ritonavir and loviride

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

It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development.

Topics: Acetamides; Acetophenones; Adult; Body Fluids; Danazol; Excipients; Female; Fenofibrate; Humans; Intestines; Male; Nitriles; Pharmaceutical Preparations; Polymers; Pyridazines; Pyrimidines; Ritonavir; Solubility; Young Adult

Research topics presented at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) are highlighted. Topics include the clinical benefits of 3TC (lamivudine), combination ritonavir/saquinavir therapy, and results of an initial study of a new protease inhibitor, 141W94, under development by Glaxo Wellcome.

Topics: Acetamides; Acetophenones; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides; Viral Load