Pharmacokinetics of Rifabutin in Japanese HIV-Infected Patients with or without Antiretroviral Therapy

<div><p>Objective</p><p>Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection.</p><p>Methods</p><p>Plasma concentrations of rifabutin and its biologically active metabolite, 25-<i>O</i>-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5–63) of rifabutin use.</p><p>Results</p><p>The mean C_max and AUC_0–24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean C_max and AUC_0–24 of 25–<i>O</i>-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing.</p><p>Conclusion</p><p>Rifabutin dose of 150 mg every other day combined with lopinavir-ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART.</p><p>Trial registration</p><p>UMIN-CTR (<a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E" target="_blank">https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E</a>) UMIN000001102</p></div

WHO Antiretroviral Therapy Guidelines 2010 and Impact of Tenofovir on Chronic Kidney Disease in Vietnamese HIV-Infected Patients

<div><p>Objective</p><p>The 2010 WHO antiretroviral therapy (ART) guidelines have resulted in increased tenofovir use. Little is known about tenofovir-induced chronic kidney disease (CKD) in HIV-infected Vietnamese with mean body weight of 55 kg. We evaluated the prevalence and risk factors of CKD in this country.</p> <p>Design</p><p>Cross-sectional study was performed.</p> <p>Methods</p><p>Clinical data on HIV-infected Vietnamese cohort were collected twice a year. To evaluate the prevalence of CKD, serum creatinine was measured in 771 patients in October 2011 and April 2012. CKD was defined as creatinine clearance less than 60 ml/min at both time points. Multivariate logistic regression was used to determine the factors associated with CKD</p> <p>Results</p><p>Tenofovir use increased in Vietnam from 11.9% in April 2011 to 40.3% in April 2012. CKD was diagnosed in 7.3%, of which 7% was considered moderate and 0.3% was severe. Multivariate analysis of October-2011 data identified age per year-increase (OR: 1.229, 95%CI, 1.170-1.291), body weight per 1 kg-decrement (1.286, 1.193-1.386), and tenofovir use (2.715, 1.028-7.168) as risk factors for CKD.</p> <p>Conclusions</p><p>Older age, low body weight and tenofovir use were independent risk factors for CKD in Vietnam. Further longitudinal study is required to evaluate the impact of TDF on renal function in Vietnam and other countries with small-body weight patients.</p> </div

Flow chart of participants through the study.

<p>PK, pharmacokinetic; ART, antiretroviral therapy.</p

Pharmacokinetic parameters for rifabutin and 25-<i>O</i>-desacetyl rifabutin.

a<p>By the Mann Whitney's <i>U</i> test.</p>b<p>In Group I, AUC_24–48 is assumed the same as AUC_0–24 and AUC_0–48 is calculated as double of AUC_0–24 for comparison with Group II.</p><p>C_max, maximum plasma concentration; AUC, area under the curve; T_max, time of C_max; CI, confidence interval.</p

Mean plasma concentrations-versus-time plots of rifabutin (A), 25-<i>O</i>-desacetyl rifabutin (B), and rifabutin plus 25-<i>O</i>-desacetylrifabutin (C).

<p>Nine patients of Group I received 300 mg of rifabutin and 7 patients of Group II received 150 mg of rifabutin every other day with lopinavir/ritonavir-containing antiretroviral therapy. <i>Solid circles:</i> Group I, <i>open circles:</i> Group II. Data are mean ±1 standard errors. Dotted line in Figure C represents data of Group I during 0–24 hour for reference. RBT, rifabutin; PI/r, ritonavir-boosted protease inhibitor.</p

Characteristics of study subjects.

a<p>By Fisher's exact test for categorical data and Mann Whitney's U test for continuous variables.</p><p>cART, combination antiretroviral therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IU, international unit.</p

Factors Associated with Acquiring AIDS-Defining Opportunistic Infections during ART.

<p>Factors Associated with Acquiring AIDS-Defining Opportunistic Infections during ART.</p

Survival Probabilities on ART in All Study Participants.

<p>(a) Survival without new AIDS events on ART. (b) Overall survival on ART. Dotted lines indicate ranges of 95% CIs.</p

Survival Probabilities on ART in Subjects without AIDS History before ART.

<p>(a) Survival without AIDS on ART in Weibull regression analysis. (b) Overall survival on ART in Weibull regression analysis. (c) Survival without AIDS on ART in semi-competing risks analysis. (d) Time to death without acquiring AIDS during ART in semi-competing risks analysis. (e) Time to death following new AIDS events during ART in semi-competing risks analysis. Dotted lines indicate ranges of 95% CIs.</p

Causes of Deaths.

<p>Causes of Deaths.</p