Wiroj Mankatitham

A Randomized Trial Comparing Plasma Drug Concentrations and Efficacies between 2 Nonnucleoside Reverse-Transcriptase Inhibitor-Based Regimens in HIV-Infected Patients Receiving Rifampicin: The N2R Study

BACKGROUND To our knowledge, to date, no prospective, randomized, clinical trial has compared standard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis (TB) who are receiving rifampicin. METHODS Rifampicin recipients with concurrent HIV-1 infection and TB were randomized to receive antiretroviral therapy that included either efavirenz (600 mg per day) or nevirapine (400 mg per day). Efavirenz and nevirapine concentrations at 12 h after dosing (C12) were monitored at weeks 6 and 12. CD4+ cell counts and HIV-1 RNA levels were assessed every 12 weeks. RESULTS One hundred forty-two patients were randomized into 2 groups equally. The mean body weight of patients was 53 kg, the mean CD4+ cell count was 65 cells/mm3, and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12, the mean C12 of efavirenz (+/- standard deviation) were 4.27+/-4.49 and 3.54+/-3.78 mg/L, respectively, and those for nevirapine were 5.59+/-3.48 and 5.6+/-2.65 mg/L, respectively. Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group (coefficient of variation, 107% vs. 47%). At week 12, 3.1% of patients in the efavirenz group and 21.3% in the nevirapine group had C12 values that were less than the recommended minimum concentrations (odds ratio, 8.396; 95% confidence interval, 1.808-38.993; P= .002). Intention-to-treat analysis revealed that 73.2% and 71.8% of patients in the efavirenz and nevirapine groups, respectively, achieved HIV-1 RNA levels <50 copies/mL at week 48, with respective mean CD4+ cell counts of 274 and 252 cells/mm3 (P> .05). Multivariate analysis revealed that patients with low C12 values and those with a body weight <55 kg were 3.6 and 2.4 times more likely, respectively, to develop all-cause treatment failure (P< .05). CONCLUSIONS Antiretroviral therapy regimens containing efavirenz (600 mg per day) were less compromised by concomitant use of rifampicin than were those that contained nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB. Low drug exposure and low body weight are important predictive factors for treatment failure.

Standard‐dose efavirenz vs. standard‐dose nevirapine in antiretroviral regimens among HIV‐1 and tuberculosis co‐infected patients who received rifampicin

There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day‐based antiretroviral therapy (ART) among HIV‐1 patients with tuberculosis (TB) and receiving rifampicin.

Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.

Background:The International Network for the Study of HIV-associated IRIS (INSHI) recently published criteria for tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) diagnosis. The performance of this definition and clinical manifestations of TB-IRIS were studied. Methods:Antiretroviral therapy-naive HIV/TB Thai patients receiving antituberculous therapy were enrolled during 2006–2007 and prospectively followed through 24 weeks of antiretroviral therapy. Patients were defined as having paradoxical TB-IRIS if they fulfilled the ‘study definition’ by French 2004 and were confirmed by an external reviewer. All were later compared by the classification according to ‘INSHI-2008’. Results:For the 126 patients, median baseline CD4 cell count was 43 cells/μl and HIV-1 RNA was 5.9 log10 Ý copies/ml. Seventy-three (58%) had extrapulmonary/disseminated TB. Twenty-two (18%) and 21 (17%) fulfilled TB-IRIS criteria according to the study definition and INSHI-2008 definition, respectively. Two (2%) were diagnosed by study definition only and one (1%) by INSHI-2008 definition only. Twenty (16%) were concordantly diagnosed by both definitions and 103 (82%) were consistently negative. Eighteen (82%) had worsening of a preexisting site, whereas four (18%) had TB-IRIS in a new location. Lymph node enlargement (73%) and fever (59%) were common in TB-IRIS. Sensitivity and specificity of INSHI-2008 was 91% (95% confidence interval, 72–98%) and 99% (95% confidence interval, 95–99.8%), respectively. Positive predictive value was 95% and negative predictive value was 98%. By multivariate analysis, factors predicting TB-IRIS were extrapulmonary TB (odds ratio, 8.63) and disseminated TB (odds ratio, 4.17). Conclusion:There was high concordance between the INSHI-2008 and French 2004 definition for TB-IRIS diagnosis in HIV/TB patients with relatively high rate of paradoxical TB-IRIS. This suggests that lack of HIV-1 RNA and CD4 cell count monitoring does not impede the ability to diagnose TB-IRIS.

Impact of Pharmacogenetic Markers of CYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

ABSTRACT Comprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable. A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Plasma efavirenz concentrations were measured at 12 weeks. The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter. The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%). The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%). The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P < 0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P < 0.05). Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations. As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta = −1.084, P = 0.027) and high body weight (beta = −0.076, P = 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.

Body weight cutoff for daily dosage of efavirenz and 60-week efficacy of efavirenz-based regimen in human immunodeficiency virus and tuberculosis coinfected patients receiving rifampin.

ABSTRACT Seventy-one human immunodeficiency virus-infected patients with tuberculosis who were receiving a rifampin (rifampicin)-containing regimen were initiated on treatment with efavirenz at 600 mg/day plus stavudine-lamivudine. Fasting efavirenz concentrations at 12 h after dosing (C12) were monitored. The mean ± standard deviation efavirenz C12 at weeks 6 and 12 and after rifampin discontinuation were 4.5 ± 4.3, 3.8 ± 3.5, and 3.5 ± 2.7 mg/liter, respectively. High body weight was associated with a low efavirenz C12 at weeks 6 and 12 (P = 0.003, r = −0.255). The efavirenz C12 regression prediction line at 1 mg/liter intercepted a mean body weight of 57.5 kg.