Are there factors which increase Neuropathy risk?

In a collaboration, the sort of which should perhaps be done much more widely, medical researchers from universities in Australia, South Africa, Indonesia and Malaysia, looked at the common factors associated with HIV-related neuropathy (see link below). It is interesting to see the often-mentioned influences of height and age being confirmed by their findings. The higher rate of neuropathy amongst Australian HIV-patients for instance, can be put down to the fact that people are taller and live longer in that land than in the others. Hopefully, this sort of research will lead to useful conclusions, especially in the field of gene therapy and adjusted medication based on neuropathy predictions.

Study collaboration in Australia, Asia and South Africa in antiretroviral toxic neuropathy
School of Pathology and Laboratory Medicine - University of Western Australia

Neuropathy (nerve damage in the feet) is a common problem for people living with HIV.

This can be caused by HIV itself, but a clinically similar neuropathy is a common side effect of some older nucleoside analog reverse transcriptase medications (“antiretroviral toxic neuropathy” or ATN). In particular, stavudine is a drug commonly associated with neuropathy.

Stavudine is still used in first-line HIV treatment in many resource-limited settings, so neuropathy is an important problem in Africa and Asia. This project addresses why some patients suffer ATN whilst others do not when treated with stavudine. This will help clinicians decide which patients may be treated safely with stavudine and who should be prioritized for access to alternative drugs. We are investigating whether a simple genetic screen could be used to determine patients’ risk. Future studies will address the underlying pathogenic mechanisms to facilitate development of better treatments for this difficult problem.

Disordered inflammation is important in the pathogenesis of HIV neuropathy and may be central to the pathogenesis of ATN. TNF genotypes influence the individual’s risk of ATN following exposure to potentially neurotoxic NRTI such as stavudine (Cherry et al, 2008). We found that alleles of TNFA and IL12B (encoding TNFa and IL-12p40 respectively) distinguished Australian patients who developed ATN within six months of starting these drugs from those who did not. Neuropathy is common among Australians with HIV. Dr Cherry and Jacquita Affandi confirmed that 44 per cent of patients attending one clinic in 2006 are affected (Smyth et al, 2007).

We then enrolled cohorts of HIV patients in Jakarta and Kuala Lumpur, confirming that neuropathy is also common among patients at both of these sites (affecting 34 per cent and 19 per cent respectively). We showed that increasing patient height and increasing patient age are risk factors for ATN – and that the higher rate of ATN in Australian patients compared to similarly treated patients at our South East Asian sites is largely attributable to these factors (Cherry et al, ASHM 2008). Initial genotyping of Indonesian patients confirmed that TNFA-1031*2, an allele associated with ATN risk in Australians, is also a risk factor for neuropathy in Indonesian HIV patients (Affandi et al, 2008).
Further patients are now being recruited, including South African HIV patients in Johannesburg. Our collaborators (Antonia Wadley and Dr Kamerman) report that neuropathy is common in their clinics. If the algorithm developed in Australian and Asian patients is confirmed in this group, it will constitute a robust tool to assess HIV patients’ risk of ATN before they start treatment. This will aid rational drug selection, especially in clinics where some use of stavudine remains an economic necessity. An improved understanding of how cytokines and inflammation are involved in ATN may also allow future development of immunotherapeutic strategies to treat this disabling problem.

Constance Chew (PhD student, UWA) has now joined the project to characterise TNF Block haplotypes associated with neuropathy in patients from Australia, Indonesia, Malaysia and South Africa (Chew et al 2008).

http://www.pathology.uwa.edu.au/research/immunology/antiretroviral