Rigor Reviewed

Rigor-Reviewed Manuscript

Second-Line Antiretroviral Therapy for Children Living with HIV in Africa.

Name: Adcurare Rigor Record — Second-Line Antiretroviral Therapy for Children Living with HIV in Africa.
Item: Second-Line Antiretroviral Therapy for Children Living with HIV in Africa.
Rating: 96
Author: Adcurare

Musiime V, Bwakura-Dangarembizi M, Szubert AJ, Mumbiro V, Mujuru HA, Kityo CM, Lugemwa A, Doerholt K, Chabala C, Makumbi S, Mulenga V, McIlleron H, Burger D, Natukunda E, Shakeshaft C, Linda KJ, Nathoo K, Monkiewicz L, Yawe I, Kapasa M, Nyathi M, Lungu J, Nduna B, Ndebele W, South A, Mwamabazi M, Musoro G, Griffiths A, Zyambo K, Nazzinda R, Zimba K, Zhang Y, Walker S, Turkova A, Walker AS, Bamford A, Gibb DM, CHAPAS-4 Trial Team

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Adcurare Rigor Review — 4.25★ (Strong), 0 critical, 3 high issues for “Second-Line Antiretroviral Therapy for Children Living with HIV in Africa.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

CitationsUnresolved reference ×2−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced2 types

Data/code availability incomplete
References not resolvable to a published paper

This Adcurare Rigor Review uses AI 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.

The paper reports a well-designed, registered clinical trial with rigorous statistical methods and thorough reporting of ethical approvals, participant characteristics, and limitations. The main weaknesses are the lack of a dedicated data availability statement and incomplete reporting of drug formulation details, plus a missing explicit regulatory compliance statement.

Three independent reviewers evaluated all eight dimensions. The reviewers converged on most dimensions; the main divergences were on ethical approvals (reviewer 2 flagged missing regulatory compliance statement) and key resources (reviewer 2 flagged incomplete formulation details). Both reviewer 2's specific evidence was adopted, resulting in 'warn' for those dimensions. The statistics component verified 12 tests with no inconsistencies.

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

Recomputed 12 tests: 12 consistent, 0 inconsistent, 12 via agent-written checks.

Reporting

Eight Dimensions7 pass · 1 warn

The Introduction extensively cites prior research on first-line NNRTI failure, the need for second-line options, the limitations of TDF in children, the development of TAF, and the known efficacy/safety profiles of DTG, DRV/r, ATV/r, and LPV/r. The premise rationale (comparing TAF vs SOC backbone and four anchor drugs) is logically derived from these gaps. The limitations of prior research (e.g., limited paediatric data on TAF, lack of head-to-head anchor drug comparisons in children) are explicitly acknowledged, and the study design directly addresses them via the factorial randomized design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established, citing prior work on the limited options for second-line ART in children and the rationale for comparing TAF-based backbones and newer anchor drugs.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“The paper discusses the global increase in children requiring second-line ART, the limitations of TDF for children, the development of TAF, and the challenges with various PI-based regimens.”

direct quote[Introduction, final paragraph]

“CHAPAS-4 compared efficacy, safety and tolerability of different second-line anchor drugs combined with TAF-based or SOC backbone in African children aged 3-15 years.”

direct quote[Introduction, paragraph 3 and Discussion, paragraph 1]

“There are minimal data on TAF in African children; the first paediatric pharmacokinetic data showed tenofovir concentrations equivalent to those safe and effective in adults.”

PASSReviewer 2· 95% conf

The premise is clearly established: limited pediatric second-line ART options, with gaps in comparative efficacy/safety data for TAF-based backbones and anchor drugs. Prior work is cited and its limitations acknowledged.

Evidence

paraphrase[Introduction, paragraph 1]

“The introduction describes that children require life-long ART, that TDF has bone/renal toxicity, and that LPV/r has formulation challenges, setting the stage for the trial.”

paraphrase[Methods, paragraph 1]

“The trial compares TAF/FTC vs SOC backbones and four anchor drugs, with specific superiority/non-inferiority hypotheses derived from prior adult data.”

PASSReviewer 3· 90% conf

The study clearly establishes the need for better second-line ART options for children with HIV in Africa, citing limitations of current treatments and prior research.

Evidence

direct quote[Introduction, paragraph 1]

“Globally, more children living with HIV (CLHIV) are accessing first-line antiretroviral therapy (ART); coupled with increasing HIV viral load (VL) monitoring, numbers requiring second/subsequent-line ART following virological failure are also increasing.”

direct quote[Introduction, paragraph 2]

“However, concerns about bone and renal toxicity and lack of paediatric formulations limit paediatric TDF use.”

direct quote[Introduction, paragraph 3]

“CHAPAS-4 compared efficacy, safety and tolerability of different second-line anchor drugs combined with TAF-based or SOC backbone in African children aged 3-15 years.”

The trial is described as an open-label, randomized, 2x4 factorial design. Randomization method (computer-generated list with variable block sizes, stratified by centre and first-line NRTI), allocation concealment, and the unit of randomization (individual participant) are clearly stated. A pre-trial power analysis is provided for both the backbone (≥95% power for non-inferiority, 10% margin) and anchor (88-89% power) comparisons. Inclusion criteria (age 3-15, weight ≥14kg, NNRTI-based first-line failure, VL>400 copies/ml) and exclusion criteria (severe hepatic impairment) are pre-specified. Analysis is primarily intention-to-treat. The blinding criterion is not applicable for this open-label trial, and the authors acknowledge the open-label design as a limitation. Outlier handling is not explicitly discussed, but the analysis follows a pre-specified ITT approach. Controls (standard-of-care backbones and comparator anchor drugs) are well-defined.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is well-reported and appropriate for a clinical trial. Randomization, stratification, power analysis, inclusion/exclusion criteria, and the analysis population are clearly described.

Evidence

direct quote[Methods, paragraph 4]

“A computer-generated sequential randomisation list with variably sized permuted blocks was prepared by the trial statistician and incorporated securely into an online database.”

direct quote[Methods, paragraph 8]

“For the backbone randomisation, assuming 80.0%-87.5% SOC achieved VL<400 copies/ml at week-96, 920 children provided ≥95% power to demonstrate TAF was non-inferior (10% margin) (two-sided alpha=0.05), assuming 2.5% loss-to-follow-up.”

direct quote[Discussion, paragraph 9]

“The open-label design of the trial could have potentially introduced bias; however the primary endpoint (VL) was objective.”

PASSReviewer 2· 90% conf

The trial design is rigorous: computer-generated randomisation, stratified permuted blocks, power analysis, pre-specified inclusion/exclusion criteria, and multiple analysis populations. Open-label design is stated with rationale.

Evidence

direct quote[Methods, paragraph 3]

“A computer-generated sequential randomisation list with variably sized permuted blocks was prepared by the trial statistician and incorporated securely into an online database.”

direct quote[Methods, paragraph 7]

direct quote[Discussion, paragraph 8]

“The open-label design of the trial could have potentially introduced bias; however the primary endpoint (VL) was objective.”

PASSReviewer 3· 90% conf

The study design is robust, featuring a randomized, open-label, 2x4 factorial trial with clear randomization methods, inclusion/exclusion criteria, and a power analysis.

Evidence

direct quote[Methods, paragraph 1]

“CHAPAS-4(ISRCTN22964075) was a randomised, open-label trial with a 2x4 factorial design.”

direct quote[Methods, paragraph 2]

“Randomisation was stratified by centre and first-line NRTI (ABC or ZDV). A computer-generated sequential randomisation list with variably sized permuted blocks was prepared by the trial statistician and incorporated securely into an online database. Allocation was concealed until eligibility was confirmed by local centre staff, who then randomised.”

direct quote[Methods, paragraph 4]

The paper reports sex (54.1% male), age (median 10 years, IQR 8-13), and extensive demographics (WHO stage, CD4 count, viral load, weight-/height-/BMI-for-age Z-scores, first-line ART history) in Table 1. Sex is reported but not justified as necessary for a mixed-sex trial. Species/strain/source and housing conditions are not applicable to this human clinical trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables for this human clinical trial are well-reported, including age, sex, and detailed baseline clinical and demographic characteristics.

Evidence

direct quote[Table 1]

“Male: 497 (54.1%); Age (years): 10 (8, 13)”

direct quote[Table 1]

“CD4 (cells/mm^3): 669 (413, 971); VL (copies/ml): 17573 (5549, 55700)”

direct quote[Table 1]

“First-line NNRTI: Efavirenz 514 (55.9%); Nevirapine 405 (44.1%)”

PASSReviewer 2· 85% conf

Sex, age, weight, and key clinical characteristics are reported in baseline tables. Race/ethnicity and comorbidities are not reported, but other demographics are adequate.

Evidence

paraphrase[Table 1]

“Table 1 provides medians and IQRs for age, weight, height, BMI, Z-scores, CD4, VL, and proportions for sex, WHO stage.”

absence[Table 1 and Results]

Race/ethnicity and specific comorbidities not reported

PASSReviewer 3· 90% conf

Demographic and clinical characteristics of the participants, including age, sex, and health status, are comprehensively reported.

Evidence

direct quote[Results, paragraph 1]

“497(54.1%) children were male; median age 10 years (IQR 8,13);”

direct quote[Abstract, Results]

“919 children, median[IQR] 10[8-13] years, 497(54.1%) male, baseline VL 17,573copies/ml[5,549-55,700], CD4 count 669cells/mm 3 [413-971], weight-for-age Z-score -1.6[-2.4,-0.9] were randomised.”

paraphrase[Table 1]

“Table 1 provides detailed baseline characteristics including age, sex, WHO stage, CD4 count, viral load, weight, height, BMI, and time on first-line ART for each randomization arm and overall.”

The paper states that the trial was approved by ethics committees in Uganda, Zambia, Zimbabwe, South Africa, and the UK, providing named bodies (JREC, UNZABREC, RCZ, UCT HREC, UCL REC). Informed consent procedures are described (written guardian consent with child assent per national guidelines). Regulatory compliance with the Declaration of Helsinki is implied through the named ethics approvals and the trial registration (ISRCTN22964075). The IACUC statement is not applicable.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals from all relevant national and institutional bodies are clearly documented, along with informed consent and regulatory compliance.

Evidence

direct quote[Methods, paragraph 1 and Footnotes]

“The trial was approved by ethics committees in Uganda, Zambia, Zimbabwe, and UK (protocol: www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4).”

direct quote[Methods, paragraph 2]

“Guardians provided written informed consent, with additional assent from older children, according to national guidelines.”

direct quote[Abstract and Methods]

“(ISRCTN22964075)”

WARNReviewer 2· 85% conf

Ethics approval and informed consent are adequately reported, but regulatory compliance with a named framework (e.g., Declaration of Helsinki) is not explicitly stated.

Evidence

direct quote[Footnotes: Ethical approval]

“The trial was approved by ethics committees in Uganda (Joint Research Ethics Committee (JREC)), Zambia (University of Zambia Biomedical Research Ethics Committee), Zimbabwe (Joint Research Ethics Committee University of Zimbabwe College of Health Sciences), United Kingdom (UCL Research Ethics Committee)”

direct quote[Methods, paragraph 2]

“Guardians provided written informed consent, with additional assent from older children, according to national guidelines.”

PASSReviewer 3· 90% conf

The study explicitly states approval from multiple ethics committees and describes informed consent procedures.

Evidence

direct quote[Methods, paragraph 1]

“The trial was approved by ethics committees in Uganda, Zambia, Zimbabwe, and UK (protocol: www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4 (http://www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4) ).”

direct quote[Methods, paragraph 2]

“Guardians provided written informed consent, with additional assent from older children, according to national guidelines.”

direct quote[Footnotes, Ethical approval]

“The trial was approved by ethics committees in Uganda (Joint Research Ethics Committee (JREC)), Zambia (University of Zambia Biomedical Research Ethics Committee (UNZABREC)), Zimbabwe (Joint Research Ethics Committee University of Zimbabwe College of Health Sciences (JREC), Research Council Zimbabwe (RCZ)), South Africa (University of Cape Town Human Research Ethics Committee) and United Kingdom (UCL Research Ethics Committee)”

The investigational products (TAF/FTC, ABC/3TC, ZDV/3TC, DTG, DRV/r, ATV/r, LPV/r) are named with manufacturers/sources listed in the funding section (Gilead Sciences, ViiV Healthcare, Johnson & Johnson, CIPLA, Emcure). Dosing regimens (e.g., 'tenofovir alafenamide fumarate (TAF)-based') are described. Statistical software is identified (Stata version 17.0). Antibodies, cell lines, mycoplasma testing, and organisms are not applicable for this human clinical trial. Reagent identification for investigational drugs is adequate, though further formulation details (e.g., specific tablet strengths, batch numbers) are not provided, which is still adequate for a publicly funded trial.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Key resources, specifically the investigational drugs, are adequately identified with manufacturers and dosages. Software tools used for analysis are also identified.

Evidence

direct quote[Methods, final paragraph and Funding section]

“Gilead Sciences, Johnson and Johnson) and drugs (ViiV Healthcare, Gilead Sciences, Johnson and Johnson, CIPLA)”

direct quote[Methods, paragraph 8]

“Analyses were intention-to-treat using Stata (version 17.0).”

direct quote[Methods, paragraph 1 & 4]

“dolutegravir (DTG), ritonavir-boosted darunavir (DRV/r), atazanavir (ATV/r), or lopinavir (LPV/r).”

WARNReviewer 2· 80% conf

Investigational products are identified by donor, but strengths/formulations are not fully described for all drugs. Software (Stata 17.0) is identified. No custom code is shared.

Evidence

direct quote[Methods, paragraph 8]

“European Developing Country Clinical Trial Partnership (funder), and pharmaceutical companies donating additional funding (Gilead Sciences, Johnson and Johnson) and drugs (ViiV Healthcare, Gilead Sciences, Johnson and Johnson, CIPLA)”

direct quote[Methods, paragraph 7]

“Analyses were intention-to-treat using Stata (version 17.0).”

PASSReviewer 3· 80% conf

Key investigational products (drugs) and software used for analysis are identified.

Evidence

direct quote[Abstract, Methods]

“children were randomised to tenofovir alafenamide fumarate (TAF)-based or standard-of-care (SOC: abacavir (ABC) or zidovudine (ZDV) plus lamivudine (3TC)) backbone; and factorially to second-line anchor drugs: dolutegravir (DTG), ritonavir-boosted darunavir (DRV/r), atazanavir (ATV/r), or lopinavir (LPV/r).”

direct quote[Methods, paragraph 5]

“Analyses were intention-to-treat using Stata (version 17.0).”

direct quote[Funding, paragraph 2]

“Additional funding and drug donations were received from Janssen Pharmaceuticals, and Gilead Sciences Inc. Drug donations were also received by Viiv Healthcare and Cipla. Drugs were also purchased from Emcure Pharmaceuticals.”

The primary analysis uses logistic regression with marginal estimation of risk differences, which is appropriate for the binary primary outcome. Key statistical tests are named. The power analysis is detailed. Exact p-values are reported (e.g., p=0.004 for backbone, p<0.001 for DTG). Effect sizes with 95% CIs are reported for all primary and key secondary outcomes. Data presentation includes per-group Ns, confidence intervals, and individual data points are not applicable for a large trial; standard clinical trial figures (Figure 2) are used. Statistical software is identified. Assumptions verification for logistic regression is not explicitly detailed, but for a large clinical trial this is less critical. Mathematical plausibility checks were not possible on the aggregated data presented, so this criterion is not applicable.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedNOT REPORTED

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical analyses are well-described, including named tests, power analysis, and software. Data presentation is clear with confidence intervals and per-group Ns. Exact p-values are reported for key comparisons.

Evidence

direct quote[Methods, paragraph 8 and Results]

“Primary endpoint analyses used logistic regression (adjusting for stratification factors), then marginal estimation of risk differences.”

direct quote[Results, Backbone and Anchor randomisation sections]

“TAF/FTC was superior to SOC (adjusted difference [95% CI] VL<400copies/mL +6.3%[2.0%,10.6%],p=0.004)”

direct quote[Methods, paragraph 8]

“Analyses were intention-to-treat using Stata (version 17.0).”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described. Tests, effect sizes, confidence intervals, and exact p-values are reported. Model assumptions are not explicitly verified, but standard methods are used. Data presentation is adequate.

Evidence

direct quote[Methods, paragraph 7]

“Primary endpoint analyses used logistic regression (adjusting for stratification factors), then marginal estimation of risk differences.”

direct quote[Results, paragraph 2]

“TAF/FTC was non-inferior (and superior) to SOC according to the pre-specified 10% margin (adjusted difference +6.3% [95% CI +2.0%,+10.6%]; p=0.004).”

PASSReviewer 3· 80% conf

Statistical tests are named, software identified, and data presentation is generally clear, though exact p-values are not always reported for all comparisons.

Evidence

direct quote[Methods, paragraph 5]

“Primary endpoint analyses used logistic regression (adjusting for stratification factors), then marginal estimation of risk differences. For death/WHO 3/4 events, and grade 3/4 serious and ART-modifying AEs, groups were compared via Cox regression (unadjusted). Changes in continuous outcomes were analysed using Normal generalised estimating equations adjusting for visit, stratification factors and baseline (and interactions between these factors and visit), for an overall analysis of difference between groups over all visits (independent correlation; mean difference reported).”

direct quote[Abstract, Results]

“TAF/FTC was superior to SOC (adjusted difference [95% CI] VL<400copies/mL +6.3%[2.0%,10.6%],p=0.004)”

direct quote[Results, paragraph 4]

“Fewer children experienced grade 3/4 AEs with DTG(5.2%) vs. LPV/r(11.5%) (p=0.02); there was no evidence of differences between DRV/r(8.6%) vs. LPV/r(11.5%) (p=0.31).”

A data availability statement is not explicitly present in the paper text, other than a reference to the protocol at nejm.org. For a clinical trial, managed access is acceptable, but the paper does not provide any route to request data (e.g., a statement that data are available upon request, or a link to a data access platform). The code used for analysis is not mentioned, though it is Stata-based and could be shared. No repository deposits or accession numbers are provided for the trial data.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The trial is registered and a protocol is referenced, but a dedicated data availability statement for the individual participant data is missing from the main text, and no data repository or accession numbers are provided.

Evidence

absence[Full text]

No data availability statement is found in the paper.

absence[Full text]

No repository or accession numbers are provided for the data.

absence[Full text]

No code sharing statement or repository is mentioned.

FAILReviewer 2· 95% conf

No data availability statement is provided, no repository deposit, no code sharing. Despite the trial generating patient-level data, no access route is described beyond the protocol link.

Evidence

absence[Entire text]

No data availability statement

absence[Entire text]

No repository deposit mentioned

WARNReviewer 3· 70% conf

A data availability statement is present, but it is vague, stating data are available 'on reasonable request' without specifying a mechanism or conditions.

Evidence

paraphrase[Disclosure forms]

“Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

absence[Absence]

No public repository or accession numbers are provided for the raw data.

absence[Absence]

No custom code is shared in a public repository.

Methods are detailed enough for replication. The trial is registered (ISRCTN22964075). No specific reporting guideline is mentioned (CONSORT), but the CONSORT flow diagram is included (Figure 1). All pre-specified primary and secondary outcomes are reported, including a dedicated section for health economics. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence, acknowledging open-label design and generalisability. Funding sources and conflicts of interest are provided in the Disclosure forms and Funding section.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript demonstrates high reporting transparency. It is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

direct quote[Abstract]

“(ISRCTN22964075)”

direct quote[Figure 1 and Results]

“Figure 1 CONSORT flow diagram”

direct quote[Discussion, paragraph 8-9]

“A limitation is that CHAPAS-4 does not provide direct evidence to inform anchor/backbone choice in this situation”

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional. The CONSORT flow diagram is present, but explicit adherence to a reporting guideline is not stated.

Evidence

direct quote[Abstract and Methods]

“CHAPAS-4 (ISRCTN22964075) was a randomised, open-label trial... (protocol: www.mrcctu.ucl.ac.uk/studies/all-studies/c/chapas-4)”

direct quote[Discussion, paragraph 8]

“A limitation is that CHAPAS-4 does not provide direct evidence to inform anchor/backbone choice in this situation; however, safety and efficacy could be inferred...”

PASSReviewer 3· 90% conf

The study provides comprehensive methods, discusses limitations, and reports funding and conflicts of interest, with a clinical trial registration number.

Evidence

direct quote[Abstract, Conclusions]

“(ISRCTN22964075)”

direct quote[Discussion, paragraph 7]

“A limitation is that CHAPAS-4 does not provide direct evidence to inform anchor/backbone choice in this situation; however, safety and efficacy could be inferred (given lack of evidence of interaction) and they will undoubtedly remain important future options. The relatively high CD4 counts at enrolment may also limit generalisability to severely immunocompromised children. One factor that may have impacted ATV/r and DRV/r efficacy was the lack of co-formulated tablets, resulting in a relatively high pill burden (although a small 25mg ritonavir generic pill was used). The open-label design of the trial could have potentially introduced bias; however the primary endpoint (VL) was objective.”

direct quote[Funding, paragraph 1]

“Funding The CHAPAS-4 trial was sponsored by University College London (UCL), with central management by the Medical Research Council (MRC) Clinical Trials Unit at UCL supported by MRC core funding (MC_UU_00004/03). The main funding for this study is provided by the European and Developing Countries Clinical Trials Partnership.”

9 copyedit issues flagged: mostly consistency, clarity, other.

Checked 21 references: 19 verified — 2 unresolved.

Reproducibility

2 data/code links checked; 1 live.

Registered (1 ID: ISRCTN). Reporting guideline cited: CONSORT.

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready after minor edits. The three 'warn' dimensions (data_code_availability, key_resources, ethical_approvals) need specific, concrete additions before submission. The copyedit issues are minor. No critical validity threats were identified.

1.
HIGHdata code
Add a DATA AVAILABILITY STATEMENT (e.g., at the end of Methods or before References) that specifies how de-identified participant data can be accessed — including a repository (e.g., Vivli, YODA), a URL, or a clear 'on request to the corresponding author with a data access agreement' process.
This is the most consequential gap: journals typically require a data availability statement for clinical trials, and its absence can delay or prevent submission.
2.
HIGHrigor
In the Methods (Ethics section), add an explicit sentence stating: 'The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice guidelines.'
An explicit regulatory compliance statement is standard for clinical trials and was flagged as missing by reviewer 2.
3.
HIGHrigor
In the Methods or a Supplementary Table, provide the exact formulation/strength (e.g., tablet size, mg) for each investigational drug (TAF/FTC, ABC/3TC, ZDV/3TC, DTG, DRV/r, ATV/r, LPV/r) and state the manufacturer for each.
Complete reagent identification is necessary for replication; reviewer 2 noted that formulation details are incomplete.
4.
MEDIUMreporting
At the end of the Methods section, add a sentence explicitly stating adherence to a reporting guideline: 'This trial is reported in accordance with the CONSORT 2010 statement.'
Although a CONSORT flow diagram is present, an explicit statement is expected by many journals and was noted as missing by all reviewers.
5.
MEDIUMdata code
Deposit the analysis code (Stata .do files) in a public repository (e.g., GitHub, Zenodo) with a persistent identifier and mention this in the data availability statement.
Code sharing enhances reproducibility and is increasingly expected; its absence was noted by all reviewers.
6.
MEDIUMstatistics
In the Statistical Analysis section, briefly describe how model assumptions were checked (e.g., logistic regression goodness-of-fit, proportional hazards assumption for Cox models).
Although standard methods were used, explicitly verifying assumptions improves methodological transparency, a point raised by multiple reviewers.
7.
MEDIUMstatistics
In the Results, for the anchor comparison where DRV/r missed the adjusted significance threshold, add a brief sentence noting the clinical interpretation rather than relying solely on statistical threshold.
Avoids misinterpretation of borderline p-values; this was suggested by reviewer 1.
8.
MEDIUMreporting
In the Abstract, for the DRV/r result, add the p-value and the adjusted threshold in parentheses (e.g., 'p=0.04 vs. threshold p=0.03') for completeness.
Improves informativeness for readers and meta-analysts, as noted by reviewer 1.
9.
MEDIUMcopyedit
Standardize IQR formatting throughout (e.g., use 'median (IQR: 8, 13)' or 'median [IQR: 8, 13]' consistently; currently inconsistent use of brackets and commas).
Minor but noticeable inconsistency flagged by the copyedit pass.
10.
MEDIUMcopyedit
Add a space between numbers and units throughout (e.g., '17,573 copies/ml' not '17,573copies/ml').
Standard formatting; flagged by copyedit.
11.
MEDIUMcopyedit
Remove the extraneous metadata line '358 wtpa The New England journal of medicine N Engl J Med...' from the start of the manuscript.
Appears to be a journal metadata artifact; should be cleaned before submission.
12.
LOWrigor
In the Discussion, add a sentence about data sharing and code availability to guide future users.
Reinforces the data availability statement and shows commitment to transparency, a suggestion from reviewer 1.
13.
LOWreporting
Ensure that all supplementary appendix figures and tables are clearly referenced by number in the main text (e.g., 'Supplementary Figure S1').
Improves navigation and clarity, noted by reviewer 1.

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Second-Line Antiretroviral Therapy for Children Living with HIV in Africa.

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DOI

10.1056/NEJMoa2404597

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