January 25, 2001; Updated
February 13, 2007|
|Susa Coffey, MD|
| 2. ||Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Delta Coordinating Committee. Lancet. 1996 Aug;348(9023):283-91|
[PubMed ID: 8709686]
BACKGROUND: Because the benefits of zidovudine (AZT) in HIV-infected individuals are small and do not last long the Delta trial was designed to test whether combinations of zidovudine with didanosine (ddl) or zalcitabine (ddC) were more effective than AZT alone in extending survival and delaying disease progression. METHODS: The trial was randomised, double blind, and international. 3207 participants were allocated to either AZT (600 mg per day) alone (1055), AZT plus ddl (400 mg per day) (1080), or AZT plus ddC (2.25 mg per day) (1072). Participants either had symptoms of HIV disease (if AIDS, with a CD4 cell count of > 50 x 10(6)/L) or a CD4 count of less than 350 x 10(6)/L; 2124 had not had zidovudine before (Delta 1) and 1083 had for at least 3 months (Delta 2). FINDINGS: Over a median follow-up of 30 months, 699 participants died, and 936 of the 2765 without AIDS at entry developed AIDS or died. In participants who had not had AZT before, both combination regimens had substantial benefits in terms of survival (regardless of disease stage at entry); a relative reduction in mortality of 42%, compared to AZT alone (95% Cl 25% to 55%), for AZT plus ddl and of 32% (95% Cl 22% to 47%) for AZT plus ddC. In participants who had had AZT before, the addition of ddl improved survival (p = 0.05; relative reduction 23% [95% Cl 0% to 41%]) but there was no direct evidence of benefit from the addition of ddC (p = 0.47; relative reduction 9% [95% Cl--17% to 29%]). The overall difference in survival between the treatment groups was significant (p < 0.0001; a relative reduction in mortality, compared to AZT alone, of 33% (95% Cl 20% to 44%) for AZT plus ddl and 21% (95% Cl 6% to 34%) for AZT plus ddC). Benefit in terms of disease progression was seen mainly in participants not previously treated with AZT and overall. There was no unexpected toxicity from the combination treatments. INTERPRETATION: Initiation of treatment with combinations of AZT plus ddl or ddC prolongs life and delays disease progression compared with AZT alone. The addition of ddl to participants already treated with AZT also improves survival, although the benefit appears less.
| 3. ||Katzenstein
The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996 Oct;335(15):1091-8
[PubMed ID: 8813039]
BACKGROUND: We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. METHODS: The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. RESULTS: After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome. CONCLUSIONS: Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.