HIV-associated sensory neuropathy 

HIV-associated sensory neuropathy (HIV-SN) is a complication of HIV infection and antiretroviral therapy and continues to impact 38 – 57% of PLWH in the post cART era ​(61)​. The proposed pathogenesis of HIV-SN involves primarily dorsal root ganglion infection/inflammation with mononuclear cellular infiltration, increased cytokine expression, and direct neurotoxic effects of viral proteins manifesting in axonal degeneration and reduced intraepidermal nerve fibre densities ​(64–66)​. Genetic polymorphism in mitochondrial DNA, upregulated inflammatory cytokines and other inflammatory proteins such as CAMKK2, P2X7R and P2X4R have been associated with HIV-SN, however targeted therapies remain theoretical ​(67)​. Multiple antiretrovirals are also associated with HIV-SN due to cumulative mitochondrial dysfunction and increased production of reactive oxygen species best characterised in the nucleoside reverse transcriptase inhibitors (stavudine, didanosine, zalcitabine). It is unclear whether protease inhibitors (indinavir, ritonavir, and saquinavir) can cause peripheral neuropathy directly, or more likely through metabolic disturbance especially insulin resistance ​(65,68)​. Risk factors for HIV-SN include low CD4 count, age, height, duration of HIV, high viral load, DM, malnutrition, neurotoxic cART regimens, and African ethnicity ​(65,66)​.  

HIV-SN presents as a distal, symmetrical anaesthesia or hyperaesthesia with associated neuropathic pain in a glove and stocking distribution ​(64–66)​. Ankle reflexes are often reduced or absent, however neurological examination can be normal. Supportive investigations include nerve conduction studies demonstrating axonal degeneration and skin biopsy revealing decreased epidermal nerve fibre density ​(67)​. Exclusion of other aetiologies of peripheral neuropathy is crucial, such as nutritional deficiencies (B12, B6, thiamine, folate), diabetes, alcoholism, hypothyroidism, inflammatory disorders, paraneoplastic disorders and or other neurotoxic drugs (isoniazid, metronidazole, amiodarone, TNF-alpha inhibitors, heavy metals and chemotherapy agents such as vincristine, taxanes and platinum). 

Management of HIV-SN involves rationalising cART to minimise neurotoxic agents, optimising HIV control, optimising other contributors to peripheral neuropathy and symptomatic therapy to reduce neuropathic pain ​(65)​. Therapeutic agents are similar for other causes of painful neuropathy including simple analgesia (paracetamol, non-steroidal anti-inflammatory drugs), tri-cyclic antidepressants, anticonvulsive drugs, selective serotonin and norepinephrine reuptake inhibitors (SNRIs), and opiate analgesia, detailed in Table 5. There is a paucity of HIV-SN specific trial data for many of these agents, with modest benefit versus placebo demonstrable for lamotrigine, gabapentin, and capsaicin and no benefit demonstrated for amitriptyline or pregabalin ​(69–72)​. Unfortunately, even with multimodal symptomatic therapy for HIV-SN, pain control is often incomplete.