COMPARISON OF THAI GOVERNMENT MANUFACTURED TENOFOVIR (TENOFOVIR GPO300) WITH PRIVATELY MANUFACTURED TENOFOVIR (VIREAD) USED ALONG WITH LAMIVUDINE AND EFAVIRENZ TO TREAT THAI HIV PATIENTS.

The Thai Government Pharmaceutical Organization (GPO) has produced a nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (Tenofovir GPO300). No clinical trial to date has compared plasma tenofovir concentrations, renal function, and treatment responses in HIV-infected patients who received Teno- fovir GPO300 versus Viread (original tenofovir) as part of an antiretroviral regimen. We studied 129 antiretroviral treatment (ART)-naive HIV-1 infected patients who received an antiretroviral regimen of lamivudine, efavirenz and Tenofovir GPO300 (n = 65) or Viread (n = 64). We examined plasma tenofovir concentrations (12 hours after dosing), serum creatinine, estimated glomerular filtration rate (eGFR) using the Modification in Diet in Renal Disease (MDRD) study formula, fractional excretion of phosphate (FEphos), CD4 and plasma HIV-1 RNA levels at 12 weeks, and CD4 and plasma HIV-1 RNA levels at 24 weeks after initiating the drugs. At baseline, the mean ± SD subject body weight was 54 ± 10 kilograms and the mean ± SD subject age was 37 ± 8 years. At baseline, the median (IQR) CD4 count was 44 (18-120) cells/ mm3 and the median (IQR) HIV-1 RNA level was 5.8 log copies/ml. At baseline, the mean ± SD eGFR was 134.8 ± 43.6 ml/min/1.73 m2. The baseline values for the two groups were not significantly different from each other (p > 0.05). At 12 weeks, the mean ± SD plasma tenofovir concentration was 106.9 ± 41.5 ng/ml among the patients who received Tenofovir GPO300 and 100.7 ± 49.4 ng/ml among those who received Viread (p = 0.437). At week 12, there were no differences between those who rceived Tenofovir GPO300 and Vilead in mean serum creatinine (0.78 vs 0.81 mg/dl, p = 0.283), mean eGFR (117.9 vs 109.1 ml/min/1.73 m2, p = 0.089), decline in eGFR from baseline (-21.8 vs -20.6 ml/min/1.73 m2, p = 0.860) or mean FEphos (11.4 vs 11.2, p = 0.923). The median CD4 cell counts and number of patients with undetectable plasma HIV-1 RNA at week 24 were not significantly different (p > 0.05) between those who took Tenofovir GPO300 and Viread. In summary, plasma tenofovir concentrations, changes in renal function, urinary phosphate excretion and treatment responses were comparable between HIV-infected patients who received Tenofovir GPO300 and Viread-containing non-nucleoside reverse transcriptase regimens.

CYP2B6 18492T->C polymorphism compromises efavirenz concentration in coinfected HIV and tuberculosis patients carrying CYP2B6 haplotype *1/*1.

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 (ß=-0.937, P=0.004) and high body weight (ß=-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.

Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients.

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.

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/mm(3) 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.

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

BACKGROUND: We 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. FINDINGS: There 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. CONCLUSION: LPV/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.

CYP2B6 haplotype and biological factors responsible for hepatotoxicity in HIV-infected patients receiving efavirenz-based antiretroviral therapy.

Data on the pharmacogenetic markers of CYP2B6 and biological factors associated with hepatotoxicity in HIV-infected patients receiving an efavirenz-based antiretroviral therapy (ART) regimen are very limited. A total of 134 HIV-infected Thai adults were prospectively enrolled to receive a once-daily regimen of efavirenz 600 mg/tenofovir/lamivudine. Seven single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped using real-time PCR. At 12 weeks after ART, plasma efavirenz concentrations at 12h after dosing were measured. The mean ± standard deviation patient age was 37 ± 8 years, and 77.6% were male. The median (IQR) CD4 count was 43 cells/mm(3) (17-105 cells/mm(3)). Eighteen patients (13.4%) had positive anti-HCV and 5 patients (3.7%) had positive HBsAg. The frequencies of heterozygous/homozygous mutants of each SNP were 64C>T (11%), 499C>G (0%), 516G>T (55%), 785A>G (63%), 1375A>G (0%), 1459C>T (3%) and 21563C>T (62%). The three most frequent haplotypes identified included *1/*6 (40.3%), *1/*1 (34.3%) and *6/*6 (8.2%). The median (IQR) plasma efavirenz concentration was 2.3mg/L (1.4-3.7 mg/L). At 24 weeks, median (IQR) serum ALP was 98 mg/dL (73-133 mg/dL) and direct bilirubin was 0.11 mg/dL (0.10-0.19 mg/dL). The proportion of grade 1 and grade 2 elevated serum ALP was 12.7% and 1.5%, respectively. By multivariate analysis, factors associated with high ALP, total bilirubin and direct bilirubin included CYP2B6 haplotype *6/*6, high serum ALP at Week 0 and positive anti-HCV (all P<0.05). In summary, HIV-infected patients with the pharmacogenetic marker 'CYP2B6 haplotype *6/*6' may have increased susceptibility to hepatotoxicity with efavirenz-based ART.