Supeda Thongyen

Declining Prevalence of Drug-Resistant Tuberculosis among HIV/Tuberculosis Co-Infected Patients Receiving Antiretroviral Therapy

BACKGROUND Drug-resistant tuberculosis (DR-TB) is a serious threat in developing countries where the prevalence of both HIV and TB are high. Antiretroviral therapy (ART) has been more accessible in these countries. The present study aimed to determine the impact of ART on the prevalence of DR-TB among HIV/TB co-infected patients. MATERIAL AND METHOD A retrospective cohort study was conducted among HIV-infected patients with culture-proved TB from 1999 to 2004. Susceptibilities of Mycobacterium tuberculosis to antituberculous drugs and rate ofART use were studied. RESULTS There were 225 patients, mean age 35.8 years, 72.4% male and median CD, 44 cells/mm(3). Patients who had received ART increased from 18.5% in 1999 to 92.1% in 2004 (p<O. 001). The prevalence of DR-TB in the years 1999 and 2004 were 48% and 7.9%, respectively (p<O.001). The prevalence of isoniazid- and rifampicin-resistance significantly declined in 2004 when compared with those in 1999 (p<O. 05). CONCLUSION The declines in the prevalence of DR-TB, INH- and RFP-resistance in HIV/TB co-infected patients are possibly attributable to the use of ART In addition to the survival benefit from ART in HIV-infected patients, increasing use of ART among HIV-infected patients may eliminate DR-TB in this population.

Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy.

Background: The impact of antiretroviral therapy (ART) on survival among patients coinfected with HIV and tuberculosis (TB) has not been well established. Methods: A retrospective cohort study was conducted among HIV-infected patients with TB between January 2000 and December 2004. Patients were categorized into ART+ group (received ART) and ART− group (did not receive ART) and were followed until April 2005. Results: A total of 1003 patients were identified; 411 in ART+ group and 592 in ART− group. Median (interquartile range) CD4 count was 53 (20-129) cells/mm3. Survival rates at 1, 2, and 3 years after TB diagnosis were 96.1%, 94.0%, and 87.7% for ART+ group and 44.4%, 19.2%, and 9.3% for ART− group (log-rank test, P < 0.001). Cox proportional hazard model showed that ART was associated with lower mortality rate; gastrointestinal TB and multidrug resistant TB were associated with higher mortality rate (P < 0.05). Among patients in ART+ group, the patients who delayed ART ≥6 months after TB diagnosis had a higher mortality rate than those who initiated ART <6 months after TB diagnosis (P 0.018, hazard ratio = 2.651, 95% confidence interval = 1.152-6.102). Conclusions: 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.

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.

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.

Incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash

To determine the incidence and risk factors of rash associated with efavirenz in HIV‐infected patients with preceding nevirapine‐associated rash.

Treatment outcomes of patients co-infected with HIV and tuberculosis who received a nevirapine-based antiretroviral regimen: a four-year prospective study

BACKGROUND The concurrent use of nevirapine-based antiretroviral therapy (ART) and rifampin-containing anti-tuberculosis regimens for the treatment of HIV and tuberculosis (TB) is common in resource-limited countries. Long-term outcomes of this concurrent treatment are unknown. METHODS Seventy HIV-infected patients receiving rifampin for active TB (TB group) and 70 HIV-mono-infected patients (control group) were enrolled to receive nevirapine 400mg/day-based ART. All were followed through 4 years of ART. Plasma HIV-1 RNA and CD4 cell counts were monitored every 12 weeks until 96 weeks, and every 24 weeks thereafter. RESULTS Of the 140 patients, the median (interquartile range (IQR)) CD4 count was 31 (14-79) cells/mm(3) and median (IQR) plasma HIV-1 RNA was 5.6 (5.2-5.9) log copies/ml at baseline . Thirty-nine (55.7%) patients in the TB group were diagnosed with extrapulmonary/disseminated TB. The median duration of concurrent administration of nevirapine and rifampin was 5.4 (4.6-6.1) months. By intention-to-treat analysis, the percentage of patients who achieved HIV-1 RNA <50 copies/ml was 52.9% in the TB group and 50% in control group (p=0.866; odds ratio 1.121, 95% confidence interval 0.578-2.176); median (IQR) CD4 counts were 352 (271-580) cells/mm(3) and 425 (308-615) cells/mm(3) in the corresponding groups (p=0.238). The proportion of ART discontinuation due to any reason at 1, 2, 3, and 4 years was 21%, 34%, 37%, and 46% in the TB group and 21%, 36%, 43%, and 49% in the control group, respectively (p=0.651). The 4-year mortality rate was 6.4% in both groups. CONCLUSIONS Nevirapine-based ART is an option for HIV-infected patients who receive rifampin in resource-limited countries or those who cannot tolerate efavirenz.

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.

ABCC2*1C and plasma tenofovir concentration are correlated to decreased glomerular filtration rate in patients receiving a tenofovir-containing antiretroviral regimen

OBJECTIVES To study the correlations of genetic variants of tenofovir tubular transporters, plasma tenofovir concentrations and clinical factors with decreased glomerular filtration rate in HIV-infected patients who received tenofovir. METHODS A total of 117 HIV-1-infected patients were administered antiretroviral therapy with tenofovir/lamivudine/efavirenz. Two single nucleotide polymorphisms (SNPs), ABCC2*1C c.-24C>T and ABCB1*6 c.3435C>T, were genotyped. At week 24, plasma tenofovir concentration at 12 h after drug intake was measured. Serum creatinine and estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease study formula were measured every 24 weeks until 96 weeks. RESULTS Overall, mean ± SD age was 37 ± 9 years. Mean ± SD baseline eGFR was 130.3 ± 35.0 mL/min/1.73 m(2). The frequencies of wild-type/heterozygous/homozygous mutants of ABCC2*1C were 57%/39%/4% and those of ABCB1*6 were 28%/51%/21%. Mean ± SD plasma tenofovir concentration at 24 weeks was 105 ± 46 ng/mL. At week 48, m-ean ± SD eGFR of ABCC2*1C CC versus CT/TT was 96 versus 108 mL/min (P = 0.005) and m-ean ± SD eGFR of ABCB1*6 CC versus CT/TT was 106 versus 99 mL/min (P = 0.157). Mean ± SD tenofovir concentration in ABCC2*1C genotype CC versus CT/TT was 113 ± 47 versus 93 ± 44 ng/mL, respectively (P = 0.018). By multivariate analysis I, decreased eGFR at week 48 was correlated to ABCC2*1C genotype CC (P = 0.001), low eGFR at baseline (P = 0.006) and older age (P = 0.048). By multivariate analysis II, decreased eGFR at week 48 was correlated to high plasma tenofovir concentration (P = 0.001) and low eGFR at baseline (P = 0.019). CONCLUSIONS 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.

Treatment outcomes and plasma level of ritonavir-boosted lopinavir monotherapy among HIV-infected patients who had NRTI and NNRTI failure

BackgroundDifferent strategies of ritonavir-boosted lopinavir monotherapy have been explored; however, data regarding salvage therapy among HIV-infected patients who failed nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) is still limited.MethodsA prospective study was conducted among HIV-infected patients who failed NNRTI-based antiretroviral therapy with M184V, TAMs, and NNRTI mutations, and were naïve to protease inhibitor. LPV/r at 400/100 mg and lamivudine 150 mg were given twice daily. CD4 and HIV-1 RNA were monitored at week 0, 12, 24, and 48. LPV Cmin was assayed for the first 14 patients using HPLC.ResultsThere were 40 patients with a mean age of 37 years and 70% were male. Median (IQR) baseline CD4 was 123 (37-245) cells/mm3 and median (IQR) HIV-1 RNA was 55,800 (9,670-100,000) copies/mL. By intend-to-treat analysis, 30 (75%) and 24 (60%) patients achieved HIV-1 RNA at <400 and <50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 29 (83%) and 23 (67%), respectively. Low-level viral rebound was found in 6 (15%) patients at week 48. Medians CD4 at week 12, 24, 36 and 48 were 249, 283, 307, and 351 cells/mm3 and significantly changed from baseline (all, P < 0.05). At 6 and 12 weeks, median (min-max) LPV Cmin was 6.52 (1.62-11.64) mg/L and 5.79 (0.75-16.31) mg/L, respectively. There were increments of mean total cholesterol and triglyceride at 48 weeks from baseline (P < 0.05).ConclusionLPV/r monotherapy with recycled lamivudine can maintain virological suppression in a substantial proportion of patients failing NNRTI-based regimen and provides adequate plasma concentrations of LPV although the incidence of low-level viremia is relatively high.

HIV-1 drug resistance-associated mutations among antiretroviral-naive Thai patients with chronic HIV-1 infection.

Antiretroviral therapy (ART) has increased in resource‐limited settings. This study determined the prevalence of HIV‐1 drug resistance‐associated mutations (DRAMs) among patients with chronic HIV‐1 infections and compare DRAMs between CRF01_AE and B subtypes. ART‐naive Thai patients who had ART initiation between 2010 and 2011 were enrolled prospectively. Genotypic assays were performed on viral reverse transcriptase and protease genes within 4 weeks before starting ART. DRAMs were assessed using the International AIDS Society‐USA 2011 list. A total of 330 patients were included. HIV‐1 subtypes included CRF01_AE (73%), B (23.9%), and others (3.1%). Median (IQR) CD4+ was 66 (23–172) cells/mm3 and median (IQR) HIV‐1 RNA was 5.2 (4.6–5.8) log copies/ml. The prevalence of patients with ≥1 DRAMs for any antiretroviral agents was 17.6%. DRAM prevalence was 17% for non‐nucleoside reverse transcriptase inhibitors (NNRTIs), 0.6% for NRTIs, and 0.6% for protease inhibitors (PIs). DRAMs to NNRTIs were V106I (7%), V179D (4.2%), V179T (1.8%), E138A (1.5%), V90I (1.2%), K103N (0.9%), Y181C (0.9%), and P225H (0.3%). DRAMs to NRTIs were M184V (0.3%) and T215S (0.3%). The only major DRAM for PIs was M46L (0.6%). Minor DRAMs to PIs including I13V, M36I, H69K, and L89M were observed more frequently in CRF_01 AE. By multivariate analysis, the factors “HIV‐1 subtype B” and “low pretreated CD4+ cell count” were associated with a higher rate of DRAMs. HIV‐1 DRAMs, especially to NNRTIs, are emerging in a middle‐income country after widespread use of NNRTI‐based ART. HIV genotypic assays before ART initiation in patients with chronic HIV‐1 infection should be considered. J. Med. Virol. 85:194–199, 2013.