didanosine and loviride

To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment.. The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1 year.. This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for clinical progression.. The correlation between 12-20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA.. After 12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10 at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x 10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71).. Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial.

Topics: Acetamides; Acetophenones; Acquired Immunodeficiency Syndrome; Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; RNA, Viral; Treatment Outcome; Viral Load; Zalcitabine; Zidovudine

Previous studies have shown that combination therapy with lamivudine plus zidovudine causes pronounced and sustained increases in CD4 counts and reductions in viral load in individuals infected with HIV-1. We assessed the clinical benefit of the addition of lamivudine to zidovudine-based regimens in patients infected with HIV-1 who had CD4 counts of 25-250/microL.. Eligible patients receiving zidovudine monotherapy or zidovudine plus zalcitabine or didanosine combination therapy were assigned 52 weeks of treatment with the addition of placebo, lamivudine (150 mg twice a day), or lamivudine (150 mg twice a day) plus loviride (100 mg three times a day). Patients were unaware of type of treatment allocated. The primary endpoint was progression to a new protocol-defined AIDS event or death.. The study was terminated following the second interim analysis because of a highly significant reduction in progression to AIDS or death in the patients treated with lamivudine rather than placebo. In the final analysis of 1840 patients, progression had occurred in 95 (20%) of 471 placebo-treated patients, 86 (9%) of 907 lamivudine-treated patients, and 42 (9%) of 462 patients who received lamivudine plus loviride (p < 0.0001, relative hazard 0.42 [95% CI 0.32-0.57]). A significant survival benefit was also seen (p = 0.0007, relative hazard 0.40 [0.23-0.69]). Significantly fewer patients in the lamivudine group than in the placebo group required hospital admission, unscheduled visits, or prescribed medications for HIV-related events. There were no differences in the frequency or severity of clinical or laboratory toxicities between the treatment groups.. The addition of lamivudine to zidovudine-containing treatment regimens significantly slowed the progression of HIV disease and improved survival. However, it is unlikely that this combination alone would be sufficient to achieve long-term complete suppression of viral replication in all patients.

Topics: Acetamides; Acetophenones; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Health Services; HIV-1; Humans; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine

Topics: Acetamides; Acetophenones; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Controlled Clinical Trials as Topic; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Survival Rate; Zalcitabine; Zidovudine

CD8+ T lymphocytes may mediate important host responses to human immunodeficiency virus (HIV) infection by human leukocyte antigen (HLA)-restricted cytotoxicity and production of soluble HIV suppressor factors. CD8+ lymphocytes are also important for the suppression of many latent pathogens responsible for opportunistic disease in HIV-infected patients. There has been no systematic analysis of the responses of CD8+ lymphocyte counts to antiretroviral therapy. We compared CD8+ lymphocyte responses in seven trials of nucleoside or non-nucleoside analog reverse transcriptase inhibitors and in two trials of ritonavir, a HIV protease inhibitor. Nucleoside analog and non-nucleoside analog reverse transcriptase inhibitor monotherapy resulted in no substantial changes in CD8+ counts relative to baseline or placebo. Combination nucleoside analog therapy resulted in variable peak responses (-145 to +240 cells/mm3), which remained significantly above baseline for 0 to 12 weeks. In contrast, ritonavir monotherapy caused a peak increase of 892 CD8+ cells/mm3, which remained significantly above baseline for 32 weeks. There was a significant correlation (Rs 0.61, p = 0.01) between the peak CD4+ cell and CD8+ responses to each therapy, but no significant correlation between the peak viral load responses and peak CD8+ cell responses. These findings suggest that the greater CD8+ response seen with ritonavir may be due to its specific inhibition of HIV protease and also that the CD8+ response is dependent on new CD4+ cell production. The CD8+ lymphocyte proliferation observed with protease inhibitor therapy could result in improved suppression of HIV replication by the immune system and should be confirmed in a prospective trial comparing protease inhibitors with both nucleoside and non-nucleoside analog therapies.

Topics: Acetamides; Acetophenones; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Lamivudine; Lymphocyte Count; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Zalcitabine; Zidovudine