Review 1: "Gene Dysregulation among Virally Suppressed People Living with HIV Links to Non-AIDS Defining Cancer Pathways"

RR:C19 Evidence Scale rating by reviewer:

• Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: Quach et al's investigation into people with HIV (PWH) undergoing antiretroviral therapy (ART) utilizing whole blood transcriptomics reveals pivotal insights. The study, encompassing an impressive 555 patients, boasts significant breadth. However, the clinical characterization appears rudimentary. All PWH are labeled "HIV+", ignoring highly relevant differences between PWH progressing to AIDS before treatment initiation versus those treated during primary infection. Such distinctions bear immense implications for opportunistic infections, cardiovascular events, cancer risks, and beyond.

Despite the extensive laboratory analyses undertaken by the authors, the limitations of whole blood transcriptomics become apparent. The pursuit of enriched Gene Ontology (GO) terms, while extensive, yields results of constrained scientific utility. Moreover, the narrative linking cellular processes to various functions lacks evidential strength.

The authors' attempt at cell deconvolution holds promise, particularly in the context of HIV's heterogeneity. Nonetheless, the absence of robust clinical phenotyping impedes validation.

Additionally, while commendable, the endeavor to integrate heritability data remains enigmatic in its relevance to diverse conditions like asthma, Crohn's disease, rheumatoid arthritis (RA), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The classification of these disparate ailments as "inflammatory" appears tenuous.

Regrettably, the authors overlook significant shortcomings, failing to delineate the limitations of their clinical cohort adequately. Furthermore, the discussion's focus on potential intracellular pathways neglects critical caveats, including the uncertainty surrounding assumptions inherent in the transition from whole blood transcriptomics to intracellular pathways, particularly in the context of HIV's impact on cellular composition. Thus, differential regulatory pathways across cell types may obscure or amplify signals unpredictably.