Questions remain about how to manage patients already on nucleoside monotherapy

It is not often that the results of clinical trials change clinical practice almost overnight. But that is what has happened with two clinical trials (Delta and ACTG175) of combination nucleoside analogue antiretroviral treatment for patients infected with HIV. The previously standard monotherapy had evident limitations in the extent and durability of response. The need for and expectations of better treatments was high, fuelling but also distorting the investigation of improved approaches. What are the practical implications of these studies?

Delta (conducted by a European/Australian group coordinated by Britain's Medical Research Council and the Agence National de Recherches sur le SIDA in France) and ACTG175 (conducted in the United States by the AIDS Clinical Trials Group of the National Institutes of Health) have recently released their main findings. They were large randomised double blind placebo controlled trials of zidovudine (AZT) monotherapy versus combinations of zidovudine and didanosine (ddI) or zidovudine and zalcitabine (ddC) with an additional limb of didanosine monotherapy in ACTG175. Both used clinical end points, and ACTG175 also used changes in CD4 cell count. Both recruited patients who had not previously been exposed to nucleosides (Delta 2124 patients, ACTG175 1067 patients) and symptomatic patients who had previously received nucleosides (Delta 1083 patients including patients with AIDS, CD4 count 50-350; ACTG175 1400 patients excluding patients with AIDS, CD4 count 200-500.)

They showed that, for patients who had never received nucleosides, combinations of zidovudine and didanosine, or zidovudine and zalcitabine, were significantly more effective than zidovudine alone in delaying disease progression. However, patients already exposed to nucleosides gained no benefit from combination therapy (though recently updated data …