Recommended rifabutin dose may not be sufficient in certain populations

Nine of 10 patients with HIV/tuberculosis coinfection who were administered lopinavir-ritonavir and 150 mg rifabutin had low maximum plasma concentration values, according to results of a recent study.

The researchers collected plasma for measurement of rifabutin (Mycobutin, Pharmacia and Upjohn), the microbiologically active 25-desacetyl-rifabutin and lopinavir by validated high-performance liquid chromatography assays in 10 patients with active TB/HIV coinfection. The sample collection schedule was as follows:

initial samples were taken 2-4 weeks after initiation of rifabutin monotherapy at 300 mg three times daily.
next samples were taken two weeks after lopinavir-ritonavir (Kaletra, Abbott) was added at 400 mg and 100 mg twice-daily to rifabutin at 150 mg three times weekly.
if rifabutin plasma concentrations were below the normal range, the next set of samples was taken two weeks after an increase in rifabutin to 300 mg three times weekly with lopinavir-ritonavir.

The schedule involving 300 mg rifabutin without lopinavir-ritonavir yielded a low maximum plasma concentration (C_max) in five of 10 patients. Adding lopinavir-ritonavir to 150 mg rifabutin resulted in nine of 10 patients with low C_max values.

There were eight patients who continued dose increases to 300 mg rifabutin with lopinavir-ritonavir. “Most free rifabutin (unbound to plasma protein) C_max values were below the TB minimal inhibitory concentration,” the researchers wrote.

Most patients demonstrated values for the area under the plasma concentration-time curve that were as low or lower than those linked to treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/U.S. Public Health Service Study 23, according to the results.

Relapse with acquired rifamycin resistance was observed in one of 10 patients.

Boulanger C et al. Clin Infect Dis. 2009;49:1305-1311.

The authors of this study hypothesized that lopinavir/ritonavir may increase the concentrations of rifabutin and/or its primary metabolite (25-desacetyl rifabutin) to toxic levels. Instead, most patients (9 of 10) on lopinavir/ritonavir and the recommended dose of rifabutin (150 mg thrice weekly) had inadequate levels of rifabutin. The dosage of rifabutin had to be increased to that used in TB patients not on ART. The data also revealed significant patient to patient variation of rifabutin’s C_max at Visit 1, which occurred before the addition of lopinavir/ritonavir. Although taking the normal dose of rifabutin (300 mg thrice weekly), five of the 10 patients had a C_maxbelow the recommended minimum before the addition of lopinavir/ritonavir. Lopinavir levels were also affected more than known previously. At Visits 2 and 3 the C_min of three patients was less than 4.0 mcg/ml, the target for treatment experienced patients.

This study is certainly not well-controlled and the sample size is small. Each patient served as his own control. More than one change occurred during the study, which sampled the patients only three times. In short, it is unclear what the exact effects of lopinavir/ritonavir and rifabutin have on each other. However, the data are provocative and support the recommendation that both the C_maxof rifabutin and the C_minof lopinavir be measured when used together. The data also support the measurement of C_maxof rifabutin in HIV infected patients in the absence of protease inhibitor use. Most HIV patients on rifabutin may be under-dosed. Further studies are needed to clarify this issue.

– Stephen Smith, MD

Infectious Disease News Editorial Board member