Simultaneously complete but not partial taste and smell losses were associated with SARS-CoV-2 infection.

OBJECTIVES: The aim of this study was to investigate the association between taste and smell losses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to elucidate whether taste preference influences such taste loss. METHODS: A matched case-control study was conducted in 366 Thai participants, including 122 who were confirmed SARS-CoV-2-positive by RT-PCR (case group) and 244 who were SARS-CoV-2-negative (control group). Taste, smell, and appetite changes were assessed by self-reported visual analog scale. Preference for sweet, salty, umami, sour, bitter, and spicy were judged using the validated TASTE-26 questionnaire. RESULTS: Partial taste and smell losses were observed in both groups, while complete losses (ageusia and anosmia) were detected only in the case group. Moreover, only ageusia and anosmia were associated with SARS-CoV-2 positivity (P < 0.001, odds ratio of 14.5 and 27.5, respectively). Taste, smell, and appetite scores were more severely reduced in the case group (P < 0.0001). Multivariate analysis showed that anosmia and ageusia were the best predictors of SARS-CoV-2 positivity, followed by appetite loss and fever. Simultaneous losses of taste and smell but not taste preferences were associated with SARS-CoV-2 positivity (P < 0.01, odds ratio 2.28). CONCLUSIONS: Complete, but not partial, losses of taste and smell were the best predictors of SARS-CoV-2 infection. During the current COVID-19 pandemic, healthy persons with sudden simultaneous complete loss of taste and smell should be screened for COVID-19.

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.

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 ±â€ŠSD age was 37 ±â€Š9 years. Mean ±â€ŠSD baseline eGFR was 130.3 ±â€Š35.0 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 ±â€ŠSD plasma tenofovir concentration at 24 weeks was 105 ±â€Š46 ng/mL. At week 48, m-ean ±â€ŠSD eGFR of ABCC2*1C CC versus CT/TT was 96 versus 108 mL/min (P = 0.005) and m-ean ±â€ŠSD eGFR of ABCB1*6 CC versus CT/TT was 106 versus 99 mL/min (P = 0.157). Mean ±â€ŠSD tenofovir concentration in ABCC2*1C genotype CC versus CT/TT was 113 ±â€Š47 versus 93 ±â€Š44 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.

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.

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.

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.

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.

Time to initiate antiretroviral therapy between 4 weeks and 12 weeks of tuberculosis treatment in HIV-infected patients: results from the TIME study.

BACKGROUND: Optimal timing for initiation of antiretroviral therapy (ART) among HIV-infected patients with tuberculosis (TB) is not well established. METHODS: HIV/TB-coinfected patients were randomized to initiate tenofovir/lamivudine/efavirenz at 4 weeks (4-week group) or 12 weeks (12-week group) of TB treatment. The primary outcome was 1-year all-cause mortality. RESULTS: Of 156 patients, 79 were in 4-week group and 77 in 12-week group. Overall, median (interquartile range) CD4 was 43 (47-106) cells per cubic millimeter and median (interquartile range) HIV-1 RNA was 5.8 (5.4-6.3) log copies per milliliter. Eleven (7%) mortalities occurred in a total follow-up period of 137 patient-years. Seven percent (6/79, 8.76 per 100 patient-years) mortalities were in 4-week group, and 6% (5/77, 7.25 per 100 person-years) mortalities were in 12-week group [relative risk (RR) = 0.845, 95% confidence interval (CI) = 0.247 to 2.893]. Twenty-eight (35%) patients in 4-week group and 25 (32%) patients in 12-week group were hospitalized (RR = 1.142, 95% CI = 0.588 to 2.217). Grade 2-4 adverse events were 39% (31/79) in 4-week group and 34% (26/77) in 12-week group (RR = 1.267, 95% CI = 0.659 to 2.435). In multivariate analysis, "low albumin" (RR = 2.695, 95% CI = 1.353 to 5.475) and "low baseline CD4 count" (RR = 4.878, 95% CI = 1.019 to 23.256) were the independent predictors of mortality. Immune reconstitution inflammatory syndrome was more frequent in 4-week group with an incidence of 8.86 versus 5.02 per 100 person-months in 12-week group over the first 6 months of ART (P = 0.069). CONCLUSIONS: 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.

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.

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/mm(3) and 330 cells/mm(3) 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.

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.

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

BACKGROUND: Different 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. METHODS: A 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. RESULTS: There were 40 patients with a mean age of 37 years and 70% were male. Median (IQR) baseline CD4 was 123 (37-245) cells/mm(3) 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/mm(3) 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). CONCLUSION: LPV/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.

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.

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.

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.

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>or=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.

Antifungal susceptibilities of Cryptococcus neoformans cerebrospinal fluid isolates and clinical outcomes of cryptococcal meningitis in HIV-infected patients with/without fluconazole prophylaxis.

OBJECTIVES: To compare the MICs of FLUconazole (FLU) and amphotericin B against isolates of Cryptococcus neoformans (C. neoformans) obtained from the CerebroSpinal Fluid (CSF); and clinical outcomes of HIV-infected patients diagnosed with cryptococcal meningitis. MATERIAL AND METHOD: There were two groups including those who did not receive FLU (group A) and those who did receive either FLU 400 mg/week for primary prophylaxis cryptococosis or 200 mg/day for secondary prophylaxis cryptococosis (group B). CSF isolates of C. neoformans from group A and group B between January 2003 and October 2004 were retrospectively studied. The MICs were determined by using the standard NCCLS broth microdilution methods (M27-A). The MICs of FLU and amphotericin B, and clinical outcomes after 10 weeks of cryptococcal meningitis treatment were determined. RESULTS: There were 98 isolates; 80 in group A and 18 in group B. The patients in group B had a higher proportion of previous opportunistic infections (p = 0.008). The other baseline characteristics between the two groups were not different. The median (range) MIC of FLU was 8.0 (0.5-32) microg/ml in group A, and 6.0 (0.5-32) microg/ml in group B (p = 0.926). The median (range) MIC of amphotericin B was 0.25 (0.03-1.0) microg/ml in group A, and 0.25 (0.12-1.0) microg/ml in group B (p = 0.384). Sixty patients from group A and 14 from group B received standard treatment and continued to follow-up. After the 10-week treatment, 39/60 (65%) patients in group A and 7/14 (50%) in group B had complete recovery (p = 0.364; RR = 0.538, 95%CI = 0.166-1.742). The overall mortality rate was 14/60 (23.3%) in group A and 7/14 (50.0%) in group B (p = 0.096; RR = 3.286, 95%CI = 0.983-10.979). CONCLUSION: The MICs of FLU and amphotericin B against CSF isolates of C. neoformans and clinical outcomes between HIV-infected patients who receive or did not receive FLU prophylaxis are not different.