Patients carrying the gene that causes haemochromatosis have a reduced risk of developing peripheral neuropathy while taking antiretroviral therapy, according to a genetic study in the 13th July edition of AIDS. This association was particularly apparent in the patients whose treatment combinations included both d4T (stavudine, Zerit) and ddI (didanosine, Videx / VidexEC). The findings suggest that more work is needed to determine the relationship between iron levels in the body and the risk of developing peripheral neuropathy.
Peripheral neuropathy is numbness and pain in the extremities, particularly the feet, which is caused both by HIV itself and by some nucleoside reverse transcriptase inhibitors (NRTIs). It is brought about by damage to the nerve cells’ mitochondria, the small bodies that provide energy for the cell.
Since low iron levels are a risk factor for the development of peripheral neuropathy and iron is necessary for mitochondria to work properly, investigators set out to determine whether the gene for haemochromatosis is linked to neuropathy in patients taking anti-HIV drugs. Haemochromatosis is a genetic disorder that causes the body to accumulate high levels of iron.
The researchers analysed the haemochromatosis gene of 507 HIV-positive adults taking part in AIDS Clinical Trials Group study 384, a large clinical trial that was comparing different treatment combinations in patients who had never taken anti-HIV drugs before. The patients were randomised to receive ddI with d4T or AZT (zidovudine, Retrovir) with 3TC (lamivudine, Epivir), along with efavirenz (Sustiva), nelfinavir (Viracept) or both.
One hundred and forty-seven (29%) of the patients developed neuropathy, 108 (73%) of whom were taking ddI and d4T.
The investigators compared the genetic make-up of the patients with and without neuropathy, finding that overall, the number of people carrying the gene was similar in the two groups of patients.
However, a multivariate analysis restricted to the patients who had ever taken d4T and ddI revealed that the gene was linked to a reduced chance of peripheral neuropathy (odds ratio 0.30; p = 0.042). This analysis controlled for age, race, disease severity and the other antiretrovirals the patients were taking. Although diabetes can also cause neuropathy, only 2% of the patients in the study were diabetic, so it was not included as a risk factor.
In total, 47 (9%) of the patients carried one copy of the genetic variant, called C282Y, and one normal copy of the gene, but no patients had two copies.
This relationship was even stronger when the investigators restricted their analysis to the white patients in the study (odds ratio 0.17; p = 0.021). While 10% of Caucasians have the C282Y genetic variant, only 2 to 3% of African Americans have the gene.
“Carriers of the major HFE gene mutation C282Y experienced significantly lower incidence of peripheral neuropathy than non-carriers during treatment with ddI / d4T,” conclude the investigators. “This association was independent of other known risk factors for NRTI-induced peripheral neuropathy.
“This is the first study to demonstrate that iron-loading genetic mutations such as C282Y are associated with a lower risk of peripheral neuropathy during antiretroviral therapy,” they add.
The investigators also examined the impact of the H63D variant, which also increases iron levels. Although there was a trend for H63D to reduce the incidence of neuropathy, this association was not statistically significant.
The authors offer several possible explanations for their observation. Although carriers of the defective gene do not develop haemochromatosis, they do have mild elevations in iron storage and alterations in iron metabolism. These elevated iron levels may attenuate the mitochondrial damage in nerve cells by altering the iron levels in nerve cells, preventing the development of neuropathy. Alternatively, the iron levels could reverse or prevent the abnormalities in white blood cells caused by NRTIs.
The investigators also suggest that checking patients’ iron levels could be useful in determining whether iron supplementation is needed to reduce the risk of peripheral neuropathy. “Further studies, including correlation of iron stores with objective measures of disease severity and peripheral neuropathy, are needed to determine the mechanism(s) underlying this association,” they write.
They also hint that genetic testing may eventually enable doctors to predict which patients are at elevated risk of developing peripheral neuropathy, and could guide drug choices: “This finding has potential implications for the prediction and prevention of NRTI-associated peripheral neuropathy, particularly in populations at risk of iron deficiency.”
Kallianpur AR et al. Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. AIDS 20: 1503-1513, 2006.