|Authors: Hulgan T, Samuels D, Bush W, Ellis R, Letendre S, Straub P, Murdock D, Franklin D, Grant I, Kallianpur A, for the CHARTER Group|
|Abstract:Background: Neurocognitive impairment (NCI) remains an important complication of HIV infection in the combination antiretroviral therapy (CART) era. Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single nucleotide polymorphisms that have been associated with neurodegenerative diseases in HIV-uninfected populations, and with HIV- and CART-associated outcomes. We hypothesized that mtDNA haplogroups are associated with NCI in HIV- infected adults, and examined these associations in CHARTER.
Methodology: CHARTER is a U.S.-based observational study of ambulatory HIV-infected adults who underwent standardized neurologic assessments. Primary outcomes were the global deficit score (GDS; both as a continuous measure and impairment defined as GDS=0.5) and HIV-associated neurocognitive disorder (HAND; defined using Frascati Criteria). Haplogroups were assigned using mtDNA sequence from whole blood and HaploGrep; analyses were race/ethnicity stratified. Multivariable regression of associations between haplogroups and GDS or HAND were performed adjusting for comorbidity status (incidental vs. contributing), current CART status (yes vs. no), plasma HIV RNA, CHARTER site, wide-range achievement test score, and CD4 T cell nadir.
Results: Haplogroups were available from 1068 persons without confounding comorbidities; median age was 43 years,
CD4 nadir was 180 cells/mm3, 763 (71%) were on CART, and 492 (46%) had HAND at baseline. In cross-sectional univariable analyses, Hispanics (N=104; 9.7%) had a greater likelihood of both GDS impairment and HAND (p<0.001 for both). Among Hispanics, those belonging to haplogroup B (N=18; 17%) had a lower median GDS (0.21 vs. 0.63; p=0.004), and lower likelihood of HAND of any severity (OR 0.30; 95% CI 0.11-0.87) and GDS impairment (OR 0.19; 0.06-0.62). These relationships persisted in stratified analyses of subgroups on CART, with detectable plasma HIV RNA, or with incidental comorbidities. There were no statistically significant differences by haplogroup among non-Hispanics. In adjusted models, haplogroup B tended to be associated with a lower GDS (ß=-0.26; p=0.06) and remained significantly associated with reduced risk of GDS impairment (adjusted OR 0.12; 0.02-0.67; p=0.02), independent of CD4 nadir and other factors listed above.
Conclusions: In this cohort of predominantly CART-treated subjects, a common Hispanic mtDNA haplogroup was associated with lower prevalence of NCI. Mitochondrial genetic variation may be an ancestry-specific host factor contributing to risk of NCI in chronically HIV-infected persons. Future studies could explore targeted genetic testing for risk stratification and personalized preventive and/or therapeutic interventions.|