Report-Level Comparator-Definition Sensitivity in FAERS Cardiometabolic Disproportionality Analysis: A Long-Acting Cabotegravir/Rilpivirine HIV Pharmacovigilance Case Study

Background/Objectives: Comparator selection can change disproportionality findings when multidrug therapies are represented by report-level listings rather than verified treatment histories. We evaluated a proxy-comparator framework for cardiometabolic reporting with long-acting cabotegravir/rilpivirine (CAB/RPV), including sensitivity to comparator definition and reporting context. Methods: We conducted a disproportionality analysis of publicly available individual case safety reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), restricted to study-defined markets and the period from the first quarter of 2022 through the second quarter of 2025. Reports were classified as CAB/RPV, regimen-only (a complete oral regimen listing alone), or regimen-plus (that listing plus other antiretrovirals). Three contrasts assessed 3-point and expanded major adverse cardiovascular events (MACE), diabetes, dyslipidemia, and hypertension using inverse probability weighting and adjusted reporting odds ratios (aRORs). Post-review analyses examined demographic completeness, reporter source, geography, and tenofovir disoproxil fumarate (TDF) inclusion. No binary signal threshold, case-by-case review, or causality adjudication was used. Results: The cohorts comprised 10,082 CAB/RPV, 4434 regimen-plus, and 14,559 regimen-only reports. In the internal oral contrast, regimen-plus showed statistically supported upward disproportionality for 3-point MACE (aROR 1.88, 95% confidence interval 1.44–2.15), expanded MACE (1.88, 1.47–2.40), and dyslipidemia (3.03, 2.39–3.84). CAB/RPV estimates were below 1 versus both proxies, although CAB/RPV versus regimen-plus lacked acceptable balance. Sensitivity analyses changed estimates and diagnostics; TDF inclusion left the CAB/RPV versus regimen-plus dyslipidemia estimate essentially unchanged but altered proxy-comparator findings. Conclusions: Proxy-comparator construction influenced cardiometabolic reporting patterns; reporting-context analyses qualified their interpretation. These hypothesis-generating findings do not establish incidence, clinical risk, causal effects, comparative safety, or a protective effect.