Toxic epidermal necrolysis is an unpredictable and severe adverse drug reaction. In toxic epidermal necrolysis, epidermal damage appears to result from keratinocyte apoptosis. This condition is triggered by many factors, principally drugs such as antiepileptic medications, antibiotics (particularly sulfonamide), nonsteroidal anti-inflammatory drugs, allopurinol, and nevirapine. Lamotrigine has been reported potentially cause serious cutaneous reactions, and concomitant use of valproic acid with lamotrigine significantly increases this risk. We describe a case of an 11-year-old girl with tic and major depressive disorders who developed toxic epidermal necrolysis after treatment with lamotrigine, and who was diagnosed both clinically and pathologically. Children are more susceptible to lamotrigine-induced rash than adults, and risk of serious rash can be lessened by strict adherence to dosing guidelines. Unfortunately, in our case, the patient was administered a higher dose than the required regimen. Therefore, clinicians should strictly adhere to the dose regimen when using lamotrigine, especially in children.
Adult ; Allopurinol ; Anti-Bacterial Agents ; Apoptosis ; Child* ; Depressive Disorder, Major ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Female ; Humans ; Keratinocytes ; Nevirapine ; Stevens-Johnson Syndrome* ; Tics ; Valproic Acid

OBJECTIVETo compare the HIV suppression rate after initiating antiretroviral treatment(ART) among AIDS patients at different immunological levels and to analyze the related factors.

METHODSData on AIDS patients initially starting antiretroviral therapy during 2008 and 2013 were collected from Chinese HIV/AIDS integrated control system. All the participants were divided into early treatment group(baseline CD4(+)T cell counts between 351/µl and 500/µl) and conventional treatment group(baseline CD4(+)T cell counts ≤ 350/µl). The rates of comprehensive virologic suppression at different time nodes after the initiation of ART were analyzed accordingly. Unconditional logistic regression model was adopted to examine the factors associated with the failure of viral suppression after 6 months after initiation of ART.

RESULTSA total of 16 103 cases were selected, among which, 1 581 cases were early treatment group, and 14 522 cases were conventional treatment group. A total of 9 428 cases were males, 6 675 cases were females, and the sex ratio was 1.41: 1. The age was 47.2 ± 11.7, and 71.55% (11 522/16 103) of cases were married or cohabiting, 57.22% (9 214/16 103) were transmitted by blood. 81.26% (13 086/16 103) were cures in the township or village treatment institution, and 77.17% (12 426/16 103) received the ART regimen as Stavudine(D4T) or Zidovudine(AZT)+Lamivudine(3TC)+Nevirapine(NVP) or Efevirenz(EFV). After 0.5, 1, 2, 3, 4, 5 and 6 years after the initiation of ART, the rates of virologic suppression in the conventional treatment cohort were 72.6% (3 008/4 144), 73.9% (4 758/6 443), 74.1% (3 641/4 915), 74.9% (2 819/3 766), 76.1% (1 729/2 272) and 78.2% (492/629), respectively. While the rates of viral suppression in the early treatment cohort at the same time nodes were 65.5% (315/481), 65.4% (448/685), 68.8% (223/324), 66.0% (155/235), 71.4% (110/154) and 61% (30/49), respectively, and the differences between the two groups were significant (P < 0.05) except at the fourth year. Non-conditional logistic regression analysis showed that in the conventional treatment group, factors associated with low HIV suppression rate were male (OR = 1.23, 95%CI:1.07-1.42) , longer time interval from confirmed HIV infection to received ART (OR = 1.26, 95%CI:1.16-1.36) , using D4T/AZT+ DDI +NVP/EFV as initial treatment regimen (OR = 3.00, 95%CI:2.26-3.98) and nearly missing doses for 7 days at treatment of six months (OR = 1.97, 95%CI:1.22-3.18) and factors associated with high HIV suppression rate were infected through homosexual transmission route (OR = 0.57, 95%CI:0.35-0.90) and treated in the county level medical institution or above (OR = 0.61, 95%CI:0.50-0.75) . Among early treatment group, cases who received treatment at county level medical institution or above had high HIV suppression rate (OR = 0.43, 95%CI:0.23-0.80) and objects with longer time interval from confirmed HIV infection to receive ART had low HIV suppression rate (OR = 1.43, 95%CI:1.09-1.88).

CONCLUSIONThe viral suppression efficacy among AIDS patients with different baseline immunologic levels after treatment was similarly satisfactory. AIDS cases who received ART at county level medical institution or above had better viral suppression effect and patients with longer time interval from confirmation to treatment had poor HIV suppression effect.

Acquired Immunodeficiency Syndrome ; Anti-HIV Agents ; Benzoxazines ; Female ; HIV Infections ; Health Facilities ; Humans ; Lamivudine ; Male ; Nevirapine ; Stavudine ; Time-to-Treatment ; Treatment Outcome ; Zidovudine

Acquired Immunodeficiency Syndrome ; prevention & control ; transmission ; Anti-HIV Agents ; therapeutic use ; Drug Resistance, Viral ; Humans ; Infectious Disease Transmission, Vertical ; prevention & control ; Nevirapine ; therapeutic use

This study is to investigate the mechanism and action characteristics of 6-chloro-3-methyl-4-(2-methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1 H)-one (XU07011) against HIV-1 replication. XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses' infectious assay. Time of addition was used to test HIV-1 reverse transcription process. RNA-dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method. Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics. The results showed that XU07011 inhibited HIV-1 replication with IC50 of (0.057 +/- 0.01) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x L(-1). The compound showed no effect on RNase H activity. XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains. This study could provide a theoretical basis for novel anti-HIV reagents development.
Anti-HIV Agents ; chemistry ; pharmacology ; Drug Resistance, Viral ; HEK293 Cells ; HIV-1 ; physiology ; Humans ; Inhibitory Concentration 50 ; Molecular Structure ; Nevirapine ; pharmacology ; Quinoxalines ; pharmacology ; RNA-Directed DNA Polymerase ; metabolism ; Ribonuclease H ; metabolism ; Thiophenes ; pharmacology ; Virus Replication ; drug effects

BACKGROUNDVirus with nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) resistant mutations show different evolution tendencies when the anti-viral therapies are interrupted. Understanding the replication fitness of drug-resistant virus is important for the study of the prevalence of drug-resistance. For this purpose, we characterized the replication capacity of HIV-1 virus carrying lamivudine (3TC) or nevirapine (NVP) resistant mutations.

METHODS3TC and NVP resistant variants were induced in vitro by selecting wild type virus in the presence of drugs. For the competitive replication assay, drug-resistant variants were cocultured with wild-type virus in the presence or absence of drugs. The ratios of the viral species were determined over time by using a real-time RT-PCR-based assay.

RESULTS3TC-resistant (M184I mutation) and NVP-resistant (Y181I mutation) virus should be selected in vitro in two different ways. The competitive replication assay showed that the ratio of virus carrying a M184I mutation increased from 98.8%, while the wild type virus decreased to 1.2% after 4 passages in the presence of 3TC; the percentage of virus carrying the Y181I mutation increased to 90.5%, while wild type virus decreased to 9.5% in the presence of NVP. In the absence of drugs, the ratio of virus carrying the M184I mutation decreased to 5.3%, while wild type virus increased to 94.7%; the ratio of virus carrying Y181I increased to 75%, while wild type virus decreased to 25% after 4 passages.

CONCLUSIONSThe NVP-resistant virus is fitter than wild type virus even in the absence of NVP that may be the reason that NNRTIs-resistant virus is spreading quickly.

Cell Line ; Drug Resistance, Viral ; genetics ; HIV-1 ; drug effects ; genetics ; growth & development ; physiology ; Humans ; Lamivudine ; pharmacology ; Mutation ; Nevirapine ; pharmacology ; Reverse Transcriptase Inhibitors ; pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Virus Replication ; genetics ; physiology

BACKGROUNDLiver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China.

METHODSSeventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups: group 1 (with liver injury, n = 45) and group 2 (without liver injury, n = 30). The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups.

RESULTSForty-five patients (60.0%), 31 (68.9%) males and 14 (31.1%) females, aged 12 to 52 years (averaged (39 ± 9) years), experienced at least one episode of liver injury. Forty (53.3%) patients were co-infected with HBV and/or HCV, 42 (56%) patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 (61.3%) and 29 (38.7%) patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 (57.8%) patients, grade 2 in 16 (35.6%), grade 3 in 2 (4.0%) and grade 4 in 1 (2.2%). Three (6.7%) patients discontinued highly active antiretroviral therapy (HAART) due to liver injury. In group 1, there were 29 (64.4%) patients co-infected with HBV and/or HCV, 32 (71.1%) patients received regimen containing nevirapine, and 30 (66.7%) patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 (11 (36.7%), 14 (46.7%) and 12 (40%), respectively; P = 0.018, 0.033, 0.023, respectively). The sex, age, baseline CD4 counts and disease stage were not factors associated with liver injury.

CONCLUSIONSLiver injury associated with HAART containing non-nucleosides reverse transcriptase inhibitors was mild to moderate and those who were co-infected with HBV and/or HCV, had concomitant use of antituberculosis drugs or cotrimoxazole and received a regimen containing nevirapine were prone to liver injury while receiving HAART.

Acquired Immunodeficiency Syndrome ; drug therapy ; Adolescent ; Adult ; Antiretroviral Therapy, Highly Active ; adverse effects ; Chemical and Drug Induced Liver Injury ; etiology ; Child ; Female ; HIV-1 ; Humans ; Male ; Middle Aged ; Nevirapine ; adverse effects ; Retrospective Studies ; Reverse Transcriptase Inhibitors ; adverse effects

Current in vitro assays for the activity of HIV-RT (reverse transcriptase) require radio-labeled or chemically modified nucleotides to detect reaction products. However, these assays are inherently end-point measurements and labor intensive. Here we describe a novel non-radioactive assay based on the principle of pyrosequencing coupled-enzyme system to monitor the activity of HIV-RT by indirectly measuring the release of pyrophosphate (PP(i)), which is generated during nascent strand synthesis. The results show that our assay could monitor HIV-RT activity with high sensitivity and is suitable for rapid high-throughput drug screening targeting anti-HIV therapies due to its high speed and convenience. Moreover, this assay can be used to measure primase activity in an easy and sensitive manner, which suggests that this novel approach could be wildly used to analyze the activity of PP(i)-generated and ATP-free enzyme reactions.
Anti-HIV Agents ; pharmacology ; Colorimetry ; Diphosphates ; analysis ; metabolism ; Drug Evaluation, Preclinical ; HIV ; drug effects ; enzymology ; HIV Reverse Transcriptase ; analysis ; antagonists & inhibitors ; metabolism ; Humans ; In Vitro Techniques ; Nevirapine ; pharmacology ; Reverse Transcriptase Inhibitors ; pharmacology ; Sequence Analysis, DNA ; Thymine Nucleotides ; metabolism

Consistent non-nucleoside reverse-transcriptase inhibitors (NNRTIs) resistant HIV-1 strains occurred due to the clinical use for more than ten years of efavirenz (EFV), nevirapine (NVP), and delavirdine (DLV). In this study, we established nine cell-based pharmacological models according to most NNRTIs-resistant clinical tested strains, Resistant mutations were introduced into vector, pNL4-3.Luc.R-E-, by overlapping PCR. Then, pseudovirions were produced by co-transfection of VSV-G plasmid and pNL4-3.Luc.R-E- -mut. All nine recombinant VSVG/HIV-mut pseudovirions (VSVG/HIV-wt, VSVG/HIV(-K103N), VSVG/HIV(-Y181C), VSVG/HIV(-L100I,K103N), VSVG/HIV(-Y188L), VSVG/HIV(-K103N,Y181C), VSVG/HIV(-K103N,P225H), VSVG/HIV(-K103N,Y188L), VSVG/HIV(-K103N,G109A) and VSVG/HIV(-K103N,V108I)) had high efficient infectivity. Furthermore, they all showed resistant characteristics to EFV and NVP with IC50 changes consisting with clinical reports, not to nucleoside reverse-transcriptase inhibitors (AZT and d4T). This series safe cell-based model, which could be carried out in BSL-2 laboratory, can be used for evaluating NNRTIs candidates.
Anti-HIV Agents ; pharmacology ; Benzoxazines ; pharmacology ; Cell Line ; Delavirdine ; pharmacology ; Drug Evaluation, Preclinical ; methods ; Drug Resistance, Viral ; Genetic Vectors ; HIV Reverse Transcriptase ; antagonists & inhibitors ; genetics ; metabolism ; HIV-1 ; drug effects ; genetics ; Humans ; Membrane Glycoproteins ; genetics ; Nevirapine ; pharmacology ; Plasmids ; genetics ; Point Mutation ; Reverse Transcriptase Inhibitors ; pharmacology ; Stavudine ; pharmacology ; Transfection ; Viral Envelope Proteins ; genetics ; Virion ; genetics ; metabolism ; Virus Replication ; Zidovudine ; pharmacology

Anti-HIV Agents ; chemistry ; pharmacology ; Benzoxazines ; Coumarins ; chemistry ; pharmacology ; Delavirdine ; chemistry ; pharmacology ; Drug Resistance, Viral ; HIV Reverse Transcriptase ; drug effects ; HIV-1 ; drug effects ; Humans ; Molecular Conformation ; Molecular Structure ; Nevirapine ; chemistry ; pharmacology ; Oxazines ; chemistry ; pharmacology ; Pyranocoumarins ; Reverse Transcriptase Inhibitors ; chemistry ; pharmacology

BACKGROUNDCD4(+) T cell counts have been used as the indicator of human immunodeficiency virus type 1 (HIV-1) disease progression and thereby to determine when to start highly active antiretroviral therapy (HAART). Whether and how the baseline CD4(+) T cell count affects the immunological and viral responses or adverse reactions to nevirapine (NVP)-containing HAART in Chinese HIV-1 infected adults remain to be characterized.

METHODSOne hundred and ninety-eight HIV-seropositive antiretroviral therapy (ART)-naive subjects were enrolled into a prospective study from 2005 to 2007. Data were analyzed by groups based on baseline CD4(+) T cell counts either between 100 - 200 cells/microl or 201 - 350 cells/microl. Viral responses, immunologic responses and adverse events were monitored at baseline and at weeks 4, 12, 24, 36, 52, 68, 84, 100.

RESULTSEighty-six and 112 subjects ranged their CD4(+) T cell counts 100 - 200 cells/microl and 201 - 350 cells/microl, respectively. The pre-HAART viral load in CD4 201 - 350 cells/microl group was significantly lower than that in CD4 100 - 200 cells/microl group (P = 0.000). After treatment, no significant differences were observed between these two groups either in the plasma viral load (pVL) or in the viral response rate calculated as the percentage of pVL less than 50 copies/ml or less than 400 copies/ml. The CD4(+) T cell counts were statistically higher in the 201 - 350 group during the entire follow-ups (P < 0.01) though CD4(+) T cell count increases were similar in these two groups. After 100-week treatment, the median of CD4(+) T cell counts were increased to 331 cells/microl for CD4 100 - 200 cells/microl group and to 462 cells/microl for CD4 201 - 350 cells/microl group. Only a slightly higher incidence of nausea was observed in CD4 201 - 350 cells/microl group (P = 0.05) among all adverse reactions, including rash and liver function abnormality.

CONCLUSIONSThe pVLs and viral response rates are unlikely to be associated with the baseline CD4(+) T cell counts. Initiating HAART in Chinese HIV-1 infected patients with higher baseline CD4(+) T cell counts could result in higher total CD4(+) T cell counts thereby achieve a better immune recovery. These results support current guidelines to start HAART at a threshold of 350 cells/microl.

Acquired Immunodeficiency Syndrome ; drug therapy ; immunology ; Adult ; Antiretroviral Therapy, Highly Active ; adverse effects ; methods ; Blotting, Western ; CD4-Positive T-Lymphocytes ; immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; HIV Infections ; drug therapy ; immunology ; Humans ; Male ; Middle Aged ; Nevirapine ; adverse effects ; immunology ; therapeutic use ; Prospective Studies