Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam.
BACKGROUND
Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured.


METHODS
This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.


RESULTS
Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.


CONCLUSIONS
Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.


BACKGROUND
ClinicalTrials.gov NCT00651066.
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam.
Nguyen Thi Ngoc
NT
Lan
Pasteur Institute, Ho Chi Minh City, Vietnam.
Nguyen Thi Nguyet
NT
Thu
Clinical Pharmacy Department, Bicêtre Hospital, Assistance-Publique Hôpitaux de Paris, Kremlin-Bicêtre, France ; Clinical Pharmacy and Pharmacokinetics Department (EA4123), University Paris Sud, Chatenay Malabry, France.
Aurélie
A
Barrail-Tran
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam.
Nguyen Hong
NH
Duc
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam.
Nguyen Ngoc
NN
Lan
ANRS, Ho Chi Minh City, Vietnam.
Didier
D
Laureillard
Pasteur Institute, Ho Chi Minh City, Vietnam.
Truong Thi Xuan
TT
Lien
Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
Laurence
L
Borand
ANRS, Ho Chi Minh City, Vietnam.
Catherine
C
Quillet
Biostatistics Unit, Medical Research Council, Durban, South Africa.
Catherine
C
Connolly
The International Union Against Tuberculosis and Lung Diseases, Paris, France.
Dominique
D
Lagarde
TB Research Unit, Medical Research Council, Durban, South Africa ; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), South Africa.
Alexander
A
Pym
World Health Organization Stop Tuberculosis Program, Geneva, Switzerland.
Christian
C
Lienhardt
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam.
Nguyen Huy
NH
Dung
Clinical Pharmacy Department, Bicêtre Hospital, Assistance-Publique Hôpitaux de Paris, Kremlin-Bicêtre, France.
Anne-Marie
AM
Taburet
The International Union Against Tuberculosis and Lung Diseases, Paris, France ; London School of Hygiene and Tropical Medicine, London, United Kingdom.
Anthony D
AD
Harries
D000328:Adult; D000904:Antibiotics, Antitubercular / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D044466:Asian People; D001682:Biological Availability; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D061466:Lopinavir / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D017828:Rifabutin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology; D014744:Vietnam
D000904:Antibiotics, Antitubercular; D017320:HIV Protease Inhibitors; D017828:Rifabutin; D061466:Lopinavir; D019438:Ritonavir