A re-evaluation of zalcitabine

Early in the HIV epidemic, zalcitabine (ddC) emerged as a nucleoside analogue reverse transcriptase inhibitor (NRTI) alternative to zidovudine (ZDV). However, a comparative study suggested ZDV monotherapy provided superior clinical benefit in treatment-naive patients with advanced immunodeficiency. Thus, ddC became most widely used in those patients no longer benefitting from or intolerant of ZDV. In ZDV-failed or -intolerant patients, ddC demonstrated similar benefit (or absence of benefit) to ddI monotherapy. In the first clinical end-point study of combination therapy, addition of ddC to on-going ZDV in patients substantially pre-treated with ZDV resulted in no overall benefit but some clinical advantage in a subset of patients with CD4 cell counts of 150 - 300/mm. Furthermore, initial studies of ddC, mostly performed in persons with advanced immunodeficiency and symptomatic HIV infection, indicated that 10 - 20% of ddC recipients developed a treatment-limiting peripheral neuropathy. Based on these early trials, a widespread perception that ddC was an antiviral with both limited activity and a potentially problematic safety profile evolved. More recent data suggest that the role of ddC requires re-evaluation. Indeed, the European Medicines Evaluation Agency (EMEA) has recently expanded the licencing claim of ddC stating that it "is indicated in HIV-infected adults in combination with other antiretroviral agents". The purpose of this short review is to discuss data that have shed new light on what in antiretroviral terms is an 'old' drug.