Budigalimab, an anti-PD-1 inhibitor, for people living with HIV-1: a randomized, placebo-controlled phase 1b study.
Ramgopal MN, Lalezari JP, Pires Dos Santos AG, Krishnan P, Vaidya TR, Zhou F, Betman H, Dorr P, Mostafa NM, Alcaide ML, Felizarta F, Routy JP
- DOI
- 10.1038/s41591-025-03993-0
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/a9da7278-b492-4bfa-8487-6e94d8ffc4b1 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy claim is based on viral load kinetics (HIV-1 RNA levels) during analytical treatment interruption, which is a surrogate marker for clinical benefit. The paper does not establish a validated link between this surrogate and hard clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond receptor saturation, which is a pharmacodynamic marker but not a validated surrogate for clinical outcome.
“In an exploratory efficacy analysis of a 12-week ATI initiated with the first of four 10 mg Q2W doses, 6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI,…”
- 02Treatment effect not shown to be clinically meaningful
The reported effect is a small fraction of the reference population: 2 of 9 (22.2%) participants achieving extended viral control, which is numerically higher than historical controls (2.5-7.4%) but still a small proportion. The paper acknowledges the exploratory nature and lack of statistical power, and does not anchor the effect to a clinically meaningful threshold.
“The result of 2 of 9 (22.2%) participants with extended viral control observed here is numerically higher than results seen in other studies involving nonprimary infection post-treatment controllers, which have reported off-ART control (<50, <400 or <1,000…”
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 1b randomized controlled trial of budigalimab in people living with HIV-1. The manuscript demonstrates strong scientific premise, rigorous design, and comprehensive reporting across all eight rigor dimensions, with only minor copyedit-level inconsistencies and a few optional reporting enhancements.
This is an interventional study (randomized controlled trial). Both reviewers agreed on the study type. The evaluation covered all eight dimensions; several sub-criteria were marked not applicable due to the human clinical trial context (e.g., cell line authentication, housing conditions, IACUC). The statistics verification covered only 1 test (limited coverage), and the citation check found no integrity issues. The copyedit pass flagged minor consistency issues in the abstract and results.
Numerical inconsistencies
1 finding · worst lowValues 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.
- Internal contradictions in the reported numbersAssessed
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p = .060 · recomputed p = .060Reviewers 1, 2P-value for CXCR5+ CD8+ T cell expansion trend
“trends were observed in budigalimab-mediated expansion of peripheral CXCR5+ CD8+ T cells (P = 0.06)”
Taken as given: The reported p-value is from a two-tailed test.; The test statistic is approximately normal (z-score).Method: Approximated two-tailed p from a z-score of 1.88, which yields 0.06.How we recomputed it: pZ(1.88)
- lowinternal contradictionThe abstract states '6 of 11 participants experienced a delayed rebound...' while the results section mentions 'six of nine participants completing treatment with four 10 mg biweekly doses'.
6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI, with 2 sustaining ART-free viral control to study end (204−252 days).
Abstractreviewer’s wording
Overstated conclusions
3 findings · worst highConclusions 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
- Conclusions only partially backed by the presented evidenceAssessed
7 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The delayed viral kinetics observed with 10 mg dosing may be an outcome of drug action.The claim is cautiously worded and supported by the lack of effect in placebo and 2 mg groups, but the authors acknowledge it is exploratory and not conclusive.Evidence: Placebo group showed no viral control; 2 mg dosing resulted in incomplete receptor saturation and no delayed kinetics.
“This expected rapid viral rebound in the placebo group and a lack of any impact with the budigalimab 2 mg dosing, which resulted in incomplete PD-1 RS, suggest that the delayed viral load kinetics observed with 10 mg dosing may be an outcome of drug action.”
Discussion ¶5Find in source - supportedReviewers 1, 2Budigalimab was well tolerated in PLWH.The safety data presented support the claim of tolerability.Evidence: 29 of 41 participants experienced an AE, mostly grade 1-2; only two grade 1 IRAEs and no treatment-related grade 3+ AEs.
“Budigalimab was well tolerated for up to 44 weeks, with 29 of 41 participants experiencing an adverse event (AE), including 2 participants who each experienced one grade 1 reversible immune-related AE (thyroiditis, hyperthyroidism).”
AbstractFind in source - supportedReviewer 1Budigalimab 10 mg Q2W resulted in near-complete PD-1 receptor saturation for ~10 weeks.Pharmacokinetic and pharmacodynamic data support this claim.Evidence: Serum concentrations remained above the estimated threshold for >95% saturation for ~10 weeks; receptor saturation was observed for a median of 30 days in stage II.
IV budigalimab 10 mg Q2W resulted in a slight accumulation of drug in serum, with concentrations remaining above the estimated concentration required for near-complete (>95%) PD-1 receptor saturation on CD8+ T cells for ~10 weeks in peripheral blood.
Abstractreviewer’s wording - supportedReviewer 1Exploratory efficacy analysis showed delayed viral rebound and/or off-ART viral control in a subset of participants.The exploratory analysis supports this claim, though the authors appropriately note it is exploratory.Evidence: 6 of 11 participants in the 10 mg Q2W group experienced delayed rebound or control; 2 sustained ART-free control to study end.
In an exploratory efficacy analysis of a 12-week ATI initiated with the first of four 10 mg Q2W doses, 6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI, with 2 sustaining ART-free viral control to study end (204−252 days).
Abstractreviewer’s wording - supportedReviewers 1, 2The study achieved prespecified endpoints.The primary endpoints (safety, tolerability, PK) were met.Evidence: Safety and PK data are reported and consistent with expectations.
“The study achieved prespecified endpoints, supporting further evaluation of budigalimab in PLWH in a phase 2 study.”
AbstractFind in source - supportedReviewer 2Budigalimab 10 mg Q2W resulted in sustained PD-1 receptor saturation.Pharmacokinetic and pharmacodynamic data support this claim.Evidence: Serum concentrations remained above the estimated threshold for >95% saturation for ~10 weeks.
“IV budigalimab 10 mg Q2W resulted in a slight accumulation of drug in serum, with concentrations remaining above the estimated concentration required for near-complete (>95%) PD-1 receptor saturation on CD8 + T cells for ~10 weeks in peripheral blood.”
AbstractFind in source - supportedReviewer 2Budigalimab 10 mg Q2W led to delayed viral rebound and/or off-ART viral control in a subset of participants.Exploratory efficacy analysis supports this claim, though it is exploratory and not powered.Evidence: 6 of 11 participants experienced delayed rebound or off-ART control, with 2 sustaining control to study end.
“In an exploratory efficacy analysis of a 12-week ATI initiated with the first of four 10 mg Q2W doses, 6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml −1 ) for ≥6 weeks during ATI, with 2 sustaining ART-free viral control to study end (204−252 days).”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy claim is based on viral load kinetics (HIV-1 RNA levels) during analytical treatment interruption, which is a surrogate marker for clinical benefit. The paper does not establish a validated link between this surrogate and hard clinical outcomes, nor does it demonstrate target engagement at the tested dose beyond receptor saturation, which is a pharmacodynamic marker but not a validated surrogate for clinical outcome.
“In an exploratory efficacy analysis of a 12-week ATI initiated with the first of four 10 mg Q2W doses, 6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI, with 2 sustaining ART-free viral control to study end (204−252 days).”
- INADEQUATEEffect sizeThe reported effect is a small fraction of the reference population: 2 of 9 (22.2%) participants achieving extended viral control, which is numerically higher than historical controls (2.5-7.4%) but still a small proportion. The paper acknowledges the exploratory nature and lack of statistical power, and does not anchor the effect to a clinically meaningful threshold.
“The result of 2 of 9 (22.2%) participants with extended viral control observed here is numerically higher than results seen in other studies involving nonprimary infection post-treatment controllers, which have reported off-ART control (<50, <400 or <1,000 copies ml−1) among 2.5% to 7.4% of participants (N = 33 to >600) for >24 weeks.”
Data authenticity concerns
None foundAn 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 foundRequired 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.
The introduction cites extensive prior research on PD-1 in HIV and SIV models, and the rationale for using budigalimab is logically linked to the study objectives. Limitations of prior research are acknowledged, such as the need for lower doses to improve tolerability.
“The doses chosen for study in HIV treatment were derived from modeling using data from first-in-human studies of budigalimab and pharmacokinetic studies of another anti-PD-1 antibody with target-mediated drug disposition and were substantially lower and of shorter exposure duration than those used in oncology.”
“The current study reported a more favorable safety profile that might be expected with substantially lower doses (≤10 mg) over a finite period and a subsequently restricted period of PD-1 receptor saturation, in a different population, namely PLWH.”
“PD-1 blockade in non-human primates infected with simian immunodeficiency virus has resulted in multiple effects, including enhancement of HIV-specific CD8 + T cell proliferative potential in the blood and gut and increased polyfunctional capacity”
“PD-1 inhibitors, therefore, offer a potential approach to enable durable viral control without ART through a reversal of T cell exhaustion and restoration of T cell function.”
“The study population size was small, as is typical for a phase 1 study.”
Randomization method (computer-generated) and unit (participant) are stated. Blinding is described (double-blind, with unblinded pharmacist and sponsor). Inclusion/exclusion criteria are extensive and pre-specified. Power analysis is not applicable as this is a phase 1 study with no hypothesis testing. Outlier handling is addressed through pre-specified analysis populations and ART-restart criteria. Controls (placebo) are used. Independent replication is not applicable for a single phase 1 trial.
“Participants were assigned a computer-generated randomization number to encode treatment group assignments according to the randomization schedule generated by study statisticians and used by a designated, unblinded site pharmacist.”
“The site investigator and other study site personnel and the participants remained blinded throughout the study.”
“Participants were assigned a computer-generated randomization number to encode treatment group assignments according to the randomization schedule generated by study statisticians”
“The site investigator and other study site personnel and the participants remained blinded throughout the study.”
“No power calculations for sample size considerations have been performed for this study that employed descriptive and exploratory analyses and had no planned hypothesis testing.”
Sex is reported (predominantly male) and the imbalance is discussed with justification. Age, BMI, and health status (CD4 counts, viral load) are reported. Demographics include race and ethnicity. Species/strain and housing are not applicable for a human trial.
“Participant demographics and baseline characteristics were balanced across treatment groups with representation of eligibility criteria, except for sex, which was predominantly male.”
“Age, median (min, max), y | 44 (24, 57) | 38.5 (26, 60) | 49.5 (22, 65) | 46 (38,63) | 48 (29, 64)”
“Participant demographics and baseline characteristics were balanced across treatment groups with representation of eligibility criteria, except for sex, which was predominantly male.”
“Age, median (min, max), y | 44 (24, 57) | 38.5 (26, 60) | 49.5 (22, 65) | 46 (38,63) | 48 (29, 64)”
“the need for contraception and the burden from the number of visits required for intensive monitoring during the ATI period may have contributed to lower female enrollment.”
The study used a central IRB (Advarra) or local ethics committees, and written informed consent was obtained. Compliance with ICH guidelines and the Declaration of Helsinki is stated. The ethics statement is specific and adequate.
“Sites used a central institutional review board (Advarra) or local ethics committees to have the study protocol, informed consent, and participant information approved.”
“Written informed consent, including a full discussion of risks of budigalimab, risks of ATI and conditions for ART reinitiation, was obtained for each participant before screening or study-specific procedures.”
“The study was conducted in accordance with International Council for Harmonisation (ICH) guidelines, and applicable regulations, guidelines, and principles had their origin in the Declaration of Helsinki.”
“Sites used a central institutional review board (Advarra) or local ethics committees to have the study protocol, informed consent, and participant information approved.”
“Written informed consent, including a full discussion of risks of budigalimab, risks of ATI and conditions for ART reinitiation, was obtained for each participant before screening or study-specific procedures.”
“The study was conducted in accordance with International Council for Harmonisation (ICH) guidelines, and applicable regulations, guidelines, and principles had their origin in the Declaration of Helsinki.”
Budigalimab is identified as an investigational humanized anti-PD-1 monoclonal antibody, with dosing regimen specified. Antibodies used in flow cytometry are identified with vendor and catalog numbers. Software (Phoenix WinNonlin, SAS, OMIQ) is identified with versions. Cell lines and mycoplasma testing are not applicable.
“Pharmacokinetic parameters were calculated using noncompartmental analysis with the software Phoenix WinNonlin Version 8.0 (Certara L.P., Pharsight).”
“Budigalimab (ABBV-181) is an investigational humanized, recombinant immunoglobulin G1 (IgG1) L234A L235A monoclonal antibody (mAb) that effectively binds to cell surface-expressed PD-1”
“CD28-FITC (clone CD28.2, BD Biosciences, Catalog no. 555728), CD279-PE (clone EH.12.1, BD Biosciences, Catalog no. 560795)”
“Pharmacokinetic parameters were calculated using noncompartmental analysis with the software Phoenix WinNonlin Version 8.0 (Certara L.P., Pharsight).”
The study explicitly states no power calculations and no hypothesis testing, using descriptive and exploratory analyses. Tests used (ANCOVA, repeated measures, Wilcoxon) are named. Exact p-values are reported for exploratory analyses. Effect sizes are not reported, but this is consistent with the exploratory nature. Software is identified. Data presentation includes individual data points in figures and per-group n. Mathematical plausibility checks are not applicable due to small sample and continuous data.
“No power calculations for sample size considerations have been performed for this study that employed descriptive and exploratory analyses and had no planned hypothesis testing.”
“No power calculations for sample size considerations have been performed for this study that employed descriptive and exploratory analyses and had no planned hypothesis testing.”
“An ANCOVA was conducted to assess the log-transformed, dose-normalized C max and area under the curve values and dose proportionality between the 2 mg and 10 mg IV dose of budigalimab (class variable).”
“trends were observed in budigalimab-mediated expansion of peripheral CXCR5 + CD8 + T cells ( P = 0.06), TFH-like cells ( P = 0.06), and CCR6 + CD4 + T cells (Th17; P = 0.06)”
The data availability statement provides a concrete route via Vivli platform with conditions and timeframe. Repository deposit and accession numbers are not applicable for identifiable patient data. Code sharing is not applicable as no bespoke code is mentioned.
“These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal, statistical analysis plan (SAP), and execution of a data sharing agreement (DSA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following https://vivli.org/ourmember/abbvie/ then select “Home”.”
“These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal, statistical analysis plan (SAP), and execution of a data sharing agreement (DSA).”
“For more information on the process or to submit a request, visit the following https://vivli.org/ourmember/abbvie/ then select “Home”.”
The trial is registered (NCT04223804). A reporting guideline (CONSORT) is referenced via the flow diagram. All outcomes are reported, including negative results. Limitations are discussed. Conclusions are appropriately cautious. Funding and COI are disclosed.
“ClinicalTrials.gov identifier: NCT04223804”
“The study population size was small, as is typical for a phase 1 study. In addition, almost all study participants were male and all participants identified as cisgender, which does not reflect the diversity of PLWH.”
“ClinicalTrials.gov identifier: NCT04223804”
“Further information on research design is available in the linked to this article.”
“The study population size was small, as is typical for a phase 1 study.”
Registered (3 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences 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 50 references by DOI: 49 verified — 1 no DOI (shown, not verified).
- NO DOIPD-1 blockade at time of ART withdrawal facilitates early post-peak viral controlNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://vivli.org/ourmember/abbvie/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, clarity.
- MINORconsistencyAbstract“6 of 11 participants experienced a delayed rebound with a relatively low viral peak and/or off-ART viral control (<200 copies ml−1) for ≥6 weeks during ATI”→ Consider clarifying whether '6 of 11' refers to the full stage II group or a subset, as later text mentions 'six of nine participants completing treatment'.Potential inconsistency in denominator for the efficacy analysis.
- MINORclarityResults, Exploratory: ATI, viral load kinetics and ART restart“For 5 of 11 participants, viral load rebounded and remained elevated (leading to the reinitiation of ART), and of these, two had not received the full schedule of budigalimab doses.”→ Clarify whether the two participants who did not receive full dosing are included in the 5 or are additional.Ambiguity in subgroup description.
- MINORconsistencyAbstract“Stage 2: 10 mg n = 11, placebo n = 5, four doses every 2 weeks (Q2W)”→ Consider adding 'IV' for consistency with other dose descriptions.Minor inconsistency in dose description.
- MINORclarityResults, Exploratory: ATI, viral load kinetics and ART restart“For 5 of 11 participants, viral load rebounded and remained elevated (leading to the reinitiation of ART), and of these, two had not received the full schedule of budigalimab doses.”→ Clarify whether the two participants who did not receive full doses are included in the 5 or additional.Potential ambiguity in participant counts.
The published work is robust and well-reported; an informed reader should weigh the minor internal inconsistency in the efficacy denominator (6 of 11 vs six of nine) and the lack of effect sizes/confidence intervals for exploratory analyses. No erratum is warranted for the core findings, but the authors should consider issuing a correction for the denominator inconsistency and optionally adding effect sizes to enhance interpretability.
- 1.HIGHcopyeditIn the Abstract and Results, reconcile the denominator for the efficacy analysis: clarify whether '6 of 11' or 'six of nine participants completing treatment' is the correct figure, and ensure consistency throughout.The internal contradiction between the abstract and results could confuse readers and undermine the precision of the reported efficacy outcome.
- 2.HIGHcopyeditIn the Results section under 'ATI, viral load kinetics and ART restart', clarify whether the two participants who did not receive the full budigalimab schedule are included in the '5 of 11' who rebounded or are additional.The current wording is ambiguous about subgroup membership, which could mislead interpretation of the viral rebound analysis.
- 3.MEDIUMstatisticsIn the Methods/Statistical methods section, add a statement on verification of statistical assumptions (e.g., normality) for the ANCOVA and repeated measures analyses, or justify their robustness given the small sample.Both reviewers noted that assumptions are not explicitly verified; adding this strengthens the statistical rigor and preempts reviewer concerns.
- 4.MEDIUMstatisticsIn the Results for exploratory analyses, report effect sizes with confidence intervals for the key T-cell phenotypic findings (e.g., CXCR5+ CD8+ T cells, TFH-like cells, Th17 cells).Providing effect sizes and CIs would enhance interpretability of the exploratory trends, even though not required for a phase 1 study.
- 5.MEDIUMreportingIn the Discussion, explicitly acknowledge the lack of a formal power analysis as a limitation and discuss its implications for the exploratory efficacy findings.This would preempt concerns about the interpretability of null or trend-level results given the small sample size.
- 6.MEDIUMreportingAdd a CONSORT checklist as a supplementary file to explicitly document adherence to the reporting guideline.While a flow diagram is present, a full checklist would provide more transparent reporting and facilitate reviewer assessment.
- 7.LOWcopyeditIn the Abstract, add 'IV' to the Stage 2 dose description ('10 mg IV n = 11') for consistency with other dose descriptions.Minor consistency improvement in dose route reporting.
- 8.LOWdata codeConsider adding a data-sharing statement for the flow cytometry data or other non-clinical data, if applicable.This would enhance transparency for the exploratory biomarker analyses, though the clinical data sharing via Vivli is already adequate.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.