Long-acting injectable cabotegravir versus daily oral TDF/FTC for HIV pre-exposure prophylaxis

Registration and administrative information (PROSPERO field set)

Extraction — every datum linked to its source

Every per-trial value this review pools, with a link to the record it came from. Derived by ssot/projectors_evidence.py for any topic whose rows carry an NCT, a PMID, an ISRCTN or a source URL.

2 of 2 rows are linked to a source; 0 carry no identifier and are shown as unlinked rather than omitted.

Outcome primary

Recompute envelope — the headline against the rows shown

Derived by ssot/recompute_envelope.py. The pooled number is recomputed from the per-trial rows this same page shows, so the arithmetic between the extraction table and the headline is checkable with no tool the reader does not already have.

Outcome primary

AGREES -- the stored point lies between the fixed-effect and DerSimonian-Laird estimates computed from the rows this page shows.

Scale used: log. Declared estimator: REML.

DerSimonian-Laird is biased at k below about ten and this project uses REML. DL is here only to WIDEN the envelope so a REML point falls inside it; it is never offered as the review's estimate.

Absolute effect at a baseline risk the reader chooses

Derived by ssot/absolute_effect.py for any topic with a pooled ratio measure AND a declared indirectness argument. Where either is missing it DECLINES with a reason rather than emitting a table the review has not licensed — a ratio becomes an absolute effect only against a baseline risk, and a baseline risk belongs to a population.

Risk of bias (RoB-2)

Variant:

Unit assessed: —

Assessor 1: (anthropic family). Assessor 2: (openai family).

Overall judgement per trial

Inter-assessor agreement

This assessment is DUAL — two assessors from different model families, the second asked blind. The agreement rate is withheld pending adjudication. Both readers were given this review’s decision rule; an earlier version of this sentence said the blinding had withheld it, and that was wrong. What the 10 domain comparison(s) show is a reading difference that runs in OPPOSITE directions by domain — on domains 1 to 3 the second assessor more often declines to judge at all, and on domains 4 and 5 it more often judges low. A single agreement rate averages those two behaviours into one number that describes neither. Both assessors’ per-result judgements are shown in the table above, unadjudicated, and neither is this review’s finding. No adjudication has been performed, so this review holds no final risk-of-bias judgement for these results.

References

Included studies

• HPTN 083 — https://clinicaltrials.gov/study/NCT02720094
• HPTN 084 — https://clinicaltrials.gov/study/NCT03164564

Regulatory documents

Methods and guidance

Sources

Visual abstract

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 2005ea69e9c9c21d), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — visual-abstract.eps, 4 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — visual-abstract.tiff, 27,685 KB.

Projected from the canonical object, so it carries the same k, the same pooled estimate and the same interval as the paper and cannot drift from them. The interval is drawn to scale against the no-difference line, which it EXCLUDES: 0.071 to 0.606, with no difference at 1.

Risk of bias, both assessors

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Only the vector format is offered for this figure, by choice: it is line art — discrete marks, glyphs and labels — which SVG reproduces exactly at any size, so a raster would add weight without adding fidelity. The build was able to rasterise; it was asked not to.

Every cell carries BOTH independent cross-family assessments and they are not reconciled: showing one column would be a reconciliation presented as an observation. Glyph as well as colour, so the panel survives greyscale printing and colour-blind reading. A trial with no judgement is shown as a row of not-assessed markers rather than omitted, so a gap in the assessment cannot be mistaken for a clean assessment. Agreement as measured: {'per domain agreed': 8, 'per domain total': 10, 'per domain rate pct': 80.0, 'overall agreed': 2, 'overall total': 2, 'overall is derived': True, 'recomputed from the stored judgements': True, 'why recomputed': 'The stored disagreement tallies were frozen as text and 12 of 22 no longer match the judgements in the object -- a later guidance pass moved 51 the randomisation process judgements and the tallies were never recomputed. This is derived from what the object holds now.'}.

GOSH

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 9091822e99aa8781), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — gosh.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — gosh.tiff, 5,537 KB.

Deliberately not drawn. Every subset meta-analysis of 2 trials is 3 points; a cloud that small cannot show the multimodality GOSH exists to reveal, and a reader would take the picture as evidence of its absence.

Trial-sequential analysis

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 25ed9800fdf56614), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — tsa.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — tsa.tiff, 6,665 KB.

TSA boundaries depend entirely on a target information size that must be pre-specified. This review's protocol registers none, so any boundary drawn here would be a parameter chosen after seeing the data -- which is the practice TSA exists to protect against.

Meta-regression

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: e35ec93bbc9a1c10), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — bubble.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — bubble.tiff, 5,537 KB.

The protocol pre-specifies no moderator, and at k = 2 a meta-regression would be fitted on 2 points. Not drawn rather than drawn with a caveat: a bubble plot invites reading a slope, and there is no slope here that any reader should read.

Summary of findings

1. This certainty rating is PENDING, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.

Reproducibility artifact

This page CANNOT be rebuilt from what is recorded here: no canonical object is recorded and no registered commit is recorded. Each figure on the Analysis tab downloads as an SVG carrying exactly the values shown.

Other recorded qualifications

Statements this review records about the limits of what it establishes, which are not shown elsewhere on this page. They are reproduced from the object verbatim and are not summarised.

Judgement register — what a harness cannot derive

Judgements a harness cannot derive, per outcome, with the alternative and its consequence. DERIVED AT BUILD TIME by ssot/topic_judgements.py — this table is not written for this topic and the same code produces it for every topic.

Outcome primary — 0 of 8 declared, 7 of 8 undeclared

A topic costs 0 declared judgements on this outcome, not four hundred. That is a stronger claim than "automated", because a reader can check a declared judgement and cannot check an inferred one.

⚠️ It does not make the judgements right, and it does not prove the SLOT LIST is complete -- the list is bounded by what its author enumerated. The honest form is "8 slots checked", never "8 judgements exist".

Paper

Each statement below cites the record it came from; those sources are listed at the end of every section. Where the record holds nothing, the section says so by name rather than being left out, so a procedure that was not carried out can be told from one that simply was never mentioned.

Title

Long-acting injectable cabotegravir versus daily oral TDF/FTC for HIV pre-exposure prophylaxis¹

Abstract

Question. In Long-acting injectable cabotegravir versus daily oral TDF/FTC for HIV pre-exposure prophylaxis, what is the effect on versus daily oral TDF/FTC on documented incident HIV infection?¹

Methods. estimates were pooled under a random-effects model with the REML estimator; risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials); and certainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons.²

Results. Documented incident HIV infection: risk ratio 0.208 (0.0715 to 0.606) across 2 trials; 1 of these pooled outcome(s) carries a stated qualification -- a referral or a recorded finding -- given in full in Results and not reproduced here; and heterogeneity was substantial (I-squared 68.8%), though heterogeneity cannot be reliably assessed with two trials.³

Introduction

¹Background. This review asks: In Long-acting injectable cabotegravir versus daily oral TDF/FTC for HIV pre-exposure prophylaxis, what is the effect on versus daily oral TDF/FTC on documented incident HIV infection? It pools 2 randomised trials, against daily oral TDF/FTC. The outcome pooled is documented incident HIV infection. Every count and denominator behind those estimates is read as follows. Registry throughout. Every count and denominator is read from ClinicalTrials.gov posted results. No publication figure is used.

Methods — search

Primary trials. No bibliographic search for primary trials was run. The 2 included trials were identified by reading named registrations on 2026-08-18. Both registrations read on 2026-08-18: conditions, arm groups with types, registered primaries, posted results counts. Published syntheses. PubMed E-utilities esearch + esummary, executed 2026-08-21. Query as executed: (cabotegravir[tiab]) and (prophylaxis[tiab] OR PrEP[tiab] OR prevention[tiab]) and (meta-analysis[pt] OR "systematic review"[pt] OR meta-analysis[tiab] OR pooled[tiab]). It matched 46 record(s), of which 46 were retrieved and 46 read; 1 appraised.¹

Methods — synthesis

For documented incident HIV infection, a random-effects model was fitted with the REML estimator.¹

Risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials) (), following . 2 result-level assessments were made.²

A ceiling applies to every risk-of-bias judgement in this review; it is stated with the assessment itself rather than summarised here.³

Certainty of evidence was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons., following . 1 pooled outcome(s) were rated.⁴

Results

The pooled risk ratio for documented incident HIV infection was 0.208 (0.0715 to 0.606) across 2 trials, against daily oral TDF/FTC.¹

Noted on this pool. Read this beside the estimate. HPTN 084 (NCT03164564) ran in botswana, eswatini, kenya, malawi, south africa, uganda and zimbabwe, in cisgender women. HPTN 083 (NCT02720094) ran in argentina, brazil, peru, south africa, thailand, the united states and vietnam, in men who have sex with men and transgender women -- one african country of seven -- and it carries the larger weight in this pool. A reader taking this page as evidence about African populations is taking half of it from a trial that was mostly not African and not in women. I-squared is 68.83% with tau-squared 0.4178. At k = 2 that statistic proves little by itself, but it does not stand by itself: the two estimates are 0.3335 (0.1785 to 0.6230) in one population and 0.1108 (0.0395 to 0.3107) in the other, and the populations differ by sex, by risk route and by region. The spread has a named cause rather than an unexplained one. Wang et al. 2023 (PMID 37498645) report RR 0.21 (0.07 to 0.61), I-squared 70%, on 17 and 75 events. This object reports 0.2081 (0.0715 to 0.6057), I-squared 68.83%, on the same 17 and 75 events. The arithmetic here has an independent external check and it passes -- which is a statement about the computation, not about whether the two trials should have been combined. Both registrations register grade 2 or higher adverse events as a second primary outcome. This review carries only the efficacy primary, so this page is not a benefit-and-harm summary.²

The trials' results were loosely consistent with one another: I-squared, the share of the variation between them that is more than chance alone would produce, was 68.8%; the estimated variance of the true effects between trials (tau-squared) was 0.418, the heterogeneity test statistic Q was 3.21, on degrees of freedom 1.³

What this does not establish: Not that either trial is free of bias -- no risk-of-bias assessment is recorded. Not that the effect is equal in men and in women; see the population note above. Not anything about adherence, which is the mechanism most likely to drive a difference between an injectable and a daily oral regimen and is not an outcome in this pool. Not reliability of the interval at k=2 -- see Hartung-Knapp.⁴

The full model output for every pooled outcome -- the call, the estimator, the heterogeneity statistics and the back-transformed interval -- is stored verbatim on this review object at `results.by_outcome.<outcome>.r_output.verbatim`. It is not reproduced as an Extended data section in this article; an earlier version of this sentence said it was, and no such section exists.⁵

Risk of bias in the included results

Risk of bias was assessed with RoB 2 at the level of each reported result, by two assessors reading independently. Their judgements differ on 0 of the 2 results and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Assessor 1 recorded: 2 at some concerns. Assessor 2 recorded: 2 at some concerns. Both are shown in the risk-of-bias table; neither is the review's finding. The per-domain judgements behind them are recorded with the extracted data.¹

Certainty of the evidence

Certainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons..¹

This certainty rating is pending, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.²

LOW certainty, and the reason is not the size of the effect -- which is large, consistent in direction, and reproduced exactly by a published synthesis. It is that two trials in two different populations across two regions have been combined into one ratio, with I-squared 68.83%, and that the adherence domain both trials turn on was not read.³

Comparison with published syntheses

Published syntheses were identified as follows. PubMed E-utilities esearch + esummary, executed 2026-08-21. Query, counts and per-record disposition in ssot/cab-prep-hiv-review/appraisal/the screen of published syntheses.json.¹

Limitations

What this review does not give a clinician: the number of events in each arm, any absolute effect or number needed to treat and any measure of harm. A relative effect cannot be turned into the benefit or the risk facing one patient without them, so this review can support a judgement about what these trials found and not a judgement about what to do.¹

Software availability

Analyses were computed under R 4.6.0 with metafor 5.0.1.¹

Note on registration

No PROSPERO registration or protocol record is held on this object. That is not the same as knowing this review was not registered, and neither claim is made. It is recorded here as an absence so that a reader does not have to infer it from silence.¹

References

Figures

Trial characteristics

Not reported in this record

The items below were not written because the record does not hold what they would be composed from. They are named here so that an absence is not mistaken for an omission.