Antiretroviral therapy substantially reduces mortality rate among HIV/TB-coinfected patients. Initiation of ART within 6 months of TB diagnosis is associated with greater survival.

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.

In middle-income countries where ART is initiated at CD4 count of <350 cells per cubic millimeter, immediate initiation of ART in HIV-infected patients with active TB was not associated with survival advantage when compared to initiation of ART at 12 weeks.

bComprehensive 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.

ObjectiveTo determine the incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash. MethodsA retrospective cohort study was conducted in HIV-infected patients diagnosed with nevirapineassociated rash who subsequently received efavirenz between July 2003 and January 2005. Patients were followed up for 3 months after receiving efavirenz. Possible risk factors, including demographics, previous opportunistic infections, CD4 cell count, viral load, severity of nevirapineassociated rash and concurrent drugs, were studied and compared between those who had (group A) and did not have (group B) rash associated with efavirenz. ResultsA total of 122 patients (52.5% male) were included in the study, with a mean age of 38.2 years. Median (and interquartile range) CD4 cell count and viral load were 55 (20-167) cells/mL and 86 150 (35 321-700 750) HIV-1 RNA copies/mL, respectively. Of the 122 patients, 10 (8.2%) developed rash associated with efavirenz and all required discontinuation of efavirenz. The baseline characteristics of group A (10 patients) and group B (112 patients) were similar. Median (and interquartile range) time from nevirapine discontinuation to efavirenz initiation was 12 (9-21) days in group A and 11 (7-21) days in group B (P 5 0.765). None of the risk factors investigated was associated with developing rash associated with efavirenz. The preceding development of severe nevirapineassociated rash had a trend towards a higher rate in group A than in group B (20.0% vs 10.7%; odds ratio 5 2.08; 95% confidence interval 0.39-10.97; P 5 0.322). ConclusionsThe majority (490%) of HIV-infected patients with CD4 counts o200 cells/mL who had preceding nevirapine-associated rash could tolerate efavirenz well. Efavirenz may be an option for subsequent use in these patients, particularly in those who had preceding nevirapine-associated rash.Keywords: efavirenz, HIV, incidence, nevirapine, rash, risk factor IntroductionHighly active antiretroviral therapy (HAART) has been widely used for treatment of patients with advanced HIV infection, and has been successful in achieving immune restoration and thus reducing morbidity and mortality [1][2][3]. Nevirapine (NVP) and efavirenz (EFV) are nonnucleoside reverse transcriptase inhibitors (NNRTIs) that have been shown to have high antiretroviral efficacy [4][5][6]. NNRTI-based HAART regimens are preferred because of their high efficacy and tolerability and lower long-term toxicity [7][8][9]. In developing countries, NVP-based HAART has been widely used because it is more readily available than other types of HAART. Skin rash is the most frequently observed adverse event associated with NVP, manifesting as a diffuse maculopapular rash or erythematous rash with or without constitutional symptoms. The risk of rash of any severity is greatest in the first 6 weeks of treatment [10]. Generally, the rash is mild and transient. However, a more severe rash including extensive maculopapular rash, serum sickness-like rea...

HIV-infected patients who carry ABCC2*1C genotype CC at position -24 or have high plasma tenofovir concentration are at risk of decreased glomerular filtration rate.

Nevirapine-based ART is an option for HIV-infected patients who receive rifampin in resource-limited countries or those who cannot tolerate efavirenz.

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 (C 12 ) were monitored. The mean ؎ standard deviation efavirenz C 12 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 C 12 at weeks 6 and 12 (P ‫؍‬ 0.003, r ‫؍‬ ؊0.255). The efavirenz C 12 regression prediction line at 1 mg/liter intercepted a mean body weight of 57.5 kg.N 2 R was a randomized clinical trial comparing the clinical efficacies of two nonnucleoside reverse transcriptase inhibitorbased highly active antiretroviral therapy (HAART) regimens for patients coinfected with human immunodeficiency virus (HIV) and tuberculosis who received rifampin (rifampicin) (9). A secondary objective was to assess body weight as a cutoff for selecting the daily dosage of efavirenz. Patients were enrolled and followed through 60 weeks after HAART. Inclusion criteria were described previously (9). All patients were started on twice-daily stavudine-lamivudine and efavirenz at 600 mg/day at bedtime. The dosages of rifampin were 450 mg/ day for body weights of Յ50 kg and 600 mg/day for body weights of Ͼ50 kg. Fasting efavirenz concentrations at 12 h after dosing (C 12 ) were measured with a validated highperformance liquid chromatography assay at weeks 6 and 12 and at 6 to 12 weeks after rifampin discontinuation. This assay was developed at the Department of Clinical Pharmacology of the University Medical Center Nijmegen, Nijmegen, The Netherlands (5).All statistical analyses were performed with SPSS version 11.5 (SPSS Inc., Chicago, IL). Pearson's correlations were used to study the relationships between parameters. Factors possibly predictive of efavirenz C 12 and an elevated serum alanine aminotransferase (ALT) activity at week 12 were evaluated with a linear-regression model. Inter-or intrapatient variability was expressed as a coefficient of variation (CV). The institutional ethics committees of the Bamrasnaradura Infectious Diseases Institute and the Thai Ministry of Public Health approved this study.Seventy-one patients were enrolled; 65% were male, and the mean Ϯ standard deviation (SD) baseline body weight was 53 Ϯ 10 kg. The mean Ϯ SD baseline CD4 cell count was 75 Ϯ 68/l, the median (interquartile range) log plasma HIV type 1 RNA copy number was 5.8 (range, 5.6 to 5.8), and the mean Ϯ SD serum ALT activity was 29 Ϯ 18 U/liter. Six (8.5%) patients were positive for hepatitis B surface antigen, and 18 (25.4%) were positive for hepatitis C antibody. The mean Ϯ SD efavirenz C 12 at weeks 6 and 12 and after rifampin discontinuation are shown in Fig. 1. After stratification into four groups by body weight (35 to 45, 46 to 55, 56 to 65, and Ͼ66 kg) at week 6, the mean C 12 were 7.6 mg/liter, 4.1 mg/liter, 2.4 mg/liter, and 1.8 mg/...