Mode of HIV exposure and excess burden of neurocognitive impairment in people living with HIV: a protocol for systematic review and meta-analysis of controlled studies

BackgroundChronic HIV infection significantly elevates the risk of brain pathology, precipitating neurocognitive impairment (NCI) among people living with HIV (PLWH). The diagnosis of NCI in PLWH hinges on evaluating deviations in neuropsychological test performance in comparison to HIV-seronegative normative controls. However, the adverse psychosocial conditions experienced by PLWH can also result in reduced test performance, potentially confounding the accurate NCI attribution to HIV infection. This planned systematic review aims to investigate potential disparities in the excess burden of NCI among PLWH in two groups of studies: (a) studies enrolling controls who shared a similar mode of HIV exposure (MoHE) with the PLWH participants (MoHE-adjusted) and (b) studies enrolling normative controls or controls without undefined MoHE (MoHE-naive).MethodsWe will systematically search five electronic databases (MEDLINE, Embase, PsycINFO, Web of Science, ProQuest) and registries (OpenGrey, ClinicalTrials.gov, ISRCTN registry). Studies reporting NCI in PLWH and HIV-seronegative controls with cross-sectional or baseline measurements, published from January 2007 to September 2023, will be included. To be classified as MoHE adjusted, a study must evidence >= 90% enrolment of both PLWH and their seronegative controls from the same MoHE group (e.g. men who have sex with men, people who use drugs or alcohol). Reports of test performance scores will be transformed into NCI proportions using simulated score distributions, applying a global deficit score cut-off >= 0.5 to estimate NCI cases.The Newcastle-Ottawa scale adapted to the purpose of the review will be used to appraise study quality. Random-effects meta-analysis will be used to pool the excess burden of NCI in prevalence ratios and test the difference between MoHE-adjusted and MoHE-naive studies. Furthermore, subgroup analyses and meta-regression will be undertaken across categorical study-level covariates (e.g. study locations, NCI diagnostic criteria) and continuous/ordinal covariates (nadir CD4, number of neurocognitive domains assessed), respectively.MethodsWe will systematically search five electronic databases (MEDLINE, Embase, PsycINFO, Web of Science, ProQuest) and registries (OpenGrey, ClinicalTrials.gov, ISRCTN registry). Studies reporting NCI in PLWH and HIV-seronegative controls with cross-sectional or baseline measurements, published from January 2007 to September 2023, will be included. To be classified as MoHE adjusted, a study must evidence >= 90% enrolment of both PLWH and their seronegative controls from the same MoHE group (e.g. men who have sex with men, people who use drugs or alcohol). Reports of test performance scores will be transformed into NCI proportions using simulated score distributions, applying a global deficit score cut-off >= 0.5 to estimate NCI cases.The Newcastle-Ottawa scale adapted to the purpose of the review will be used to appraise study quality. Random-effects meta-analysis will be used to pool the excess burden of NCI in prevalence ratios and test the difference between MoHE-adjusted and MoHE-naive studies. Furthermore, subgroup analyses and meta-regression will be undertaken across categorical study-level covariates (e.g. study locations, NCI diagnostic criteria) and continuous/ordinal covariates (nadir CD4, number of neurocognitive domains assessed), respectively. DiscussionThis systematic review will contribute towards a greater appreciation of the unique psychosocial conditions of PLWH that are missing from the current case definition of HIV-associated neurocognitive disorder. The findings will additionally highlight possible disparities in the distribution of the excess burden of NCI by MoHE groups, thereby guiding the prioritization of mitigation efforts.Systematic review registrationPROSPERO CRD42021271358