Minimising Peripheral Neuropathy in Patients Treated With HAART

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Avoid Overlapping Toxicities

Nucleoside analogue reverse transcriptase inhibitors are more effective in double or triple therapy regimens than as monotherapy. The current standard of care is to use HAART, which comprises 2 nucleoside analogues combined with a drug from a second therapeutic class.[1] It is therefore important that there is no overlapping toxicity with the chosen combination of drugs.

An increased incidence of peripheral neuropathy has not been seen with the addition of zidovudine to currently recommended dosages of zalcitabine (see table 1).[2] In the ACTG 155 study, after a median follow-up of 17.8 months, the incidence of severe peripheral neuropathy was 6% in both the zalcitabine monotherapy and combination groups and 4% in the zidovudine monotherapy group.[2]

The incidence of peripheral neuropathy with combined zidovudine and didanosine at the currently recommended dose (see table 1) is essentially the same as that seen for zidovudine alone. In ACTG 175, moderate or worse peripheral neuropathy after 143 weeks of follow-up was reported for 9, 8 and 8% of zidovudine, zidovudine plus didanosine and didanosine recipients, respectively.[2,7]

The combined administration of zalcitabine and the protease inhibitor saquinavir does not appear to increase the likelihood of patients developing peripheral neuropathy and may even decrease it. In a randomised, double-blind, placebo-controlled study of zalcitabine 0.75mg 3 times daily compared with saquinavir 600mg 3 times daily and the 2 drugs combined in patients with HIV infection, the incidence of peripheral neuropathy was lower in the combination group (9%) compared with zalcitabine alone (25%).[8]

Furthermore, with a triple therapy regimen of zalcitabine, saquinavir and zidovudine, no difference in the incidence of peripheral neuropathy was seen compared with double combinations of zidovudine/zalcitabine and zidovudine/ saquinavir.[9] The overall incidence of peripheral neuropathy in this study was very low (1.9 to 2.6%); this was probably due to the inclusion of patients with early HIV disease who had no or only minimal previous exposure to antiretroviral therapy.[2]

Although the combination of stavudine and didanosine is being increasingly used, its safety during prolonged usage has not been well documented. In an early dose-finding study of this combination, 86 patients were treated in 5 dose groups ranging from stavudine 10mg twice day plus didanosine 100µg twice daily up to the approved doses of both drugs (see table 1).[10] Only 2 cases of grade 3 or worse peripheral neuropathy, requiring treatment withdrawal were seen during 1 year of follow-up. Further data are needed to confirm this finding.


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