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1.  Patient-Based Transcriptome-Wide Analysis Identify Interferon and Ubiquination Pathways as Potential Predictors of Influenza A Disease Severity 
PLoS ONE  2014;9(11):e111640.
Background
The influenza A virus is an RNA virus that is responsible for seasonal epidemics worldwide with up to five million cases of severe illness and 500,000 deaths annually according to the World Health Organization estimates. The factors associated with severe diseases are not well defined, but more severe disease is more often seen among persons aged >65 years, infants, pregnant women, and individuals of any age with underlying health conditions.
Methodology/Principal Findings
Using gene expression microarrays, the transcriptomic profiles of influenza-infected patients with severe (N = 11), moderate (N = 40) and mild (N = 83) symptoms were compared with the febrile patients of unknown etiology (N = 73). We found that influenza-infected patients, regardless of their clinical outcomes, had a stronger induction of antiviral and cytokine responses and a stronger attenuation of NK and T cell responses in comparison with those with unknown etiology. More importantly, we found that both interferon and ubiquitination signaling were strongly attenuated in patients with the most severe outcomes in comparison with those with moderate and mild outcomes, suggesting the protective roles of these pathways in disease pathogenesis.
Conclusion/Significances
The attenuation of interferon and ubiquitination pathways may associate with the clinical outcomes of influenza patients.
doi:10.1371/journal.pone.0111640
PMCID: PMC4218794  PMID: 25365328
2.  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 (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.
doi:10.1128/AAC.02384-13
PMCID: PMC4023787  PMID: 24492364
3.  Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine 
The Journal of Infectious Diseases  2013;207(Suppl 2):S70-S77.
Background
The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.
Methods
We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.
Results
Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.
Conclusions
Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
doi:10.1093/infdis/jit114
PMCID: PMC3657117  PMID: 23687292
HIV-1; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; NRTI; stavudine; d4T; zidovudine; AZT; tenofovir; TDF; subtypes
4.  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.
doi:10.1128/AAC.02023-12
PMCID: PMC3553682  PMID: 23254426
5.  Virological failure of staggered and simultaneous treatment interruption in HIV patients who began Efavirenz-based regimens after allergic reactions to nevirapine 
Objective
The objective of this work was to study the virological outcomes associated with two different types of treatment interruption strategies in patients with allergic reactions to nevirapine (NVP). We compared the virological outcomes of (1) HIV-1-infected patients who discontinued an initial NVP-based regimen because of cutaneous allergic reactions to NVP; different types of interruption strategies were used, and second-line regimen was based on efavirenz (EFV); and (2) HIV-1-infected patients who began an EFV-based regimen as a first-line therapy (controls).
Methods
This retrospective cohort included patients who began an EFV-based regimen, between January 2002 and December 2008, as either an initial regimen or as a subsequent regimen after resolving a cutaneous allergic reaction against an initial NVP-based regimen. The study ended in March 2010. The primary outcome was virological failure, which was defined as either (a) two consecutive plasma HIV-1 RNA levels >400 copies/mL or (b) a plasma HIV-1 RNA level >1,000 copies/mL plus any genotypic resistance mutation.
Results
A total of 559 patients were stratified into three groups: (a) Simultaneous Interruption, in which the subjects simultaneously discontinued all the drugs in an NVP-based regimen following an allergic reaction (n=161); (b) Staggered Interruption, in which the subjects discontinued NVP treatment while continuing nucleoside reverse transcriptase inhibitor (NRTI) backbone therapy for a median of 7 days (n=82); and (c) Control, in which the subjects were naïve to antiretroviral therapy (n=316). The overall median follow-up time was 43 months. Incidence of virological failure in Simultaneous Interruption was 12.9 cases per 1,000 person-years, which trended toward being higher than the incidences in Staggered Interruption (5.4) and Control (6.6). However, differences were not statistically significant.
Conclusions
Among the patients who had an acute allergic reaction to first-line NVP-based therapy and later began an EFV-based regimen, virological outcomes resulting from a staggered interruption of treatment (with a continuation of NRTI backbone therapy for 7 days after discontinuing NVP) did not differ from those of the patients who began an EFV-based regimen as their initial therapy (Control). However, the virological failure of Simultaneous Interruption was possibly higher than those of Control and Staggered Interruption.
doi:10.1186/1742-6405-10-4
PMCID: PMC3576311  PMID: 23347647
Nevirapine hypersensitivity or allergy; Efavirenz; Simultaneous interruption; Staggered interruption; Thai
6.  Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients 
HIV medicine  2009;11(4):276-281.
Synopsis
Objectives
The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections.
Methods
A randomized trial was conducted in HIV-infected patients receiving 3 different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 hours after dosing) and CSF samples were taken at Baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography.
Results
Sixty-four treated patients had fluconazole measurements; 11 in AmB group, 12 in AmB+Fluc400 group and 41 in AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated for AmB+Fluc800 (p<0.001, r=0.873) and for AmB+Fluc400 (p=0.005, r=0.943). Increased Serum AUC appears associated with decreased mortality at day 70 (p=0.061, odds-ratio=2.19) as well as with increased study composite endpoint success at Days 42 and 70 (p=0.081, odds-ratio=2.25 and 0.058, 4.08; respectively).
Conclusion
High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear associated with increased survival and primary composite endpoint success.
doi:10.1111/j.1468-1293.2009.00778.x
PMCID: PMC3418324  PMID: 20002501
7.  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.
doi:10.1186/1742-6405-9-8
PMCID: PMC3317876  PMID: 22409789
HIV; Lopinavir; Monotherapy; Lamivudine; Resistance; Thailand
8.  Health Related Quality of Life among Patients with Tuberculosis and HIV in Thailand 
PLoS ONE  2012;7(1):e29775.
Introduction
Health utilities of tuberculosis (TB) patients may be diminished by side effects from medication, prolonged treatment duration, physical effects of the disease itself, and social stigma attached to the disease.
Methods
We collected health utility data from Thai patients who were on TB treatment or had been successfully treated for TB for the purpose of economic modeling. Structured questionnaire and EuroQol (EQ-5D) and EuroQol visual analog scale (EQ-VAS) instruments were used as data collection tools. We compared utility of patients with two co-morbidities calculated using multiplicative model (UCAL) with the direct measures and fitted Tobit regression models to examine factors predictive of health utility and to assess difference in health utilities of patients in various medical conditions.
Results
Of 222 patients analyzed, 138 (62%) were male; median age at enrollment was 40 years (interquartile range [IQR], 35–47). Median monthly household income was 6,000 Baht (187 US$; IQR, 4,000–15,000 Baht [125–469 US$]). Concordance correlation coefficient between utilities measured using EQ-5D and EQ-VAS (UEQ-5D and UVAS, respectively) was 0.6. UCAL for HIV-infected TB patients was statistically different from the measured UEQ-5D (p-value<0.01) and UVAS (p-value<0.01). In tobit regression analysis, factors independently predictive of UEQ-5D included age and monthly household income. Patients aged ≥40 years old rated UEQ-5D significantly lower than younger persons. Higher UEQ-5D was significantly associated with higher monthly household income in a dose response fashion. The median UEQ-5D was highest among patients who had been successfully treated for TB and lowest among multi-drug resistant TB (MDR-TB) patients who were on treatment.
Conclusions
UCAL of patients with two co-morbidities overestimated the measured utilities, warranting further research of how best to estimate utilities of patients with such conditions. TB and MDR-TB treatments impacted on patients' self perceived health status. This effect diminished after successful treatment.
doi:10.1371/journal.pone.0029775
PMCID: PMC3256183  PMID: 22253777
10.  Protease polymorphisms in HIV-1 subtype CRF01_AE represent selection by antiretroviral therapy and host immune pressure 
AIDS (London, England)  2010;24(3):411-416.
Background
Most of our knowledge about how antiretrovirals and host immune responses influence the HIV-1 protease gene is derived from studies of subtype B virus. We investigated the effect of protease resistance-associated mutations (PRAMs) and population-based HLA haplotype frequencies on polymorphisms found in CRF01_AE pro.
Methods
We used all CRF01_AE protease sequences retrieved from the LANL database and obtained regional HLA frequencies from the dbMHC database. Polymorphisms and major PRAMs in the sequences were identified using the Stanford Resistance Database, and we performed phylogenetic and selection analyses using HyPhy. HLA binding affinities were estimated using the Immune Epitope Database and Analysis.
Results
Overall, 99% of CRF01_AE sequences had at least 1 polymorphism and 10% had at least 1 major PRAM. Three polymorphisms (L10 V, K20RMI and I62 V) were associated with the presence of a major PRAM (P < 0.05). Compared to the subtype B consensus, six additional polymorphisms (I13 V, E35D, M36I, R41K, H69K, L89M) were identified in the CRF01_AE consensus; all but L89M were located within epitopes recognized by HLA class I alleles. Of the predominant HLA haplotypes in the Asian regions of CRF01_AE origin, 80% were positively associated with the observed polymorphisms, and estimated HLA binding affinity was estimated to decrease 19–40 fold with the observed polymorphisms at positions 35, 36 and 41.
Conclusion
Polymorphisms in CRF01_AE protease gene were common, and polymorphisms at residues 10, 20 and 62 most likely represent selection by use of protease inhibitors, whereas R41K and H69K were more likely attributable to recognition of epitopes by the HLA haplotypes of the host population.
doi:10.1097/QAD.0b013e3283350eef
PMCID: PMC2913588  PMID: 20009919
CRF01_AE; HIV; HLA; polymorphisms; protease; resistance
12.  Immunologic Markers as Predictors of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV and Tuberculosis Coinfected Persons in Thailand 
AIDS Research and Human Retroviruses  2009;25(11):1083-1089.
Abstract
This study analyzes immunologic markers to predict and diagnose tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV and TB coinfected adults who initiated antiretroviral therapy (ART) in Thailand. T helper 1 cytokines interleukin (IL)-2, IL-12, and interferon-gamma (IFN-γ) levels in response to PPD and RD1 antigens were assessed prior to ART, at weeks 6, 12, and 24 of treatment, and at time of TB-IRIS. Of 126 subjects, 22 (17.5%) developed TB-IRIS; 14 (64%) subjects received steroid treatment and 3 (14%) received NSAIDs; none of the subjects died. Median interval between ART initiation and TB-IRIS development was 14 days. IFN-γ, IL-2, and IL-12 responses did not differ between TB-IRIS and no TB-IRIS subjects (p > 0.05). More research into the immunopathogenesis of TB-IRIS and diagnostic potential of cytokine markers is warranted.
doi:10.1089/aid.2009.0055
PMCID: PMC2828258  PMID: 19886838
13.  Renal impairment after switching from stavudine/lamivudine to tenofovir/lamivudine in NNRTI-based antiretroviral regimens 
Background
During stavudine phase-out plan in developing countries, tenofovir is used to substitute stavudine. However, knowledge regarding whether there is any difference of the frequency of renal injury between tenofovir/lamivudine/efavirenz and tenofovir/lamivudine/nevirapine is lacking.
Methods
This prospective study was conducted among HIV-infected patients who were switched NRTI from stavudine/lamivudine to tenofovir/lamivudine in efavirenz-based (EFV group) and nevirapine-based regimen (NVP group) after two years of an ongoing randomized trial. All patients were assessed for serum phosphorus, uric acid, creatinine, estimated glomerular filtration rate (eGFR), and urinalysis at time of switching, 12 and 24 weeks.
Results
Of 62 patients, 28 were in EFV group and 34 were in NVP group. Baseline characteristics and eGFR were not different between two groups. At 12 weeks, comparing mean ± SD measures between EFV group and NVP group were: phosphorus of 3.16 ± 0.53 vs. 2.81 ± 0.42 mg/dL (P = 0.005), %patients with proteinuria were 15% vs. 38% (P = 0.050). At 24 weeks, mean ± SD phosphorus and median (IQR) eGFR between the corresponding groups were 3.26 ± 0.78 vs. 2.84 ± 0.47 mg/dL (P = 0.011) and 110 (99-121) vs. 98 (83-112) mL/min (P = 0.008). In NVP group, comparing week 12 to time of switching, there was a decrement of phosphorus (P = 0.007) and eGFR (P = 0.034). By multivariate analysis, 'receiving nevirapine', 'old age' and 'low baseline serum phosphorus' were associated with hypophosphatemia at 24 weeks (P < 0.05). Receiving nevirapine and low baseline eGFR were associated with lower eGFR at 24 weeks (P < 0.05).
Conclusion
The frequency of tenofovir-associated renal impairment was higher in patients receiving tenofovir/lamivudine/nevirapine compared to tenofovir/lamivudine/efavirenz. Further studies regarding patho-physiology are warranted.
doi:10.1186/1742-6405-7-37
PMCID: PMC3020664  PMID: 20937122
14.  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 ▿  
Antimicrobial Agents and Chemotherapy  2009;53(10):4545-4548.
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.
doi:10.1128/AAC.00492-09
PMCID: PMC2764182  PMID: 19667281
15.  Effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine levels when co-administered with rifampicin in HIV/TB co-infected Thai adults 
Background
Cytochrome P450 2B6 (CYP2B6) metabolizes efavirenz and nevirapine, the major core antiretroviral drugs for HIV in Thailand. Rifampicin, a critical component of tuberculosis (TB) therapy is a potent inducer of CYP enzyme activity. Polymorphisms of CYP2B6 and CYP3A4 are associated with altered activity of hepatic enzyme in the liver and pharmacokinetics resulting in treatment efficacy. This study aimed to investigate whether CYP2B6 or CYP3A4 polymorphisms had effects on plasma efavirenz and nevirapine concentrations when co-administered with rifampicin in HIV/TB co-infected Thai adults.
Results
We studied 124 rifampicin recipients with concurrent HIV-1/TB coinfection, receiving efavirenz (600 mg/day) (n = 65) or nevirapine (400 mg/day) (n = 59) based antiretroviral therapy (ART). The frequencies of GG, GT and TT genotypes of CYP2B6-G516T were 38.46%, 47.69% and 13.85% in efavirenz group and 44.07%, 52.54% and 3.39% in nevirapine group, respectively. The mean 12-hour post-dose plasma efavirenz concentration in patients with TT genotype at weeks 6 and 12 of ART and 1 month after rifampicin discontinuation (10.97 ± 2.32, 13.62 ± 4.21 and 8.48 ± 1.30 mg/L, respectively) were significantly higher than those with GT (3.43 ± 0.29, 3.35 ± 0.27 and 3.21 ± 0.22 mg/L, respectively) (p < 0.0001) or GG genotypes (2.88 ± 0.33, 2.45 ± 0.26 and 2.08 ± 0.16 mg/L, respectively) (p < 0.0001). Likewise, the mean 12-hour post-dose plasma nevirapine concentration in patients carrying TT genotype at weeks 6 and 12 of ART and 1 month after rifampicin discontinuation (14.09 ± 9.49, 7.94 ± 2.76 and 9.44 ± 0.17 mg/L, respectively) tended to be higher than those carrying GT (5.65 ± 0.54, 5.58 ± 0.48 and 7.03 ± 0.64 mg/L, respectively) or GG genotypes (5.42 ± 0.48, 5.34 ± 0.50 and 6.43 ± 0.64 mg/L, respectively) (p = 0.003, p = 0.409 and p = 0.448, respectively). Compared with the effects of CYP2B6-516TT genotype, we could observe only small effects of rifampicin on plasma efavirenz and nevirapine levels. After 12 weeks of both drug regimens, there was a trend towards higher percentage of patients with CYP2B6-TT genotype who achieved HIV-1 RNA levels <50 copies/mL compared to those with GT or GG genotypes. This is the first report to demonstrate the effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine concentrations when co-administered with rifampicin in HIV/TB co-infected Thai adults.
Conclusions
CYP2B6-TT genotype had impact on plasma efavirenz and nevirapine concentrations, while rifampicin co-administration had only small effects.
doi:10.1186/1742-6405-7-8
PMCID: PMC2859392  PMID: 20338069
16.  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/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).
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.
doi:10.1186/1742-6405-6-30
PMCID: PMC2805683  PMID: 20030841
17.  Durability of Stavudine, Lamivudine and Nevirapine among Advanced HIV-1 Infected Patients with/without Prior Co-administration of Rifampicin: A 144-week Prospective Study 
Background
To date, data on the durability of a regimen of stavudine, lamivudine and nevirapine are very limited, particularly from the resource-limited settings.
Methods
A prospective cohort study was conducted among 140 antiretroviral-naïve patients who were enrolled to initiate d4T, 3TC and NVP between November 2004 and March 2005. The objectives were to determine immunological and virological responses after 144 weeks of antiretroviral therapy. Seventy patients with tuberculosis also received rifampicin during the early period of antiviral treatment (TB group).
Results
Of all, median (IQR) baseline CD4 cell count was 31 (14–79) cells/mm3; median (IQR) baseline HIV-1 RNA was 433,500 (169,000–750,000) copies/mL. The average body weight was 55 kilograms. By intention-to-treat analysis at 144 weeks, the overall percentage of patients who achieved plasma HIV-1 RNA <50 copies/mL was 59.3% (83/140). In subgroup analysis, 61.4% (43/70) patients in TB group and 57.1% (40/70) patients in control group achieved plasma HIV-1 RNA <50 copies/mL (RR = 1.194, 95%CI = 0.608–2.346, P = 0.731). Eight (5.8%) patients discontinued d4T due to neuropathy and/or symptomatic lactic acidosis.
Conclusion
The overall durability and efficacy of antiviral response of d4T, 3TC and NVP are satisfied and they are not different between HIV-1 infected patients with and without co-administration of rifampicin due to tuberculosis. However, stavudine-related adverse effects are concerns.
Trial registration
ClinicalTrials.gov Identifier NCT00703898
doi:10.1186/1471-2334-8-136
PMCID: PMC2577100  PMID: 18851761
18.  Effectiveness and metabolic complications after 96 weeks of a generic fixed-dose combination of stavudine, lamivudine, and nevirapine among antiretroviral-naive advanced HIV-infected patients in Thailand: A prospective study 
Background: Generic fixed-dose combination (FDC) antiretroviral therapy (ART) has been widely used in resource-limited settings. Treatment based on these combinations provide low pill burden and are less expensive.
Objective: The aim of this study was to determine the long-term effectiveness and metabolic complications of a generic FDC of stavudine (d4T)/lamivudine (3TC)/ nevirapine (NVP), among ART-naive HIV-infected patients.
Methods: A prospective study was conducted among patients who were initiated on d4T/3TC/NVP between November 2004 and March 2005. Plasma HIV-1 RNA, CD4 and alanine transaminase were assessed every 12 weeks. Fasting plasma glucose (FPG) and lipid profile were determined at 96 weeks. Adverse events and genotypic drug resistance were recorded. The primary outcome of interest was the proportion of patients who achieved plasma HIV-1 RNA <50 copies/mL after 96 weeks of ART and analyzed by intent-to-treat (ITT) and on-treatment (OT) populations.
Results: There were 140 patients (mean [SD] age, 35.7 [7.6] years; male, 67.9%) enrolled in the study. Median (interquartile range [IQR]) baseline CD4 was 31 (14–79) cells/mm3 and HIV-1 RNA count was 433,500 (169,000–750,000) copies/mL. At week 96, 87 patients (ITT, 62.1%; OT, 87.0%) achieved HIV-1 RNA –50 copies/mL. Median (IQR) CD4 at 96 weeks was 328 (229–450) cells/mm3. The reasons for drug discontinuation were as follows: drug resistance (9.3%), lost to follow-up (9.3%), NVP- related rashes (7.9%), death (5.0%), d4T-related adverse events (3.6%), and transferred to another hospital (2.1%). At 96 weeks, 25 patients (28.7%) had low-density lipoprotein cholesterol (LDL-C) >130 mg/dL, 7 (8.0%) had LDL-C >160 mg/dL, 6 (6.9%) had triglycerides >400 mg/dL, and 2 (2.3%) had FPG >126 mg/dL. Eleven patients (12.6%) had a lactic acid level >2.5 mmol/L. Eight patients (9.2%) needed to take antihypertensive agents. Of 13 patients who developed virologic failure, 76.9% and 61.5% had M184V/I and Y181C/I mutations, respectively.
Conclusions: Initiation of this FDC ofd4T/3TC/NVP in these ART-naive patients with advanced HIV infection and low baseline CD4 cell count was effective at 96 weeks of follow-up with regard to virologic and immunologic responses. However, long-term metabolic complications, particularly dyslipidemia, were common and should be closely monitored.
doi:10.1016/j.curtheres.2008.02.007
PMCID: PMC3969962  PMID: 24692786
HIV; effectiveness; metabolic; GPOvir-S; nevirapine
19.  Safety and efficacy of a generic fixed-dose combination of stavudine, lamivudine and nevirapine antiretroviral therapy between HIV-infected patients with baseline CD4 <50 versus CD4 ≥ 50 cells/mm3 
Background
Antiretroviral therapy (ART) with a generic fixed-dose combination (FDC) of stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) is widely used in developing countries. The clinical data of this FDC among very advanced HIV-infected patients is limited.
Methods
A retrospective cohort study was conducted among ART-naïve HIV-infected patients who were initiated a generic FDC of d4T/3TC/NVP between May 2004 and October 2005. Patients were categorized into 2 groups according to the baseline CD4 (group A: <50 cell/mm3 and group B: ≥ 50 cell/mm3).
Results
There were 204 patients with a mean ± SD age of 37.1 ± 8.9 years, 120 (58.8%) in group A and 84 (41.2%) in group B. Median (IQR) CD4 cell count was 6 (16–29) cells/mm3 in group A and 139 (92–198) cells/mm3 in group B. Intention-to-treat analysis at 48 weeks, 71.7% (86/120) of group A and 75.0% (63/84) of group B achieved plasma HIV RNA <50 copies/ml (P = 0.633). On-treatment analysis, 90.5% (87/96) in group A and 96.9% (63/65) in group B achieved plasma HIV RNA <50 copies/ml (P = 0.206). At 12, 24, 36 and 48 weeks of ART, mean CD4 were 98, 142, 176 and 201 cells/mm3 in group A and 247, 301, 336 and 367 cells/mm3 in group B, respectively. There were no differences of probabilities to achieve HIV RNA <50 copies/ml (P = 0.947) and CD4 increment at 48 weeks between the two groups (P = 0.870). Seven (9.6%) patients in group A and 4 (8.5%) patients in group B developed skin reactions grade II or III (P = 1.000). ALT at 12 weeks was not different from that at baseline in both groups (P > 0.05).
Conclusion
Initiation of FDC of d4T/3TC/NVP in HIV-infected patients with CD4 <50 and ≥ 50 cells/mm3 has no different outcomes in terms of safety and efficacy. FDC of d4T/3TC/NVP can be effectively used in advance HIV-infected patients with CD4 <50 cells/mm3.
doi:10.1186/1742-6405-4-6
PMCID: PMC1828738  PMID: 17352834
20.  Plasma nevirapine levels, adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole 
Background
The clinical data of plasma NVP level, safety and efficacy of antiretroviral therapy (ART) for the concurrent use of nevirapine (NVP)-based ART and fluconazole (FLU) is scanty.
Methods
A retrospective study was conducted in patients who were initiated NVP-based ART between October 2004 and November 2005. The objectives were to compare NVP levels, adverse events, and 36-week efficacy of NVP-based ART between patients who did not receive FLU (group A) and those who received FLU 200 mg/day or 400 mg/day (group B).
Results
There were 122 patients with mean ± SD age of 36 ± 9 years; 81 in group A and 41 in group B. Median (IQR) baseline CD4 cell count was 29 (8–79) cell/mm3 in group A and 19 (8–33) cell/mm3 in group B (P = 0.102). Baseline characteristics between the two groups were similar. Mean ± SD NVP levels were 6.5 ± 3.0 mg/L in group A and 11.4 ± 6.1 mg/L in group B(P < 0.001). One (2.4%) patient in group B developed clinical hepatitis (P = 0.336). Six (7.4%) patients in group A developed NVP-related skin rashes (P = 0.096). There were no differences in term of 36-week antiviral efficacy between the two groups (P > 0.05).
Conclusion
Co-administration of NVP and daily dosage of FLU (200 mg/day and 400 mg/day) results in markedly increased trough plasma NVP level when compared to the administration of NVP alone. The concurrent use of NVP and FLU in very advanced HIV-infected patients is well-tolerated. The immunological and virological responses are favorable.
doi:10.1186/1471-2334-7-14
PMCID: PMC1828732  PMID: 17352798
21.  Safety and tolerability of nevirapine-based antiretroviral therapy in HIV-infected patients receiving fluconazole for cryptococcal prophylaxis: a retrospective cohort study 
Background
To compare the adverse events after initiation of nevirapine-based ART among HIV-infected patients who did not receive fluconazole (group A), received fluconazole 400 mg/week (group B), and received fluconazole 200 mg/day (group C).
Methods
A retrospective cohort study was conducted among HIV-infected patients who began NVP-based ART between December 2003 and September 2004. Patients were followed up for 6 months. Clinical hepatitis, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 3 times from baseline), and skin rashes were studied.
Results
There were 686 patients; 225, 392, and 69 patients in group A, B, and C, respectively. Baseline characteristics including age, previous opportunistic infections, use of antituberculous drugs, and baseline aminotransferase levels among the three groups were similar. Group C had a higher proportion of men (p = 0.016). Baseline median (IQR) CD4 cell counts were 85 (21–159), 18 (7–48), and 16 (5–35) cell/mm3 in group A, B, and C, respectively (p < 0.001). Of 2/225 (0.9%), 4/392 (1.0%), and 0/69 (0%) patients in group A, B, and C developed clinical hepatitis (p = 0.705). There were no significant difference of elevated AST or ALT among the three groups (p > 0.05). By logistic regression, receiving fluconazole was not predictive of clinical hepatitis, elevated aminotransferase, or skin rashes. At 6 months after initiating NVP, 174 (77.3%) patients in group A, 309 (78.8%) patients in group B, and 58 (84.1%) patients in group C remained on NVP.
Conclusion
Initiation of NVP-based ART among Thais with advance HIV disease receiving fluconazole is safe and well-tolerated. nevirapine should not be contraindicated for patients receiving fluconazole for treatment or prophylaxis of cryptococcosis.
doi:10.1186/1471-2334-5-67
PMCID: PMC1199598  PMID: 16120209

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