A study of profile of patients failing first line NACO recommended ART

Background: Failure of first line NACO recommended Therapy has been reported in 1-5% cases of HIV/AIDS. Various factors are associated with failure. This study describes the profile of patients failing first line ART (FLA) in a predominately lower socioeconomic population. The objective of the present study was to identify factors associated with failure of FLA.Methods: Retrospective data analysis of patients failing first line therapy. Epidemiological information, clinical parameters and laboratory reports were taken into consideration. Data was analysed as per standard statistical analysis.Results: Out of a total 3926 patients on first line ART for varying periods of time from our ART centre 54 patients were on second line ART. Males (2.20%) had a high failure rate than females (0.50%). The average time of failure was 64.11 months with a median of 56.50 months. 74.1% (40/54) of the patients had very low CD4 count at the time of initial diagnosis. Failure rate of FLA was higher in the patients having Stavudine based regimen (NRTI) (6.61%) and 3.64% in patients having Nevirapine based regimen (NNRTI).Conclusions: Second line therapy is required only in a small number of patients at present, but as it is related to the duration on first line ART and also with initial low CD4 count, more and more patients will require SLA in the near future.

Mitochondrial DNA content of peripheral blood mononuclear cells in ART untreated & stavudine/zidovudine treated HIV-1-infected patients

Background & objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) are known to cause mitochondrial toxicity. This study was done to estimate mitochondrial DNA (mtDNA) content of peripheral blood mononuclear cells (PBMCs) among human immunodeficiency virus (HIV) infected, NRTI treated and antiretroviral therapy (ART)-naïve patients and evaluate the utility of mtDNA content as a biomarker of mitochondrial toxicity. Methods: mtDNA content in PBMCs of 57 HIV-infected ART untreated and 30 ART treated with stavudine (d4T) or zidovudine (AZT) containing regimen were compared against 24 low-risk healthy controls (LoRHC). Results: There was a significant (P=0.01) reduction in mtDNA content among HIV-infected (104; 80-135) compared to LoRHC (127; 110-167), and it was the same in both the treated (104.8; 88-130) and untreated patients (104.7; 78-142). mtDNA significantly (P=0.014) declined in ART treated patients symptomatic for toxicity (97; 74-111) than the asymptomatic patients (128; 103- 153). Interpretation & conclusions: mtDNA depletion in PBMCs was evident among HIV-infected individuals on ART. Moreover, as mtDNA content was reduced among the patients symptomatic for toxicity than the asymptomatic in both the HIV-infected groups, the current study supports mtDNA content of PBMCs to serve as a biomarker of mitochondrial dysfunction induced by NRTI and HIV. Longitudinal studies with a large sample need to be done to confirm these findings.

Dipole Moment, Solvation Energy, and Ovality Account for the Variations in the Biological Activity of HIV-1 Reverse Transcriptase Inhibitor Fragments

Objective: A computational approach was employed to determine the interaction of molecular descriptors and the biological activity of the different fragments of HIV-1 reverse transcriptase inhibitors (RTIs). Methods: Using multiple linear regression analysis and leave-one-out validation method, a quantitative structure activity relationship (QSAR) model was developed to relate the biological activity (log IC50) of the different fragment-sized compounds against HIV-1 RT(WT) DNA-dependent DNA polymerase and molecular descriptors of these compounds. Results: QSAR model identified dipole moment, solvation energy, and ovality of fragment-sized compounds to confer reverse transcriptase inhibitory action. A highly significant correlation with log P, molecular weight, polarizability, molecular energy, zero-point energy, constant volume heat capacity at 298 K, and entropy was identified to account for the variations in the potency of RTIs. An increase in ovality, log P, and molecular weight of the fragment-sized compound renders a more active reverse transcriptase inhibition. Conclusion: The quality of the established QSAR model has been validated and demonstrates its potential as a tool for computational design and synthesis of next generation RTIs.

Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection / 中华医学杂志(英文版)

Background@#Nucleoside reverse transcriptase inhibitors (NRTIs) are the earliest and most commonly used anti-human immunodeficiency virus drugs and play an important role in high active antiretroviral therapy. However, NRTI drug therapy can cause peripheral neuropathic pain. In this study, we aimed to investigate the mechanisms of rapamycin on the pain sensitization of model mice by in vivo experiments to explore the effect of mammalian target of rapamycin (mTOR) in the pathogenesis of neuropathic pain caused by NRTIs.@*Methods@#Male Kun Ming (KM) mice weighing 20-22 g were divided into control, 2 mg/kg rapamycin, 12 mg/kg stavudine, and CMC-Na groups. Drugs were orally administered to mice for 42 consecutive days. The von Frey filament detection and thermal pain tests were conducted on day 7, 14, 21, 28, 35, and 42 after drug administration. After the last behavioral tests, immunohistochemistry and western blotting assay were used for the measurement of mTOR and other biomarkers. Multivariate analysis of variance was used.@*Results@#The beneficial effects of rapamycin on neuropathic pain were attributed to a reduction in mammalian target of rapamycin sensitive complex 1 (mTORC1)-positive cells (70.80 ± 2.41 vs. 112.30 ± 5.66, F = 34.36, P < 0.01) and mTORC1 activity in the mouse spinal cord. Mechanistic studies revealed that Protein Kinase B (Akt)/mTOR signaling pathway blockade with rapamycin prevented the phosphorylation of mTORC1 in stavudine-intoxicated mice (0.72 ± 0.04 vs. 0.86 ± 0.03, F = 4.24, P = 0.045), as well as decreased the expression of phospho-p70S6K (0.47 ± 0.01 vs. 0.68 ± 0.03, F = 6.01, P = 0.022) and phospho-4EBP1 (0.90 ± 0.04 vs. 0.94 ± 0.06, F = 0.28, P = 0.646).@*Conclusions@#Taken together, these results suggest that stavudine elevates the expression and activity of mTORC1 in the spinal cord through activating the Akt/mTOR signaling pathway. The data also provide evidence that rapamycin might be useful for the treatment of peripheral neuropathic pain.

Antiangiogenic VEGF165b expression in human breast MCF-7 and MCF-10A cells exposed to reverse transcriptase and protease inhibitors / Expresión de VEGF165b antiangiogénico en células MCF-7 y MCF-10A de mama humana expuesto a inhibidores de la transcriptasa inversa y la proteasa

The combined antiretroviral therapy (cART), a multidrug combination regimen, usually consisting Nucleoside Reverse Transcriptase Inhibitors, non- Nucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors has altered the morbidity pattern affecting HIV-infected individuals to include non-AIDS-defining malignancies (nADMs). The speculation is rife; does cART induce or promote the progression of nADMs such as breast cancer? This study was therefore designed to investigate of the effects of some antiretroviral drugs (at clinically relevant concentrations) on the expression of anti-angiogenic gene; VEGF165b in two human breast cell lines; MCF-7 and MCF-10A by Real Time qPCR and immuno-fluorescence. All of the antiretroviral drugs and combinations tested produced patterns of slight up or downregulation of VEGF165b mRNA expression but the alterations did not attain statistical significance. They also did not alter VEGF165bprotein localisation in both cell lines. The findings reported here suggest that antiretroviral drugs probably do not influence the angiogenic pathway in the development of breast cancer in patients under the combined antiretroviral regimen.

El tratamiento antirretroviral combinado (TARc), un régimen de combinación de múltiples fármacos, consistiendo generalmente en inhibidores nucleósidos de la transcriptasa reversa, inhibidores no-nucleósidos de la transcriptasa reversa e inhibodres de proteasa que alteran el patrón de mortalidad que afecta a infectados por el VIH incluyendo neoplasias definidas como no HIV (nADMs). La especulación es moneda corriente; TARc induce o promueve la progresión de nADMs como cáncer de mama? Por lo tanto, este estudio se diseñó para investigar los efectos de algunos de los fármacos antirretrovirales (en concentraciones clínicamente relevantes) sobre la expresión del gen anti-angiogénico; VEGF165b en dos líneas celulares de mama humana; MCF-7 y MCF-10A por PCR tiempo real e inmunofluorescencia. Todos los fármacos antirretrovirales y las combinaciones probadas pueden regular en forma ligera hacia arriba o hacia abajo la expresión de ARNm producidos por VEGF165b pero las alteraciones no fueron estadísticamente significativos. Además, no se alteran los niveles de proteína VEGF165b, para la localización en ambas líneas celulares. Los resultados aquí presentados sugieren que los medicamentos antirretrovirales probablemente no influyen en la vía angiogénica en el desarrollo del cáncer de mama en pacientes bajo el régimen antirretroviral combinado.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)resistance-related gene mutations among AIDS patients with antiviral treatment failure in Guangdong province 2015 / 中华临床感染病杂志

Objective To investigate the prevalence and characteristics of non-nucleoside reverse transcriptase inhibitors (NNRTIs)resistance-related gene mutations among the AIDS patients with virological suppression failure in Guangdong Province 2015.Methods Plasma samples from AIDS patients receiving highly active antiretroviral therapy for more than one year with viral loads > 1000 copies/mL from Guangdong province (except Shenzhen)were collected from January to December 2015.Total 612 HIV-1 gene fragments were amplified from plasma samples using self-developed lab method.Sub-genotypes were determined by phylogenetic tree according to the sequences,NNRTIs resistance-related mutations were determined in Stanford University HIV-1 Drug Resistance Database. The NNRTIs-resistance, the relationships of NNRTIs resistance-related mutations with baseline CD4 +T lymphocyte counts,transmission routes,antiviral regimens and HIV-1 genotypes were analyzed.SPSS 17.0 software was used to analyze the data.Results In 612 patients with virological suppression failure,the main NNRTIs resistance-related mutations were K103 (26.80%),Y181 (14.71 %),V179 (13.73%),G190 (11 .44%) and V106 (10.62%).The susceptibility rate of 310 patients (50.65%)to NNRTIs had changed,the highly resistant rate to nevirapine was 49.51 %,which was higher than that of efavirenz (43.14%),etravirine (5.56%) and rilpivirine (12.25%),respectively,and the differences were statistically significant (χ2 =5.00,296.3 and 198.0,all P 200 cells/μL was lower than that in those with baseline CD4 +T lymphocyte counts <200 cells/μL (χ2 =17.93,P <0.01 );the incidence rate of drug resistance was lower in intravenous drug abusers than that of sexually transmitted patients (χ2 =44.21 ,P <0.01 );while the incidence of drug resistance in patients receiving NVP-containing regimens was higher than that in those receiving EFV-containing regimens (χ2 =8.93,P <0.01 ),and the incidence rate was higher in patients with CRF01 _AE than that in those with CRF07_BC and CRF08 _BC (χ2 =8.46 and 8.47,P <0.01 ).Conclusions The results suggest that compliance education and follow-up should be strengthened in patients with high baseline CD4 +T lymphocyte counts and intravenous drug users,and patients with liver diseases should avoid using drugs containing NVP regimens.

Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

Pharmacokinetics study of the anti-HIV lead compound DAAN-5508 in rats / 中国药学杂志

OBJECTIVE: To develop and validate a LC-MS/MS method for quantitative analysis of the new anti-HIV candidate DAAN-5508 in rat plasma, and to study its pharmacokinetics and bioavailability in rats. METHODS: The plasma samples were treated with methanol for precipitating proteins. The chromatographic separation was performed with a gradient elution using 0.1% formic acid solution and methanol containing 0.1% formic acid. The flow rate was 0.3 mL · min-1. The MS detection was conducted using an LC-MS/MS in positive ion electrospray and multiple reactions monitoring (MRM) mode. RESULTS: Good linearity was obtained over the concentration range of 0.2-2500 ng · mL-1 for DAAN-5508 (r2=0.9998), with the lower limit of quantification at 0.2 ng · mL-1. The recovery of DAAN-5508 was greater than 80%. The precision and the accuracy met the requirements for bioanalysis. The method was applied for pharmacokinetics study of DAAN-5508 in rats. After a single iv(5 mg · kg-1) or oral dose (15 mg · kg-1) of DAAN-5508 to rats, the plasma concentration of DAAN-5508 showed a biphasic decline. The elimination half-lives were 2.6 and 4.6 h for intravenous and oral administration, respectively. The absorption of DAAN-5508 was rapid after oral administration. The peak level (188.0 ± 62.33) ng · mL-1 was reached at 1 h. The oral bioavailability was 12%. CONCLUSION: The developed the LC-MS/MS method is selective, sensitive, rapid and simple. It is suitable for the in vivo pharmacokinetics study of DAAN-5508 in rats.

Administração de tenofovir em ratas Wistar durante a gestação: efeitos na prole / Administration of tenofovir during pregnancy in Wistar rats: effects on the offspring

Introdução: Tenofovir disoproxil fumarate (TDF) é um inibidor da transcriptase reversa análogo nucleotídeo que tem sido usado por gestantes para o tratamento da infecção pelo vírus da imunodeficiência humana (HIV), bem como para a prevenção da transmissão vertical do vírus. Até o momento, não há estudos experimentais ou em humanos sobre a incidência de alterações renais nos fetos expostos a esquemas contendo TDF. Objetivo: Verificar a ocorrência de alterações renais e sistêmicas fetais causadas pelo uso do TDF durante a gestação. Metodologia: Ratos Wistar fêmeas receberam dieta padrão com ou sem adição de TDF (100mg/Kg de dieta) desde uma semana antes do cruzamento até o parto. A prole proveniente do grupo TDF foi colocada com uma mãe adotiva não tratada durante o período de amamentação e foi comparada com a prole de ratas que receberam dieta padrão durante a gestação (grupo controle). Controle e TDF foram acompanhados até três (n=9 para cada grupo) e seis (n=12 e n=10, respectivamente) meses de idade. Foram avaliados: peso corporal (PC) e pressão arterial sistólica (PAS) mensais, contagem de glomérulos, função renal (através do clearance de inulina), parâmetros bioquímicos (proteinúria, colesterol total, sódio e potássio séricos e urinários), e expressão proteica do tecido renal para componentes do sistema renina angiotensina aldosterona (SRAA) e para transportadores de sódio. Resultados: A prole TDF apresentou menor PC ao nascimento em comparação com o controle. Após o 3º mês, o grupo TDF demonstrou um crescimento compensatório, atingindo o sexto mês com maior PC. O peso renal foi menor no grupo TDF, porém, não houve diferença do número de néfrons entre os grupos. O grupo TDF apresentou alterações estruturais glomerulares. Observou-se também um aumento progressivo da PAS após o segundo mês de idade no grupo TDF. Não houve diferença estatística na função renal entre os grupos. Os níveis plasmáticos de aldosterona foram mais elevados...

Introduction: Tenofovir disoproxil fumarato (TDF) is a nucleotide reverse transcriptase inhibitor that has been used in pregnants for treatment of maternal HIV infection and for prevention of vertical transmission. Currently, there are no published studies providing data regarding the occurrence of renal abnormalities in fetuses exposed to TDF-containing regimens. Objective: To evaluate the occurrence of systemic and renal abnormalities in offspring of Wistar rats exposed to TDF during pregnancy. Methods: Female Wistar rats received a standard diet, with or without addition of TDF (100 mg/Kg diet), one week before mating and during pregnancy. Offspring from the TDF group were placed with an untreated foster mother during breastfeeding and compared with offspring from rats maintained on a standard diet during mating and pregnancy (control). Control and TDF were followed up at three and six months of age. Analyzed data: monthly body weight and systolic blood pressure (SBP), glomerular counting, renal function, biochemical parameters, and renal tissue immunoblotting for renin angiotensin aldosterone system (RAAS) and renal sodium transporters. Results: TDF offspring showed lower birth weight compared with the control group. After the third month, growth among the TDF group experienced a rapid catch-up. SBP increased progressively after the second month of age in the TDF group. The nephron number did not differ between groups. The TDF group showed glomerular structural changes. There was no significant difference in renal function between the groups studied. Plasma aldosterone was higher in the TDF group, associated with a significant increase in renal expression of RAAS. The TDF rats showed upregulation of renal sodium transporters and consequently lower urinary sodium excretion. Conclusions: This is the first demonstration using an experimental model that maternal exposure to TDF during gestation results in over activation of RAAS, upregulation of renal...

The comparison of the therapeutic impacts on metabolism in hepatitis C virus and human immunodeficiency virus co-infected patients / 中华内分泌代谢杂志

To explore and compare the response of the protease inhibitors or non-nucleoside reverse transcriptase inhibitors-based therapeutic impact on metabolic indices in hepatitis C virus (HCV)/human immunodeficiency virus(HIV) co-infected patients.A randomized,open,and control approach was performed to enroll 273 cases of HCV/HIV co-infected patients on their initial visits and to choose protease inhibitors(PIs group) or non-nucleoside reverse transcriptase inhibitors (NNRTIs group) based therapy treatments for one year.Laboratory results of metabolic indices before and after the treatment were collected.After treatment,the levels of triglyceride in NNRTIs and Pls groups were (1.93 ± 0.99) mmol/L and (1.62 ± 0.93) mmol/L respectively,high density lipoprotein-cholesterol were(1.28 ± 0.55) mmol/L and (1.08 ± 0.53) mmol/L,low density lipoprotein-cholesterol were (2.60 ± 1.44) mmol/L and (2.22 ± 1.16) mmol/L,fasting plasma glucose were (5.92 ± 1.21) mmol/L and (4.79 ± 0.47) mmol/L,serum creatinine were (70.5 ± 14.6) μmol/L and (56.6 ± 8.3) μmol/L,and serum amylase were(66.9 ± 27.5) U/L and(62.7 ± 33.8) U/L respectively.The difference between the two groups was statistically significant(all P＜0.01).There is a therapeutic impact on metabolic indices in patients wtih HCV / HIV co-infection after non-nucleoside reverse transcriptase inhibitors-based regimen.

High performance liquid chromatographic assay for the determination of Protease Inhibitors (PIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in human plasma.

Objective: To develop and validate a high performance liquid chromatography (HPLC) method for simultaneous quantitative determination of five HIV protease inhibitors (PIs): indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and two non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine (NVP), and efavirenz (EFV) in human plasma. Methods: A sample of 200 µL of plasma and an internal standard were extracted with tert-butyl methyl ether. The compounds were separated on a reversed-phase C18 column with gradient phase of 25 mM phosphate buffer (pH 4.9) and acetonitrile. The limit of quantation, accuracy, precision, specificity, stability and recovery were tested. Results: The lower limit of quantitation for all drugs was 75 ng/mL. The standard curve was linear in the range of 75 ng/mL to 20,000 ng/mL. Intra-day and inter-day variability ranged from 0.1% to 2.4% and 0.3% to 4.1%, respectively. Accuracy ranged from 98.4%-102.4% for three quality controls (75, 100, and 1,000 ng/mL) for all drugs measured. The extraction recovery ranged from 98.7%-101.3%. Conclusion: This method provides a simple, accurate, and precise method for monitoring of plasma concentrations of five PIs and two NNRTIs in the case of weak economy and out of date instrumental limitations.

Short-term exposure to stavudine results in neuron apoptosis, neurite shrink and down-regulated expression of thymidine kinase 2 / 中华传染病杂志

Objective To investigate the central neurotoxicity induced by nucleoside analog reverse transcriptase inhibitors (NRTIs)-stavudine (D4T).Methods Mouse primary cortical neurons were cultured and treated with different concentrations of stavudine.Neuron apoptosis was analyzed by calcein/acetomethoxy/propidium iodide (AM/PI) staining. Morphological change of neuron was confirmed by immunofluorescence.Mitochondrial DNA copies which were usually evaluated through Cycloxygenase 2 (COX-2) and thymidine kinase2 (TK2) mRNA were determined by real-time quantitative polymerase chain reaction.Chi-square test,student t test and Wilcoxon nonparameter test were used to analyze the data.Results Neuronal apoptosis observed in 50 μmol/L D4T treatment group was more significant than that in 0μmol/L D4T treatment group and 25 μmol/L D4T treatment group (51.3％±12.4％ vs 24.9％±8.2％ and 26.5％±10.6％,respectively; x2 =7.25 and 6.93,respectively; both P＜0.01).The average neurite numbers of each neuron were 11.2±3.6 in 0μmol/L D4T treatment group,8.6±2.8 in 25 μmol/L D4T treatment group and 4.3±2.4 in 50 μmol/L D4T treatment group.The difference was statistically significant between 25 μmol/L D4T treatment group and 0 μmol/L D4T treatment group (t=4.06,P＜0.01) and between 50 μmol/L D4T treatment group and 25 μmol/L D4T treatment group (t =4.35,P＜ 0.01). Furthermore,the average lengths of neuritis were (319.9±100.2) μm in 0 μmol/L D4T treatment group,(298.3±83.9) μm in 25 μmol/L D4T treatment group and (258.4±82.2) μm in 50 μmol/L D4T treatment group.The difference was statistically significant between 25 μmol/L D4T treatment group and 0 μmol/L D4T treatment group (t=4.58,P＜0.01) and between 50 μmol/L D4T treatment group and 25 μmol/L D4T treatment group (t=4.65,P＜0.01).TK2 mRNA expression dramatically decreased along with the increasing D4T concentration.The fold changes were 0.34 in 25 μmol/L D4T treatment group and 0.08 in 50 μmol/L D4T treatment group. The difference was statistically significant between 25 μmol/L D4T treatment group and 0μmol/L D4T treatment group (Z=- 3.28,P＜0.01) and between 50 μmol/L D4T treatment group and 25 μmol/L D4T treatment group (Z=-4.25,P＜0.01).Compared with 0μmol/L D4T treatment group,the relative fold changes of COX-2 copies were 1.01 in 25 μmol/L D4T treatment group and 1.12 in 50 μmol/L D4T treatment group.The differences were not significant among the three groups (Z=0.98 and 1.24,respectively; both P＞0.05).Conclsion It suggests that short-term exposure to D4T may result in neuron apoptosis,neurite shrink and down-regulated expression of TK2,but the level of mitochondrial DNA copies keeps stable.

Efficacy and safety of efavirenz-based regimens in human immunodeficiency virus/hepatitis C virus co-infected patients / 中华传染病杂志

Objective To evaluate the efficacy and safety of efavirenz-based therapy in patients with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection. Methods Fiftythree HIV/HCV co-infected patients received efavirenz-based therapy were followed up for 7 years.The changes of CD4+ T lymphocyte count, HIV virus load, hepatic function, hepatic fibrosis index,blood lipid, blood glucose, blood uric acid and blood routine were observed. The comparison of means before and after treatment was performed by t-test. Results The HIV RNA levels at baseline and endpoint were (4. 56±0. 88) lg copy/mL and (1.70±1.10) lg copy/mL, respectively (t=14. 781, P＜0.01). The peripheral blood CD4+ T lymphocyte counts were ( 188.37±151.14)×106/L and (445.18±314.25)×106/L, respectively (t=5.362, P＜0.01).The alanine aminotransferase (ALT) levels were (36.6±16.3) U/L and (57.2±9.9) U/L, respectively (t=7.864, P＜0. 01).The glycocholic acid levels were (444.22±476.74) mg/L and (556.88±733.05) mg/L, respectively (t=0.938, P＜0.05). The Ⅳ-collagen(Ⅳ-C) levels were (45.13±8.25) ng/mL and (47.88±4.51) ng/mL, respectively (t= 2.129, P＜0.05). The riacylglycerol levels were (1.57±0.65)mmol/L and (2.51±1.29) mmol/L, respectively (t=4.737, P＜0.01). The blood uric acid levels were (298.5±48.2) mmol/L and (495.1±89.4) mmol/L, respectively (t= 14.092, P＜0.01).Conclusions The efavirenz-based therapy is efficacious in HIV/HCV co-infected patients, but it could cause liver injury and metabolic disorder.

Nuevos y viejos anti-retrovirales en pediatría: Nuevas dosis, presentaciones y asociaciones / New and “old” antiretroviral drugs in Pediatrics: New doses, formulations and associations

De los 25 anti-retrovirales disponibles en el mercado, sólo 16 están autorizados en la edad pediátrica. Los antiretrovirales, pertenecientes a las tres primeras familias, usados desde hace dos décadas, continúan vigentes y son parte importante de la terapia anti-retroviral en niños naïve. Se describen las dosis, presentaciones y asociaciones actuales de estos fármacos en la edad pediátrica y además se comentan las nuevas co-formulaciones que permitirán disminuir el número de dosis, mejorar la tolerancia y por lo tanto conseguir mejor adherencia de los pacientes pediátricos.

Of the 25 antiretroviral drugs available in the market, only 16 are allowed for prescription in the pediatric patients. The antiretroviral, pertaining to the first three families, used for two decades, remain valid and are important components of antiretroviral therapy in naive children. We describe doses, presentations and current associations for these drugs in children, and also discuss new co-formulations that will reduce the number of doses, improve tolerance and therefore achieve better adherence of pediatric patients.

Evaluation of therapeutic effects of antiretroviral therapy on pediatric acquired immune deficiency syndrome / 中华传染病杂志

Objective To evaluate the therapeutic effects of antiretroviral therapy(ART)on human immunedeficiency virus (HIV)-1-infected children. Methods Twenty-two HIV-1-infected children who met World Health Organization (WHO) criteria for treatment received ART and were prospectively enrolled in this study. ART contained two kinds of nucleoside reverse transcriptase inhibitor (NRTI) combined with one kind of non-nucleoside reverse transcriptase inhibitor (NNRTI).Before ART and 1-36 months after ART, height, body weight, blood routine, peripheral CD4+ and CD8+ T cell counts and plasma viral load were followed up regularly. Comparison between groups was done by test. Results Among the 22 pediatric AIDS patients, 19 cases (86.4%) achieved clinical improve, whose height and body weight increased significantly 6 months after ART (height = 1 :1.04±0. 02, t=2. 356, P<0. 05; body weight= 1: 1. 14±0. 01,t=2. 567,P< 0. 05) and opportunistic infection rate decreased (72.7 % vs. 27.3 %) ; 3 patients (13.6 % ) deteriorated, whose height and body weight increased slowly and even decreased, 2 of them died. In the 19 improved patients, viral load declined to <2.7 lg copy/mL at month 3 of ART, CD4+ T cell counts and CD4+/CD8+ ratio significantly increased at month 3 of ART (CD4+ T cell counts: 145.50±86.72 vs. 262.80±213.62,t=2. 668, P<0.05; CD4+/CD8+ ratio: 0. 14±0. 11 vs. 0.23±0. 21,t=2. 607, P<0. 05) and CD4+/CD8+ ratio peaked at month 9 and absolute number of CD4+ T cell counts peaked at month 12 and maintained at high level until month 36, peripheral white blood cells (WBC) and red blood cells (RBC) both decreased, while hemoglobin (Hb) contents increased significantly (107.29 ± 13.74 vs. 112. 15±11.20,t=2. 325,P<0. 05). Conclusion ART is an effective strategy for inhibition of HIV-1 replication,reconstruction of immune responses and improvement of clinical symptoms in AIDS children.

Study of genotypic resistance mutations of protease and reverse transcriptase in non-therapeutic acquired immune deficiency syndrome patients in Heiiongjiang Province / 中华传染病杂志

Objective To study the presence of drug resistant mutations of protease and reverse transcriptase among human immunodeficiency virus (HIV)-1 strains isolated from treatment naive HIV/ acquired immune deficiency syndrome (AIDS) patients in Heilongjiang Province of China and to provide the baseline data for starting antiretroviral therapy in this area. Methods The protease and reverse transcriptase gene sequences were amplified by nested-polymerase chain reaction (PCR) and then sequenced. The results were compared to the subtype B consensus amino acid sequence and analyzed with Stanford HIV-db drug resistance sequence interpretation. Results The results showed that HIV strains from 49 patients were classified as subtype B'. No primary mutations associated with protease inhibitor were detected. Some secondary mutations associated with protease inhibitor were detected, which included V77I(91.5%), L63P(76.6%), I93L(74.5%), E35D(61.7%), R57K (19.1%), R41K(10.6%), A71V(8.5%), M36I(8.5%), L10I(6.4%), D60E(6.4%), L89M (4.2%) and G16E(2. 1%). Only one case had a primary mutation M184I that was associated with resistance to reverse transcriptase inhibitors. However, many secondary mutations associated with resistance to reverse transcriptase inhibitors were found, including I135L/T/R/V(81.8%), V106I(22.7%), V179D/E(11.4%), R211K(9.1%), L214F(4.5%), V189I(4.5%) and V108I(2. 3%).Conclusions The prevalence of genotypic anti-HIV drug resistance is very low in treatment naive HIV/AIDS patients in Heilongjiang Province. However, closely monitoring on drug resistance mutation is very important for preventing the development and prevalence of multi-drug resistant or cross drug resistant HIV.

Non-nucleoside reverse transcriptase inhibitors(Part 18): Synthesis and anti-HIV activity of 4-allylamino or 4-azido substituted diaryltriazines / 药学学报

Eight new diaryltriazine derivatives containing 4-allylamino and 4-azido substitutes guided by molecular docking have been designed and synthesized based on our previous work.The evaluation of HIV inhibitory activity demonstrated that all compounds were potent against HIV-1 replication.The most active compound 7c exhibited activity against HIV-1 (IC50=0.034 μmol·L-1,SI=6475)and the double mutant strain (IC50=9.39 μmol·L-1)in the micromolar range, which was more potent than nevirapine.

Anti-human immunodeficiency virus type 1 activity of two new nonnucleoside reverse transcriptase inhibitors in combination with other 3 antiretroviral agents in vitro / 军事医学科学院院刊

Objective:To evaluate the anti-HIV-1 activity of two new nonnucleoside reverse transcriptase inhibitors (NNRTIs), JB25 and JB26, in combination with 3 approved drugs (AZT, EFV, SQV)in vitro.Methods:The serially diluted 10 concentrations of JB25 and JB26 were combined with 7 serially diluted AZT, EFV and SQV respectively.The combination was added to 384 cell culture plates and then cocultured with HIV-1 ⅢB infected MT-2 cells for 3 days. Finally, the HIV-1 production was determined by measuring the expression of reporter genes of TZM bl cells. The data were analyzed by MacSynergy Ⅱ software.Results:The average capacity of synergism/antagonism of JB25 with AZT, EFV and SQV was 244.45/-5.05(nmol/L)~2%, 119.58/-65.93 (nmol/L)~2% and 145.83/-0.32 (nmol/L)~2% respectively;the average capacity of synergism/antagonism of JB26 with AZT, EFV and SQV was 398.90/0(nmol/L)~2%, 103.62/-0.49(nmol/L)~2% and 138.473/-0.27 (nmol/L)~2% respectively. Conclusion:Two new NNRTIs JB25 and JB26 develop synergism when combined with 3 approved drugs, respectively. MacSynergy Ⅱ software could evaluate the anti-HIV-1 activity of drug combination.

Selective kinetics of HIV-1 non-nucleoside reverse transcriptase inhibitor drug resistanace-associated mutations in AIDS patients receiving highly active anti-retrovirul therapy / 中华检验医学杂志

Objective To elucidate the molecular evolutional characteristics of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance-associated mutations in AIDS patients receiving highly active antiretroviral therapy (HAART).Methods Four AIDS patients receiving HAART with good adherence within a HlV-1 drug resistance cohort from a rural region in central China were selected,who possessed susceptible virus at the beginning of treatment and gradually came to produce resistance to NNRTIs during the process of antiretroviral therapy (ART),reverse transcriptase (RT) genes from each patient's peripheral blood samples (from 3 to 30 months after withdrawal) were cloned and sequenced in succession.Results To sequenced total 855 clones and obtained the HIV-1 NNRTI drug resistance-asseciated mutations patterns of the four patients: (1)G190A often appeared with F227 L and had the tendency of accumulating P236V during the process of treatmenL (2)Y188C always presented alone and sometimes it concured with P236V.(3) YI81C frequently concured with VI79D or KIO3N and the combination varies from patient to patient.(4)K103N often combined with Y181C or M230L Conclusions The molecular evolutional characteristics of HIV-1 NNRTI drug resistance-asseciated mutations in the 4 AIDS patients are summarized.They showed different pathways on HIV-1 NNRTI drug resistance-associated mutations and those mutations detected early tend to be predominant strains.