Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common neurological complication of
HIV infection. It affected 57% of South African patients whose antiretroviral
therapy (ART) included
stavudine and was influenced by genotypes of the P2X-block (P2X7R, P2X4R and CAMKK2). We investigate associations between HIV-SN and P2X-block genotypes in patients who never received
stavudine. An adjacent gene,
ANAPC5, was included. 75 HIV+ individuals were assessed using the Brief
Peripheral Neuropathy Screen before treatment and after 6-8 months on
stavudine-free regimens.
DNA was genotyped for 48 polymorphisms across the four genes using an OpenArray™ platform. Haplotypes were derived using fastPHASE. Associations with HIV-SN were assessed using bivariate and multivariate analyses. Nine individuals (12%) were diagnosed with HIV-SN prior to ART and a further 20 individuals (27%) developed HIV-SN within 6-8 months. Five polymorphisms, rs503720*G (OR = 133) in P2X7R, rs10849861*A (OR = 5.99), rs1653586*T (OR = 67.8) and rs11065504*C (OR = 0.02) in CAMKK2, and rs2089886*A (OR = 6.68) in
ANAPC5, associated with HIV-SN after adjusting for
body weight, nadir CD4 T-cell counts and prior
tuberculosis (model p < 0.0001, n = 69, Pseudo R2 = 0.54). Three CAMKK2 haplotypes were associated with HIV-SN (OR = 2.82, 3.42 and 6.85) after adjusting for
body weight, nadir CD4 T-cell counts and prior
tuberculosis (model p < 0.0005, n = 71, Pseudo R2 = 0.26). The results support a role for CAMKK2 in HIV-SN, independent of mechanisms invoked by
stavudine. SIGNIFICANCE STATEMENT: HIV-associated sensory neuropathy (HIV-SN) remains a clinically relevant complication of
HIV infection and its treatment, affecting 38% of patients treated without neurotoxic
stavudine. HIV-SN can impact an individual's ability to work and quality of life, with few effective therapeutic options, so an understanding of the underlying mechanisms would have clinical value. We confirm that CAMKK2 polymorphisms and haplotypes influence susceptibility to HIV-SN in South Africans treated without
stavudine. This provides further evidence for a role for the
protein encoded by CAMKK2 in the pathogenesis of HIV-SN, independent of mechanisms initiated by
stavudine.