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Nucleoside analogue reverse transcriptase inhibitors form the basis of the majority of treatment regimens for patients with HIV infection. The current standard of care, highly active antiretroviral therapy (HAART), is a combination of 2 nucleoside analogues and a third agent from another therapeutic class.[1] The development of peripheral neuropathy during therapy with nucleoside analogues is one of the factors which needs to be considered when selecting appropriate combination regimens for HIV-infected individuals.[2]
Relating the onset of neuropathy to the commencement of treatment may help determine causality, but a firm diagnosis can only be made if symptoms improve or resolve within 1 to 2 months of stopping the suspected nucleoside analogue.[2]
Neuropathy Dose Related For Zalcitabine...
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]
...And Stavudine
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]
Minimal Neuropathy With Didanosine
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.
Zidovudine Combinations Look Promising...
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]
...As Does Zalcitabine Plus Saquinavir
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]
Confirmation Required for Stavudine/Didanosine
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.
Some of the most important risk factors for the development of nucleoside analogue-related peripheral neuropathy in HIV-infected individuals are outlined in table 2. The existence of any of these factors should be ascertained by taking a careful medical history, performing routine diagnostic procedures and examining the lower limbs for signs of peripheral neuropathy.
For 'at risk' patients or those with an equivocal clinical picture of peripheral neuropathy, nerve conduction studies may be helpful in determining whether to use didanosine, zalcitabine or stavudine.[2]
Treat Neuropathic Pain
For those who develop peripheral neuropathy, adequate treatment of any associated pain is important. Nonsteroidal anti-inflammatory drugs and simple analgesics may be sufficient.[2] For more severe, chronic pain tricyclic antidepressants, such as amitriptyline, may be helpful.[2] Anticonvulsants such as carbamazepine, valproic acid or possibly gabapentin, can be tried to alleviate severe lancinating pain.[2]
Symptom Intensification on Drug Withdrawal
If treatment with nucleoside analogues is withdrawn, patients should be warned that a period of symptom intensification may occur after stopping treatment. This has especially been noted following the withdrawal of zalcitabine. Patients need to be reassured that although symptom intensification may last for several weeks to months, recovery of the sensory loss will usually occur.[2]
Consider Future Treatment Carefully
If a decision is made to discontinue the suspected nucleoside analogue, a careful assessment of the remaining treatment options needs to be made.Avoiding suboptimal antiviral cover needs to be taken into account as does the patient's history of past antiretroviral treatment and desire for further therapy.
Consideration should be given to the following options:[2]
If it is not appropriate to further treat the patient with nucleoside analogues, dual protease inhibitor combinations can be tried or treatment with a protease inhibitor plus a non-nucleoside reverse transcriptase inhibitor could be initiated.
Feature Drug Zalcitabine Didanosine Stavudine Recommended dose: oral 0.75mg tid 200mga bid 40mg bid intravenous 0.01 mg/kg 8-hourly 2.5 mg/kg 12-hourly 0.6 mg/kg 12-hourly With monotherapy at the recommended dose:b likelihood of developing PN 25%[2] 14%[4] 23%[5] likelihood of withdrawing from therapy because of PN 10%[2] 6%[6] 13%[5]
a 200mg chewable tablet is equivalent to 250mg of the sachet formulation used in early clinical trials. b Percentages are approximate. Abbreviations: bid = twice a day; tid = 3 times a day.
Existing peripheral neuropathy Prior history of peripheral neuropathy Low CD4+ cell counts (<100/µl) Prior AIDS-defining opportunistic infection or neoplasm Use of other neurotoxic agents [e.g. heavy consumption of alcohol (ethanol)] Nutritional deficiencies [e.g. low serum hydroxocobalamin (vitamin B12) levels] Use of drugs associated with peripheral neuropathy (e.g. dapsone) Diabetes mellitus
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