods, Study design and participants]

paraphrase[Table 1]

“Maternal age (years) | 29·2 (5·6) | 29·2 (5·7) | | Weight (kg) | 63 (10·8) | 62 (10·1)”

paraphrase[Table 1]

“Residence | Rural | 330/448 (74%) | 338/456 (74%) | | Semi-urban or urban | 118/448 (26%) | 118/456 (26%)”

PASSReviewer 2· 90% conf

Biological variables are well reported: sex (all female), age, weight, height, and other maternal characteristics are provided in Table 1. Demographics are comprehensive.

Evidence

paraphrase[Table 1]

“Maternal age (years) | 29.2 (5.6) | 29.2 (5.7)”

paraphrase[Table 1]

“Residence | Rural | 330/448 (74%) | 338/456 (74%)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly documented: named ethics committees approved the study, and written informed consent was obtained from all participants.

Evidence

“Ethics committees of the Kenya Medical Research Institute (KEMRI), the College of Medicine in Malawi, and the Liverpool School of Tropical Medicine approved the study.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

paraphrase[Methods, Study design and participants]

“The study was approved by multiple ethics committees, indicating compliance with ethical regulations.”

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented: named ethics committees approved the study, and written informed consent was obtained from all participants.

Evidence

“Ethics committees of the Kenya Medical Research Institute (KEMRI), the College of Medicine in Malawi, and the Liverpool School of Tropical Medicine approved the study.”

MethodsFind in source

“All participants provided written informed consent.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (co-trimoxazole and dihydroartemisinin-piperaquine) are identified with manufacturer and dose, and statistical software is named.

Evidence

paraphrase[Methods, Procedures]

“Statistical analyses were done with Stata version 17.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Key resources are adequately identified: the investigational products (co-trimoxazole and dihydroartemisinin-piperaquine) are named with manufacturers, and statistical software is identified.

Evidence

paraphrase[Methods, Procedures]

“Statistical analyses were done with Stata version 17.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well described, with exact p-values and effect sizes with confidence intervals reported; no arithmetic inconsistencies were found.

Evidence

paraphrase[Methods, Statistical analysis]

“Log-binomial regression was used for dichotomous endpoints to obtain RRs and corresponding 95% CIs and modified Poisson regression in case of non-convergence.”

paraphrase[Results, paragraph 3]

PASSReviewer 2· 90% conf

Statistical analysis is rigorous: tests are named, effect sizes with confidence intervals are reported, software is identified, and data presentation is appropriate for a clinical trial.

Evidence

paraphrase[Methods, Statistical analysis]

“Log-binomial regression was used for dichotomous endpoints to obtain RRs and corresponding 95% CIs and modified Poisson regression in case of non-convergence.”

paraphrase[Results, paragraph 3]

“risk ratio 0.45, 95% CI 0.30-0.67; p=0.0001”

paraphrase[Results, paragraph 3]

“incidence rate ratio 0.32, 95% CI 0.22-0.47, p<0.0001”

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A data availability statement is present, naming a concrete repository (WWARN) with a timeframe, which is adequate for individual patient data.

Evidence

“Individual participant data will be available from the Worldwide Antimalarial Resistance Network (WWARN) repository approximately 3 months after publication.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately addressed: individual participant data will be available from the WWARN repository, a concrete managed-access route.

Evidence

“Individual participant data will be available from the Worldwide Antimalarial Resistance Network (WWARN) repository approximately 3 months after publication.”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is transparent: trial registration is provided, methods are detailed, limitations are discussed, and conclusions are proportional to the evidence.

Evidence

“This trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT04158713 (https://clinicaltrials.gov/ct2/show/NCT04158713) .”

Statistical analysisFind in source

Discussion ¶8Find in source

paraphrase[Discussion, final paragraph]

PASSReviewer 2· 95% conf

Reporting is transparent: trial is registered, methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are declared.

Evidence

“This trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT04158713”

Statistical analysisFind in source

Discussion ¶8Find in source

paraphrase[Funding and Declaration of interests]

“This study received financial support from the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme under Horizon 2020; ... We declare no competing interests.”

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 33 references by DOI: 1 verified — 32 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

1 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 1 minor suggestion below.

1 copyedit issue flagged: mostly typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMreporting
Add an explicit statement in the Methods (or Acknowledgements) that the trial was reported in accordance with the CONSORT guideline.
Both reviewers noted the reporting guideline is not explicitly mentioned; adding this strengthens transparency and aligns with journal expectations.
2.
MEDIUMethics
Add a sentence in the Methods stating that the study was conducted in accordance with the Declaration of Helsinki.
Reviewer 2 flagged regulatory_compliance as inadequate because the ethical framework is not explicitly named; this is a simple fix.
3.
MEDIUMcopyedit
Correct the typo in Table 3 footnote: change 'n=4l6' to 'n=416'.
The copyedit pass identified this typographical error; it should be fixed to avoid confusion.
4.
LOWdata code
Consider adding a link to the statistical analysis plan or protocol in the data sharing section.
Reviewer 2 suggested this to enhance transparency and reproducibility.
5.
LOWreporting
Consider reporting exact p-values for all secondary endpoints in the text, as some are only reported as thresholds in tables.
Reviewer 1 noted that some secondary endpoints only report p<0.0001; providing exact values would improve precision.
6.
LOWdata code
Clarify the data access procedure for the WWARN repository, including any conditions for access.
Reviewer 1 suggested this to fully meet the data availability criterion.

Full text (71,316 chars)Analyzed: Aug 16, 2026