Peripheral neuropathy is most often a side-effect of the d-drugs ddC (zalcitabine, Hivid), ddI (didanosine, VidexEC) and d4T (stavudine, Zerit). In one study, symptomatic peripheral neuropathy was about three times more common in patients treated with ddI and d4T compared with AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir)^[1]. The d-drugs drugs have additive neurotoxicity when used in combination^[2]. Symptoms of neuropathy typically begin to develop after a few weeks on the drugs.

The d-drugs can cause mitochondrial toxicity, damage to small energy-producing structures in the cells. Mitochondrial toxicity can cause lactic acidosis (elevated blood lactate levels) and appears to be the mechanism underlying peripheral lipoatrophy (fat loss in the face and limbs) and peripheral neuropathy.

One study found that ddC was also associated with mitochondrial damage and depleted mitochondrial DNA (mtDNA) in nerve biopsy samples from patients with peripheral neuropathy^[3]. Another study found that levels of mtDNA in fat cells were lower in HIV-positive patients with peripheral neuropathy than in HIV-positive participants without these side-effects or HIV-negative controls^[4]. This accords with the finding that mtDNA levels are lower in patients taking d-drugs^[5]. In one study, a specific mitochondrial genetic variant was associated with a five-fold higher risk of developing peripheral neuropathy when using d4T and ddI^[6].

The remaining NRTIs - abacavir (Ziagen), AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and FTC (emtricitabine, Emtriva) - are not independently associated with a significantly increased risk of peripheral neuropathy. The same is true of the sole nucleotide reverse transcriptase inhibitor, tenofovir (Viread); the non-nucleoside reverse transcriptase inhibitors (NNRTIs); and the protease inhibitors, with the possible exception of indinavir (Crixivan). The entry inhibitor T-20 (enfuvirtide, Fuzeon) has been linked to peripheral neuropathy in some studies.

Several factors increase the risk that a person will develop peripheral neuropathy while taking the d-drugs:

• More advanced HIV disease or AIDS diagnosis.
• CD4 cell count below 100 cells/mm³.
• Viral load above 10,000 copies/ml.
• Older age.
• Past history of neuropathy due to any cause.
• Use of other neurotoxic drugs besides antiretrovirals.
• Certain nutritional deficiencies.
• Co-existing medical conditions such as diabetes and hepatitis C.
• Heavy alcohol consumption.

A variant in the gene for haemochromatosis, which affects the levels of iron in the body, has also been linked to the risk of developing peripheral neuropathy^[7].

Even though some antiretroviral drugs can cause or worsen pre-existing peripheral neuropathy, overall, antiretroviral therapy has been shown to reduce the likelihood and severity of neuropathy in people with HIV^[8][9].

Other drugs

Along with antiretrovirals, several drugs used to treat HIV-related opportunistic illnesses may also contribute to neuropathy. These include hydroxycarbamide (Hydrea), a drug that has been used to boost the activity of ddI and slow the replication of HIV; isoniazid for tuberculosis; dapsone for Pneumocystis pneumonia; ethambutol (Myambutol) for Mycobacterium aviumintracellulare; and metronidazole (Flagyl, Metrolyl) for fungal infections. Certain cancer therapies, including vincristine (Oncovin), cisplatin (Platinol), and thalidomide, and high doses of vitamin B₆ can also cause neuropathy.