HIV-1 VIRAL LOAD, PHENOTYPE, AND RESISTANCE IN A SUBSET OF DRUG-NAIVEPARTICIPANTS FROM THE DELTA-TRIAL

Background The Delta trial showed that combination therapy (zidovudine plus didanosine and zidovudine plus zalcitabine) substantially length ened life and reduced disease progression compared with zidovudine mon otherapy. We did a nested virological study in three countries (France , the Netherlands, and the UK) to investigate changes in markers for v iral load and antiretroviral-drug resistance during therapy. Methods 2 40 zidovudine-naive HIV-l-infected patients were randomly assigned zid ovudine only (n=87), zidovudine plus didanosine (n=80), or zidovudine plus zalcitabine (n=73). Viral load in peripheral-blood mononuclear ce lls and plasma was measured by quantitative culture. Plasma HIV-1 RNA was measured by reverse-transcriptase PCR amplification, and serum p24 antigen by ELISA. Resistance to antiretroviral drugs was measured phe notypically by culture and genotypically by detection and quantificati on of drug-related point mutations in the pol gene. Analyses were done by intention to treat. Findings The reduction in viral load was great est 4-12 weeks after the start of therapy and was most pronounced in t he combination-therapy study groups (median reductions of RNA at 4 wee ks 1.58, 1.28, and 0.49 log(10) copies/mL for zidovudine plus didanosi ne, zidovudine plus zalcitabine, and zidovudine only, respectively). R NA levels at 8 weeks were predictive of disease progression and death after allowance for baseline values. At 48 weeks, the proportion of pa rticipants with phenotypic zidovudine resistance was similar in all th ree groups: didanosine and zalcitabine resistance were rare; zidovudin e genomic resistance correlated with phenotypic resistance (r=0.54, p< 0.0001) and developed earlier in the combined-therapy groups. However, participants in the zidovudine monotherapy group had higher circulati ng loads of resistant virus than those in the combined-therapy groups. Interpretation Combined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance w as common in monotherapy and combined-therapy groups, circulating conc entrations of resistant virus were substantially lower in the combinat ion groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine.