HIV PrEP NMA: All Modalities Including Dapivirine Ring and Investigational Agents (Lenacapavir, CAB-LA)

[howard6204]

HIV Pre-Exposure Prophylaxis: Comprehensive NMA Including Dapivirine Ring and Investigational Agents

Twice-yearly lenacapavir (SUCRA 99.1%, efficacy 97%) and bimonthly cabotegravir LA (SUCRA 79.2%, efficacy 86%) rank highest among all 8 PrEP modalities; the dapivirine vaginal ring provides a woman-controlled option with a 29% point-estimate reduction.

Project path: projects/hiv-prep-nma/

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Background

HIV pre-exposure prophylaxis (PrEP) has expanded from daily oral TDF/FTC in 2010 to include long-acting injectables, on-demand dosing, and the dapivirine vaginal ring -- each approved in different jurisdictions. No prior NMA has included all 8 modalities in a single network, particularly agents not yet universally approved (lenacapavir, dapivirine ring). This analysis synthesises 14 RCTs across 31 arms to rank all options simultaneously.

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Included Studies (14 RCTs, ~50,743 participants)

Trial	Year	Population	Interventions
iPrEx	2010	MSM/TGW	TDF/FTC vs Placebo
Partners PrEP	2012	Serodiscordant couples	TDF/FTC, TDF vs Placebo (3-arm)
TDF2	2012	Heterosexual adults	TDF/FTC vs Placebo
FEM-PrEP	2012	Cisgender women	TDF/FTC vs Placebo
VOICE	2015	Cisgender women (Africa)	TDF/FTC, TDF vs Placebo (3-arm)
IPERGAY	2015	MSM/TGW	TDF/FTC on-demand vs Placebo
PROUD	2016	MSM	TDF/FTC immediate vs deferred
ASPIRE	2016	Cisgender women	Dapivirine ring vs Placebo
Ring Study	2016	Cisgender women	Dapivirine ring vs Placebo
DISCOVER	2020	MSM/TGW	TAF/FTC vs TDF/FTC
HPTN 083	2021	MSM/TGW	CAB-LA vs TDF/FTC
HPTN 084	2022	Cisgender women	CAB-LA vs TDF/FTC
PURPOSE 1	2024	Cisgender women	Lenacapavir vs TAF/FTC, TDF/FTC
PURPOSE 2	2024	MSM/TGW/NB	Lenacapavir vs TDF/FTC

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Figure 1: Evidence Network

Hub-and-spoke network with TDF/FTC as the central node. Node size proportional to participants; line width proportional to number of studies per comparison.

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Figure 2: NMA Forest Plot

Random-effects NMA estimates (IRR vs placebo). The dapivirine ring is the only intervention with 95% CI crossing unity in the network analysis (p = 0.069).

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Figure 3: SUCRA Rankings

Surface Under the Cumulative Ranking curve from 10,000 Monte Carlo simulations. Lenacapavir dominates (99.1%); long-acting injectables clearly superior to oral agents as a class.

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Figure 4: League Table Heatmap

Pairwise IRR (95% CI) for all treatment combinations. Green = row treatment favoured; red = column favoured.

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Figure 5: Direct vs NMA Estimates

Comparison of direct evidence (diamonds) vs NMA-synthesised estimates (squares). Good consistency across the network.

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Key Findings

1. Lenacapavir ranks first -- IRR 0.03 (95% CI 0.008-0.099), efficacy 97%, SUCRA 99.1%. Near-complete protection in both PURPOSE 1 (cisgender women) and PURPOSE 2 (MSM/TGW).
2. CAB-LA ranks second -- IRR 0.14 (95% CI 0.069-0.273), efficacy 86%, SUCRA 79.2%. Confirmed in HPTN 083 (MSM) and HPTN 084 (women).
3. TDF/FTC on-demand ranks third -- IRR 0.14 (95% CI 0.031-0.680), efficacy 86%, SUCRA 76.2% -- but validated only in MSM/TGW (IPERGAY).
4. Dapivirine ring -- IRR 0.71 (95% CI 0.484-1.028), p = 0.069 in NMA. Not statistically significant in network synthesis despite individually significant direct trials. Provides a critical woman-controlled prevention option.
5. Moderate heterogeneity -- tau2 = 0.051, I2 = 52.3%, driven primarily by adherence-confounded trials (FEM-PrEP, VOICE).

Clinical Implications

• Highest-risk patients with injectable access: lenacapavir or CAB-LA as first choice
• Resource-limited settings: daily oral TDF/FTC remains effective, accessible, affordable
• Cisgender women where injectables face access/social barriers: dapivirine ring provides meaningful woman-controlled protection
• TDF/FTC on-demand (2-1-1): appropriate only for MSM with predictable exposure patterns
• Priority evidence gap: direct head-to-head RCT of lenacapavir vs CAB-LA

Methodology

• Analysis: Frequentist random-effects NMA, graph-theoretic approach (Rucker 2012)
• Software: Python 3.14 (NumPy, SciPy, Matplotlib, Pandas)
• Heterogeneity: DerSimonian-Laird tau2 = 0.051; I2 = 52.3%
• Ranking: SUCRA via Monte Carlo simulation (n = 10,000)
• Consistency: Node-splitting (all p > 0.10)
• Network: 8 nodes | 14 RCTs | 31 arms | reference = Placebo

Pipeline

Stages 00-07 complete: protocol -> search -> screening -> extraction -> NMA -> manuscript (Quarto)

Deliverables: 6 figures, 3 result tables (NMA estimates, SUCRA, league table), full Quarto manuscript with PROSPERO protocol.

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Generated with meta-pipe -- AI-assisted meta-analysis pipeline

#NMA #HIV #PrEP #Lenacapavir #CabotegravirLA #DapivirineRing #InfectiousDisease #Prevention