Samruay Nilkamhang

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.

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.

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.

CYP2B6 18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying CYP2B6 Haplotype *1/*1

ABSTRACT Data regarding the effect of the CYP2B6 18492T→C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C→T, 499C→G, 516G→T, 785A→G, 1375A→G, 1459C→T, and 21563C→T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T→C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean ± standard deviation (SD)], 56 ± 10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T→C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (±SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8 ± 1.6, 1.7 ± 0.9, and 1.4 ± 0.5 mg/liter, respectively (P = 0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4 ± 0.8, 1.7 ± 0.8, and 1.2 ± 0.4 mg/liter, respectively (P = 0.003). A low efavirenz concentration was independently associated with 18492T→C (β = −0.937, P = 0.004) and high body weight (β = −0.032, P = 0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P = 0.254). In summary, the CYP2B6 18492T→C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis.

Long-term treatment outcomes of ritonavir- boosted lopinavir monotherapy among HIV- infected patients who experienced NRTI and NNRTI failure

BackgroundWe continue the previously described prospective cohort study of ritonovir-boosted lopinavir (LPV/r) monotherapy for second-line therapy in HIV-infected patients with prior failure and extensive resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), with the objective being to determine the three-year treatment responses.FindingsThere were 40 patients with a mean ± SD age of 37 ± 8 years. 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. All patients received twice daily LPV/r 400/100 mg and recycled lamivudine 150 mg. By intend-to-treat analysis at 144 weeks, 26 (65%) and 22 (56%) patients achieved HIV-1 RNA at < 400 and < 50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 26 of 28 (93%) and 22 of 28 (78%), respectively. Low-level viral rebound (HIV-1 RNA 50-400 copies/mL) was found in 6 (15%), 6 (15%), and 4 (10%) patients at week 48, 96 and week 144, respectively. Medians CD4 at week 48, 96, and 144 were 351, 481, and 584 cells/mm3 and significantly changed from baseline (all, P < 0.05). There were increments of mean triglycerides at 48 weeks and 144 weeks from baseline (P < 0.05). No major protease resistance-associated mutations emerged after virologic failure.ConclusionLPV/r monotherapy with recycled lamivudine can maintain long-term virologic suppression in a relatively small proportion of patients failing NNRTI-based regimen and having limit option for active NRTI. More antiretroviral classes are needed be accessible in resource-limited countries.

Single-Boosted Protease Inhibitor versus Double-Boosted Protease Inhibitors for the Salvage Therapy in HIV-Infected Patients.

Objective: To compare treatment outcomes between the regimens of single-boosted protease inhibitor (PI) and double-boosted PIs for the salvage therapy in patients who failed nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Methods: A total of 64 patients from 2 cohorts, 40 in twice daily ritonavir-boosted lopinavir (LPV/r) at 400/100 mg plus lamivudine (3TC) and 24 in once daily ritonavir-boosted atazanavir and saquinavir (ATV/SQV/r) at 300/1600/100 mg/d, were studied. Results: At 48 weeks, 30 (75%) patients in LPV/r group and 20 (83%) patients in ATV/SQV/r group achieved HIV-1 RNA at <400 copies/mL (P = .790). In all, 24 (60%) and 16 (67%) achieved HIV-1 RNA at <50 copies/mL (P = .541). Low-level viral rebound (51-400 copies/mL) was found in 6 (15%) in LPV/r group and 4 (17%) in ATV/SQV/r group (P = 1.000). Medians CD4 counts were 336 cells/mm3 and 330 cells/mm3 in the corresponding groups (P = 0.937). Conclusion: No additional benefit is found with double-boosted PIs compared to single-boosted PI in terms of treatment responses in HIV-infected patients failing NNRTI-based regimen.