title: Pharmacokinetics and 48 week efficacy of adjusted dose indinavir/ritonavir in rifampicin-treated HIV/tuberculosis-coinfected patients: a pilot study.
abstract: HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/μl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.
authors.affiliation: HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Center, Pathumwan, Bangkok, Thailand. anchalee.a@hivnat.org
authors.forename: Anchalee
authors.initials: A
authors.lastname: Avihingsanon
authors.forename: Jasper
authors.initials: J
authors.lastname: van der Lugt
authors.forename: Umaporn
authors.initials: U
authors.lastname: Singphore
authors.forename: Meena
authors.initials: M
authors.lastname: Gorowara
authors.forename: Mark
authors.initials: M
authors.lastname: Boyd
authors.forename: Jintanat
authors.initials: J
authors.lastname: Ananworanich
authors.forename: Praphan
authors.initials: P
authors.lastname: Phanuphak
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Kiat
authors.initials: K
authors.lastname: Ruxrungtham
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D012367:RNA, Viral; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013785:Thailand; D017211:Treatment Failure; D014376:Tuberculosis / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D019562:Viral Load
chemical_list: D000904:Antibiotics, Antitubercular; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019469:Indinavir; D019438:Ritonavir; D012293:Rifampin