Brief Report: Demographic and Genetic Associations With Markers of Small and Large Fiber Sensory Neuropathy in HIV Patients Treated Without Stavudine

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 85; no. 5; pp. 612 - 616
• Main Authors: Safri, Ahmad Yanuar, Gaff, Jessica, Octaviana, Fitri, Setiawan, Denise Dewanto, Imran, Darma, Cherry, Catherine L., Laws, Simon M., Price, Patricia
• Format: Journal Article
• Language: English
• Published: United States JAIDS Journal of Acquired Immune Deficiency Syndromes 15-12-2020; Copyright Wolters Kluwer Health, Inc. All rights reserved; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adult; Alleles; Anti-HIV Agents - adverse effects; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Biomarkers; Bivariate analysis; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; CD4 antigen; Clinical trials; Damage; Data links; Female; Fibers; Genetic Predisposition to Disease - genetics; Genotypes; HIV; HIV Infections - drug therapy; Human immunodeficiency virus; Humans; Lymphocytes T; Male; Middle Aged; Nerve conduction; Neurotoxicity; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - etiology; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - pathology; Peripheral neuropathy; Replication; Risk analysis; Risk Factors; Skin; Stavudine; Stavudine - adverse effects; Wrinkling; Young Adult
• ISSN: 1525-4135; 1944-7884
• DOI: 10.1097/QAI.0000000000002503

Neurotoxic antiretroviral therapy (ART) such as stavudine has been now 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 fibers 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 fibers. 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 fiber neuropathy was assessed by nerve conduction (NC) and small fiber 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 patientsʼ 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 skin wrinkling. Overall the data link CAMKK2 genotypes with small rather than large fiber damage. SSW may reflect pathology distinct from that identified using BPNS.