ritonavir and Mycobacterium-Infections

Our primary aim was to evaluate the plasma exposures and safety of rifabutin and its active 25-O-desacetyl metabolite during concomitant therapy of intermittent rifabutin dosing regimens with a combination of ritonavir and saquinavir.. Twenty-four patients without mycobacterial infection who were human immunodeficiency virus seropositive and who were receiving 400 mg each of ritonavir and saquinavir twice daily participated in a 3-period, 2-group longitudinal pharmacokinetic study. Patients were equally randomized to receive 300 mg of rifabutin every 7 days (group 1) or 150 mg of rifabutin every 3 days (group 2) for 8 weeks. Blood samples were collected over the dosing intervals of the protease inhibitors at baseline (period 1) and of the 3 drugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement of plasma concentrations of the 3 drugs and 25-O-desacetylrifabutin.. Nineteen patients (group 1, n = 10; group 2, n = 9) completed the study. Five individuals withdrew from the study; 3 of them experienced side effects, and 2 were lost to follow-up. For combined groups, mean saquinavir and ritonavir overall (area under the concentration-time curve [AUC]) and peak (C(max)) plasma exposures averaged over periods 2 and 3 did not change significantly (8% to 19%; P > .05) compared with those in period 1 (90% confidence intervals, -7% to 26% for ritonavir and -2% to 38% for saquinavir). Rifabutin and metabolite AUC and C(max) exposures were stable over the 8 weeks, with intraindividual coefficients of variation of 12% to 19%. Oral clearance of rifabutin was similar in both groups (321 mL/min in group 2 versus 372 mL/min in group 1; P = .34). Rifabutin C(max) values were significantly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rifabutin and metabolite predose levels were significantly higher in group 2 (rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 28 ng/mL; P < .002).. Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing over 8 weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir.

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Analysis of Variance; Antibiotics, Antitubercular; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Male; Mycobacterium Infections; Rifabutin; Ritonavir; Saquinavir

Mycobacterial infection occurs frequently in patients that receive protease inhibitors, which are drugs used to treat AIDS, but are known for metabolic effects. Proteases of microbial antigens have been recognized as important regulators of host inflammation and cellular response. To evaluate protease inhibitor effect on a mycobacterial infection, a pilot animal model was established. Mycobacterium bovis (bacillus Calmette-Guerin, or BCG) infection was compared in rats that received ritonavir and those that did not. Tissues and serum from one drug-treated and one control were analyzed weekly. Fewer acid-fast bacilli (AFBs) were consistently found in the drug-treated group by 3 separate measures: culture of tissue homogenates on solid media, tissue granuloma counts on organ sections, and staining of tissues for AFBs. Possible mechanisms of the observed relative resistance to BCG infection in ritonavir-treated rats were explored, by evaluating M. bovis cell wall lipids and proteins and by measuring infection-related cytokines in treated and control animals.

Topics: Animals; Bacterial Proteins; Cell Wall; Cholesterol; Disease Models, Animal; HIV Protease Inhibitors; Humans; Lipoproteins; Liver; Lung; Male; Mycobacterium bovis; Mycobacterium Infections; Rats; Rats, Sprague-Dawley; Ritonavir; Spleen; Triglycerides

To analyse the characteristics of opportunistic infections in patients receiving highly active antiretroviral treatment (HAART).. A retrospective study performed in seven hospitals, included all patients starting treatment by ritonavir or indinavir between 26 March and 31 December 1996. Patients were evaluated for the development of AIDS-defining events. Clinical evaluation, plasma HIV-1 RNA quantification, CD4 cell count were recorded at baseline and at the onset of the event.. Four hundred and eighty-six patients were included: 44.2% had a CD4 cell count below 50 x 10(6) cells/l. Fifty clinical events were recorded in 46 patients with a mean follow-up of 6.1 months, of which 34 events (68%) were observed during the first 2 months of HAART. Eighteen of these occurred despite a reduction of viral load by at least 1.5 log10) and a 100% increase of the CD4 cell count compared with that at the onset of the event, corresponding to 11 cytomegalovirus infections, five mycobacterial infections, one case of cryptococcosis, and one case of Varicella-Zoster virus-related acute retinal necrosis. Among the 16 events observed after the second month, six occurred despite a marked biological improvement, corresponding to a recurrence in five of six patients who had stopped their maintenance therapy. Events were one cytomegalovirus infection, two mycobacterial infections, one episode of oesophageal candidiasis and one cryptococcal meningitis.. In patients at high risk of developing an opportunistic infection prior to the institution of a HAART regimen, prophylaxis should not be discontinued during the first 2 months of treatment, and maintenance therapy should be carried on despite a significant increase in the CD4 cell count.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Candidiasis; CD4 Lymphocyte Count; Cryptococcosis; Cytomegalovirus Infections; Disease Progression; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Hospitals, University; Humans; Indinavir; Mycobacterium Infections; Pneumonia, Pneumocystis; Retrospective Studies; Ritonavir; RNA, Viral; Toxoplasmosis, Cerebral; Viral Load