Safety and activity of zalcitabine and zidovudine combination in HIV-positive people with CD4 cell counts < or = 300 cells/mm3. The Roche M50002 Study Group

We carried out an open-label, single-arm, multicentre 1-year study of the safety and activity of therapy with a zalcitabine-zidovudine combination in 561 patients with CD4 cell counts < or = 300 cells/mm3 who were either established on zidovudine or had not previously received antiretroviral therapy. Additionally, we assessed the impact of baseline characteristics on clinical outcome during therapy. The study used specialist HIV-care centres in Argentina, Belgium, Brazil, Hungary, Italy, Luxembourg, Mexico, Peru, Spain and Venezuela. Participants were regularly assessed for adverse experiences, changes in laboratory values and clinical progression. A total of 561 patients entered the study, with 353 completing 12 months of follow-up. The 492 zidovudine-experienced patients had a mean duration of previous therapy of 18.5 months. No unexpected adverse events were reported. Peripheral neuropathy was observed in 12.7% of patients and was more common in participants with CD4 cell counts < or = 100 cells/mm3 at baseline. Clinical disease progression was significantly associated with lower baseline CD4 cell counts, a history of previous AIDS-defining events and a baseline haemoglobin < 11 g/dl. The median CD4 cell count at baseline was 141.5 cells/mm3, rising to 174 cells/mm3 after 12 weeks and to 148 cells/mm3 at 12 months. In conclusion, zalcitabine-zidovudine combination therapy was found to be well tolerated in this patient population, although patients with CD4 cell counts < or = 100 cells/mm3 were found to require more intensive monitoring for toxicities and disease events. The changes in the CD4 cell count seen in this study and in others provide evidence of the therapeutic activity of this combination.     

Immunological and virological activity of zalcitabine and zidovudine in combination in HIV-positive people with CD4 cell counts of between 200-500 cells/mm3

We evaluated the effect of combination therapy with zidovudine (AZT) plus zalcitabine (ddC) in human immunodeficiency virus type 1 (HIV-1)-infected patients who had not previously received antiretroviral treatment ('naive' patients). The immunological and virological parameters evaluated were CD4 cell count, syncytium-inducing (SI) viral phenotype and plasma HIV-1 RNA copies/ml (HIV viral load). A total of 75 patients entered the study, with CD4 cell counts between 200 and 500 cells/mm3. All received zidovudine (200 mg) plus zalcitabine (0.75 mg) three times daily for 24 weeks. Treatment was well tolerated. However, four patients presented with anaemia (haemoglobin < 10.0 g/dl) and one patient had both anaemia and neutropenia (0.8 x 10(9) neutrophils/l). Combination therapy with zidovudine plus zalcitabine resulted in a pronounced improvement of virological and immunological markers. Approximately 25% of patients achieved undetectable plasma HIV RNA levels (< 200 copies/ml) at week 24. At the end of the study (24 weeks) a significant reduction (> 0.5 log) of plasma HIV RNA was observed in approximately 70% of patients and in 50% an even greater decrease (> 1 log) was achieved. The most significant decrease in mean plasma HIV RNA levels was observed at week 4, whereas the highest increase in CD4 cell count was found at week 24. Approximately 80% of patients who showed baseline plasma HIV RNA levels below 20000 copies/ml had less than 5000 copies/ml at week 24. The plasma HIV RNA reduction observed at week 4 was significantly maintained at week 24. Therefore, we can rapidly select those who will not respond to therapy and adjust the treatment after a short interval. Our study supports the idea of early therapy because all patients who reached undetectable levels of plasma HIV RNA at week 24 had at baseline a median plasma HIV RNA load of 2560 copies/ml. In conclusion, zidovudine in combination with zalcitabine was well tolerated in the majority of patients and led to a significant reduction in plasma HIV RNA copies in most of the patients with initial viraemia lower than 20000 copies/ml.