saquinavir and Tuberculosis

To assess the drug concentrations, efficacy and safety of concomitant use of rifampicin and regimens containing ritonavir/saquinavir (400mg/400mg twice daily) in tuberculosis-HIV treatment-naive patients.. This was an open-label, non-randomised, multiple-dose study. On study day (D)1, tuberculosis treatment (rifampicin 600mg/isoniazid 400mg per day fasting plus pyrazinamide 2 g/day) was introduced in 30 patients. On D31, highly active antiretroviral therapy (HAART) consisting of two nucleoside analogues plus ritonavir/saquinavir 400mg/400mg twice daily was initiated (n = 20). The pharmacokinetics were assayed with a validated reversed-phase HPLC method before the introduction of HAART on D30 (for rifampicin), after 30 days of HAART at D60 (for rifampicin plus ritonavir/saquinavir), and at the end of the study (without rifampicin) on D210 (for ritonavir/saquinavir). Clinical evaluations were performed on a monthly basis. CD4 counts and viral load were collected on D30, D60 and D180. Genotyping test for HIV was collected at baseline and at D180. Primary endpoints were drug concentration and viral load at D180 (<80 copies/mL). Secondary endpoints were presence of grade 3 and serious adverse events, clinical improvement, CD4 count and genotypic resistance to ritonavir/saquinavir.. Ten patients dropped out of the study during tuberculosis therapy alone. Mean (+/- SD) baseline CD4 count (on D30) was 151.89 (+/- 146.77) cells/mm(3) and viral load was 5.34 (+/- 0.4) log. During the antiretroviral therapy, 15 patients dropped out, 14 because of adverse events. One patient (of five) presented a viral load of <80 copies/mL at D180. All but one patient increased CD4 counts from baseline. No genotypic resistance was detected. Clinical improvement was evident in all five patients who tolerated the therapy. Serum concentrations of ritonavir/saquinavir and rifampicin remained within the therapeutic range.. Therapeutic concentrations of the studied drugs and reduction of viral load were achieved; adverse events are the main limitation of use of a ritonavir/saquinavir regimen in treatment-naive patients, but its clinical benefits were evident.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Area Under Curve; Bisexuality; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Half-Life; HIV Infections; HIV Protease Inhibitors; Homosexuality; Humans; Karnofsky Performance Status; Male; Metabolic Clearance Rate; Rifampin; Ritonavir; Saquinavir; Time Factors; Treatment Outcome; Tuberculosis; Viral Load

To assess the efficacy and safety of a once-daily regimen with didanosine, lamivudine, saquinavir, and low-dose ritonavir in antiretroviral (ARV)-naive patients with tuberculosis treated with rifampin and the influence of rifampin on plasma trough concentration (Ctrough) of saquinavir.. Single-arm, prospective, multicenter, open-label pilot study, including 32 adult ARV-naive subjects with HIV infection and tuberculosis under standard treatment that included rifampin (600 mg q.d.) and isoniazid (300 mg q.d.). After 2 months of tuberculosis treatment, patients were started on once-daily ARV therapy, consisting of didanosine, lamivudine, ritonavir (200 mg), and saquinavir soft gel capsules (1600 mg). HIV RNA level, CD4 cell count, clinical and laboratory toxicity, and saquinavir Ctrough during and after antituberculosis therapy were analyzed.. After 48 weeks of follow-up, 20 of 32 patients (62.5%; 95% CI: 45.8% to 79.2%) in the intent-to-treat population and 20 of 28 (71.4%; 95% CI: 54.4% to 88.4%) in the on-treatment population had an HIV RNA level <50 copies/mL. Treatment tolerance was acceptable in all patients except for 2 with biologic hepatic toxicity leading to discontinuation. Seven patients had virologic failure. In 10 patients (36%), saquinavir Ctrough was <0.05 microg/mL during tuberculosis therapy and 5 of them had virologic failure. The median saquinavir Ctrough was 44% lower (interquartile range: 19% to 71%) with coadministration of rifampin than without.. The combination of didanosine, lamivudine, saquinavir, and ritonavir may be a useful treatment regimen for patients with tuberculosis in whom a once-daily protease inhibitor-containing regimen is considered indicated. Nevertheless, on the basis of pharmacokinetic profile the dose of 1600/200 mg of saquinavir/ritonavir cannot be recommended. Further studies with higher doses of saquinavir (2000 mg) boosted with ritonavir are warranted.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Pilot Projects; Ritonavir; Saquinavir; Spain; Treatment Outcome; Tuberculosis

Topics: Cathepsins; Host-Pathogen Interactions; Humans; Liposomes; Macrophages; Mycobacterium tuberculosis; Saquinavir; Tuberculosis

Topics: Blood Donors; Cathepsins; CD4-Positive T-Lymphocytes; Cell Proliferation; Cell Survival; Cells, Cultured; Coinfection; Drug Repositioning; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Interferon-gamma; Macrophages, Alveolar; Mycobacterium tuberculosis; Saquinavir; Signal Transduction; Tuberculosis

To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs).. Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions.. Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid.. There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Chromatography, High Pressure Liquid; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Models, Statistical; Rifampin; Ritonavir; Saquinavir; Spectrophotometry, Ultraviolet; Tuberculosis

Topics: Antiretroviral Therapy, Highly Active; Coinfection; HIV Infections; Humans; Rifampin; Saquinavir; Tuberculosis

Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Developing Countries; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Rifampin; Ritonavir; Saquinavir; Tuberculosis

Topics: Acquired Immunodeficiency Syndrome; Antibiotics, Antitubercular; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Rifampin; Saquinavir; Treatment Outcome; Tuberculosis

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Rifampin; Ritonavir; RNA, Viral; Saquinavir; Treatment Outcome; Tuberculosis

A 30-year-old man with a known HIV infection for 7 years presented for treatment with antiretroviral drugs. He was known to have had herpes zoster, oral hairy leukoplakia and recurrent Candida stomatitis, but was otherwise without symptoms.. The CD4 lymphocyte count was 19 cells/mm3 and there were 41,000 HIV-RNA copies/ml.. The HIV infection was in CDC stage B3, indicating the need for combined antiretroviral treatment. A week after starting stavudine, saquinavir and ritonavir he had to be admitted because of nausea and vomiting, colicky abdominal pain, diarrhea, fever up to 39 degrees C and a rise of C-reactive protein to 207 mg/dl. Bacteriological examination of feces and biopsy of an enlarged retroperitoneal lymph node revealed atypical mycobacteria. Antituberculosis treatment was started. The CD4 cell count rose to 56/mm3 and the viral count fell to 11,000/ml. Each time after initiating a different antiviral regimen the symptoms recurred.. This case illustrates an atypical manifestation of on opportunistic infection: during combined antiviral treatment the CD4 cell count rose and thus precipitated an heretofore subclinical mycobacterial infection with focal lymphadenitis. If, on starting antiretroviral treatment at a late HIV stage, new symptoms develop within 1-3 weeks, one should consider drug-induced side effects or the onset of an opportunistic infection that has become manifest as the result of an improved immunological state.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lymphadenitis; Male; Mesenteric Lymphadenitis; Mycobacterium avium-intracellulare Infection; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Time Factors; Tuberculosis

Topics: Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Mycobacterium tuberculosis; Rifampin; Ritonavir; Saquinavir; Tuberculosis