Long term exposure to nucleoside analogues and peripheral nerve function
Paul Blanchard, HIV i-Base
Distal sensory peripheral neuropathy (DSPN) is the most common neurological dysfunction experienced by patients with HIV-infection. It is complex in that it may be caused by HIV-infection itself and some antiretrovirals used to treat HIV-infection that may themselves be neurotoxic.
It manifests as tingling, burning and other paraesthesias predominantly affecting the feet but also involving the hands in more advanced cases and may be extremely disabling. DSPN is a die back neuropathy of the sensory peripheral nerves whose pathophysiology remains ill defined. Treatment is predominantly symptomatic with analgesics, anticonvulsants and antidepressants often with disappointing levels of efficacy.
This study presented at the 2nd IAS meeting in Paris used quantitative sensory testing (QST) and electrophysiological testing of peripheral nerves to determine infra-clinical alterations of small peripheral nerve fibres in patients who had been exposed long term to nucleoside reverse transcriptase inhibitors (NRTIs). The usefulness of capsaicin topical application for developing optimal QST of heat pain sensation was also evaluated as an additional method to determine the loss of small afferent fibres.
A case control study was performed of 32 patients with HIV-infection who had been exposed to NRTIs for more than 60 months and with mild to moderate symptoms of lipodystrophy. Fourteen untreated HIV-infected or seronegative subjects matched for age and sex were used as case controls.
Nerve conduction velocities and electromyographic examination was performed on both upper and lower limbs. Distal motor latency and motor nerve conduction was also determined on peroneal and median nerves. QST was carried out on the dorsum of the feet in all subjects. Both detection and pain thresholds were determined using nylon calibrated von Frey hairs. Thermal thresholds were tested using standardised thermal sensory testing equipment. Capsaicin was applied to a patch of skin on the dorsum of the foot and thermal stimuli used 15 minutes later in order to produce local activation of c-fibre nociceptors and compared to an untreated area of skin on the contralateral foot. Subjects judged the magnitude of pain sensations on a visual analogue scale (VAS).
Overall the mean duration of exposure to NRTIs was 86.9 months in the 32 patients. Mean CD4 cell count at the time of QST was 619 cells/mL and mean plasma HIV RNA was 5,335 copies/mL. Sensory symptoms in the distal part of the limbs was reported by six patients (19%) the remainder being asymptomatic.
Results of VAS responses to thermal stimuli after capsaicin stimulation showed that NRTI exposed patients experienced less pain compared to the matched controls (mean VAS 0.5 Vs. 1.6, p=0.008). Twenty-one patients (65%) reported no sensory pain (VAS=0) after capsaicin application versus two controls (1.4%).
No correlation was observed between VAS responses and duration of HIV-infection, between VAS responses and plasma viral load or CD4 count at time of QST, or between VAS responses and global duration of exposure to NRTIs.
The researchers concluded that this study demonstrates that HIV-infected patients who are durably exposed to NRTIs show infra-clinical alterations of small peripheral nerve fibres. This adds to the data already accumulated using skin biopsy to assess intraepidermal nerve fibre density, which shows a loss of nerve fibre density in HIV-related DSPN correlated to both symptoms and QST.
They go on to hypothesise that increases in detection and pain thresholds for thermal stimuli demonstrated in both this and previous studies are probably linked to mitochondrial dysfunction induced by a durable exposure to NRTIs and propose to investigate this link by examining the depletion of mtDNA in PBMCs or in SAT.
The researchers further propose that QST after the topical application of capsaicin may be a useful, non-invasive and sensitive method to detect small fibre sensory neuropathies that are not currently well assessed by standard electrodiagnostic studies.
Jarrousse B, Bouillaguet S, Letoumelin PH et al. Assessment of small peripheral nerve fibres alterations in HIV-infected patients exhibiting lipodystrophy symptoms after long-term exposure to nucleoside reverse transcriptase inhibitors (NRTIs). 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003, Paris. Abstract 209.