Efficacy of acetyl-L-carnitine for antiretroviral toxic neuropathy

6 September 2004. Related: Side effects.

Leighton Davies MD, for HIV i-Base

The results of a recently published trial by Andrew Hart and colleagues from Blond McIndoe Centre, Manchester, and the Royal Free Hospital in London, provide confirmatory evidence for the use of acetyl-l-carnitine as a pathogenesis-based treatment for antiretroviral-associated toxic neuropathy (ATN). [1]

ATN is the commonest cause of distal symmetrical neuropathy affecting between 11% and 66 % of individuals on antiretroviral therapy and is usually associated with the dideoxynucleoside analogue drugs ddC, d4Tand ddI (the ‘d-drugs’).

Currently available therapies – analgesics +/- adjuvant therapies (tricyclic antidepressants, anticonvulsants, mexiletine and peptide T) offer little in the way of symptom amelioration.

The proposed mechanism of ATN is impairment of neuronal mitochondrial oxidative metabolism (mediated by RTI inhibition of DNA-gamma-polymerase, upon which mitochondrial DNA replication is dependent). This results in reduced metabolic function in the long peripheral axons, producing a dieback effect that is responsible for the glove and stocking distribution of symptoms. Abnormal sweating patterns (night sweats) have also been described, suggestive of an autonomic neuropathy.

Acetyl L-Carnitine (LAC), which is crucial for normal mitochondrial function, is also thought to potentiate nerve growth factor actions, promote peripheral nerve regeneration and is thought to be generally neuroprotective, based on animal studies of diabetic neuropathy.

This elegant study provides 33-month data on the efficacy of LAC at 1500mg twice daily in a cohort of 21 HIV-positive individuals with established stable dysaesthetic neuropathic symptoms (of grade 2-4 severity). Skin biopsies were taken from the legs of patients before LAC treatment and at 6-12 month intervals thereafter alongside five HIV-negative non-neuropathic control volunteers. The degree of neuronal re-growth was then assessed by means of immunohistochemical staining of the biopsies with nerve-fibre specific antibodies directed towards PGP (protein gene product 9.5) as a non-specific indicator of re-growth, CGRP (calcitonin gene-related product) as specific for C and A-delta (small sensory) fibres. Sections were then examined by fluorescence microscopy and a fractional area of immunostaining calculated as a representation of neuronal re-growth, which was then used for statistical comparisons. The results of the study showed that immunological parameters remained stable throughout the study. Median baseline CD4 count and viral load were 286 cells/mm3 and <400 copies/mL respectively and median neuropathy duration prior to the study was 11 months (range 2-41 months).

Morphologically, patients with established ATN exhibited reduced total innervation of epidermis, dermis and most markedly, sweat glands prior to commencing treatment. There was a statistically significant increase in neuronal regeneration during the course of LAC treatment. The increase in small sensory fibres (epidermis 100%, p=0.006; dermis 133%, p<0.05) was more than that for all fibre types (epidermis 16%, p= 0.04; dermis 49%, p<0.05; sweat glands 60%, p< 0.001) or for sympathetic sudomotor fibres (sweat glands 41%, p<0.0003). The benefits continued to improve after 24 months treatment while re-innervation of sweat glands stabilised. This correlated with an improvement in grade of neuropathic symptoms in 15 of 21 patients (76%). The temporal pattern of improvement accounts for the slow resolution of symptoms on starting LAC therapy.

This study reported that LAC treatment is associated with an improvement in neurological symptoms in 76% patients and remained unchanged in 19%. A randomised controlled clinical trial is now underway which will use a validated visual analogue pain scale to establish symptomatic benefit conclusively. Traditionally peripheral neuropathy has been the principal complication limiting the use of certain NRTIs, for which LAC many now offer an effective management approach.

Comment

First results from this study in six patients from 2000 were reported over four years ago in HTB Vol 1 No 2. (May 2000).
http://www.i-base.info/pub/htb/vol1/htb2/htb2.html#L-Acetyl

These results should in a larger number of patients should now make LAC easier to prescribe in the UK.

Reference:

Hart AM, Wilson ADH, Youle M et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 18(11):1549-1560, July 23, 2004.