HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibit...HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.展开更多
AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for prol...AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors(NRTIs), nonnucleoside reverse transcriptase inhibitors(NNRTIs), and protease inhibitors(PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase(GPDH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher's Least Significant Difference test. RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI(14% at 48 h, P < 0.001) and PI + NRTI(19% at 48 h, P < 0.001) with additional suppression when ritonavir(RTV) was added(26% at 48 h). The drug combination of atazanavir(ATV) + RTV + emtricitabine(FTC) + tenofovir(TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity(64%) or lipid accumulation(39%), P < 0.001. Combining NRTIs with a PI(ATV + FTC + TDF) significantly suppressed differentiation(GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added(ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.展开更多
Background Liver 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 ...Background Liver 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.Methods Seventy-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.Results Forty-five patients （60.0%）, 31 （68.9%） males and 14 （31.1%） females, aged 12 to 52 years （averaged （3g±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.Conclusions Liver 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.展开更多
There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study charact...There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study characterizes the rates and changes in HIV genotypic mutations and antiretroviral resistance among viremic patients from 2001 to 2006 at the VA Medical Center located in Washington, DC. The District of Columbia is the metropolitan area with the highest HIV prevalence within the United States. De-identified, linked HIV RNA, genotypic reverse transcriptase (RT) and protease (Pr) mutations and antiretroviral resistance results were assessed for changes during the 6-year period. Aggregated clinic and antiretroviral utilization, and HIV acquisition risk data were evaluated for patients in care during this time. Among 990 viremic samples, the rate of any detected RT or Pr mutation fell from 100% in 2001 to 95% in 2006. This was primarily attributable to the 15% - 20% decrease seen for RT gene mutations against nucleoside/nucleotide class and non-nucleoside class during this period. Resistance to didanosine, stavudine, zidovudine, nevirapine and efavirenz decreased, and tenofovir resistance increased. Despite stable rates of Pr gene mutations, atazanavir resistance increased by 22% from 2003 to 2006. Some but not all changes in genotypic mutations and resistance patterns reflected our patients’ antiretroviral drug utilization. As sexual contacts (77%) and injection drug use (22%) were the leading acquisition risks disclosed by our HIV-infected patients, the high prevalence and changing patterns of HIV genotypic mutations and drug resistance among these patients have had pivotal impacts not only on HIV treatment but potential transmission into our community.展开更多
基金supported by the grants from Chinese National Science Foundation(No.30472166)the Tianjin Commission of Sciences and Technology under the Contract(No.06YFGZSH07000)
文摘HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.
文摘AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors(NRTIs), nonnucleoside reverse transcriptase inhibitors(NNRTIs), and protease inhibitors(PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase(GPDH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher's Least Significant Difference test. RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI(14% at 48 h, P < 0.001) and PI + NRTI(19% at 48 h, P < 0.001) with additional suppression when ritonavir(RTV) was added(26% at 48 h). The drug combination of atazanavir(ATV) + RTV + emtricitabine(FTC) + tenofovir(TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity(64%) or lipid accumulation(39%), P < 0.001. Combining NRTIs with a PI(ATV + FTC + TDF) significantly suppressed differentiation(GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added(ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.
文摘Background Liver 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.Methods Seventy-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.Results Forty-five patients （60.0%）, 31 （68.9%） males and 14 （31.1%） females, aged 12 to 52 years （averaged （3g±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.Conclusions Liver 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.
文摘There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study characterizes the rates and changes in HIV genotypic mutations and antiretroviral resistance among viremic patients from 2001 to 2006 at the VA Medical Center located in Washington, DC. The District of Columbia is the metropolitan area with the highest HIV prevalence within the United States. De-identified, linked HIV RNA, genotypic reverse transcriptase (RT) and protease (Pr) mutations and antiretroviral resistance results were assessed for changes during the 6-year period. Aggregated clinic and antiretroviral utilization, and HIV acquisition risk data were evaluated for patients in care during this time. Among 990 viremic samples, the rate of any detected RT or Pr mutation fell from 100% in 2001 to 95% in 2006. This was primarily attributable to the 15% - 20% decrease seen for RT gene mutations against nucleoside/nucleotide class and non-nucleoside class during this period. Resistance to didanosine, stavudine, zidovudine, nevirapine and efavirenz decreased, and tenofovir resistance increased. Despite stable rates of Pr gene mutations, atazanavir resistance increased by 22% from 2003 to 2006. Some but not all changes in genotypic mutations and resistance patterns reflected our patients’ antiretroviral drug utilization. As sexual contacts (77%) and injection drug use (22%) were the leading acquisition risks disclosed by our HIV-infected patients, the high prevalence and changing patterns of HIV genotypic mutations and drug resistance among these patients have had pivotal impacts not only on HIV treatment but potential transmission into our community.
