Minimising Peripheral Neuropathy in Patients Treated With HAART

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Not All Nucleoside Analogues Implicated

Peripheral neurotoxicity is not a feature of all the nucleoside analogues. In general it is accepted that zidovudine, lamivudine and abacavir† are not associated with peripheral neuropathy whereas zalcitabine, didanosine and stavudine are (see table 1).[2]

In early studies with zalcitabine, a clear dose-response relationship was seen for both the development of peripheral neuropathy and the time to onset of symptoms. The mean time to onset of symptoms was 7.3 weeks when dosages of up to 0.06 mg/kg 4 hourly were used. However, with a dose of 0.01 mg/kg 4 hourly (twice the current recommended daily dose) the mean time to symptom onset was 9.3 weeks.[2]

A number of large studies and expanded access programmes of zalcitabine monotherapy with the currently recommended dose for periods of 6 months or more, indicate that the overall incidence of peripheral neuropathy is approximately 25% (see table 1).[2] However, the proportion of patients in whom peripheral neuropathy is severe and requires treatment cessation is only about 10%.[2]

As for zalcitabine, early phase I/II studies quickly established the occurrence of a dose-related peripheral neuropathy with stavudine. Dosages in excess of 4 mg/kg/day resulted in a 64 to 73% incidence of peripheral neuropathy.[2] With the present dosage recommendation (40mg twice daily), the incidence of peripheral neuropathy appears to be similar to that seen with zalcitabine (see table 1). A large parallel-track program in the US reported the overall incidence of peripheral neuropathy to be 23% with stavudine 40mg twice daily, with only 13% discontinuing because of peripheral neuropathy.[5]

Although early phase studies with didanosine identified peripheral neuropathy as a dose-limiting toxicity, at the currently recommended dose (see table 1) the incidence of peripheral neuropathy appears to be no different to that occurring with zidovudine, a drug which is not considered to be neurotoxic.[2] In one large study (ACTG 116b/117),[4] didanosine doses of 750 mg/day, 500 mg/day (equivalent to the currently recommended dosage) or zidovudine monotherapy were administered to zidovudine-experienced patients with a median CD4+ cell count of 95/µl. The annualised incidence of grade 2 or worse peripheral neuropathy was 13% and 14% for the didanosine 750 and 500 mg/day recipients and 14% for the zidovudine recipients.[4]

† Abacavir is not available in Germany and Spain.

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