Demographic and genetic associations with markers of small and large fibre sensory neuropathy in HIV patients treated without stavudine.

Neurotoxic anti-retroviral therapy (ART) such as stavudine has now been replaced with safer therapies, reducing the prevalence of neuropathy from 34% to 15% in HIV+ Indonesians. However, it is unclear whether the residual cases display damage to small or large nerve fibres, and whether both are influenced by known risk factors, including alleles of CAMKK2 associated with neuropathy in HIV patients. The encoded protein influences the growth and repair of nerve fibres.HIV-positive adults on ART for > 12 months without exposure to stavudine were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen (BPNS). Large fibre neuropathy was assessed by nerve conduction (NC) and small fibre neuropathy using Stimulated Skin Wrinkling (SSW) applied to the fingers. CAMKK2 alleles were assessed by TaqMan OpenArray technology.Neuropathy diagnoses were more common with SSW than BPNS (49/173 vs 26/185, χ; p=0.0009), with poor alignment between these outcomes (p=0.60). NC and BPNS diagnosed neuropathy at similar frequencies (29/151 vs 26/185; p=0.12) and were aligned (p<0.0001). In bivariate analyses, all diagnoses were associated with patients' age and persistent HIV replication, with minor effects from CD4 T-cell counts and time on ART. CAMKK2 alleles associated with neuropathy diagnosed with BPNS and SSW, but not NC. Multivariable analyses confirmed the importance of age and HIV replication, with distinct CAMKK2 polymorphisms affecting BPNS and SSW. Paradoxically, height was protective against abnormal skin wrinkling.Overall the data link CAMKK2 genotypes with small rather than large fibre damage. SSW may reflect pathology distinct from that identified using BPNS.