Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,U...Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events.For this study,we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda,a low-income country.Methods:We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T,which represents approximately 5%of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment.Next generation sequencing(DEEPGEN^(TM)HIV)and multiplex oligonucleotide ligation assays(AfriPOLA)were then performed on a subset of patient samples to detect low frequency drug resistant mutations.CD4 cell counts,viral RNA loads,and treatment changes were analyzed in a cohort of treatment success and failures.Results:Over 80%of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC(Lamivudine)and non-nucleoside RT inhibitors(NNRTIs)in the treatment regimen but only 45%had resistance AZT/d4T associated resistance mutations(TAMs).TAMs were however detected at low frequency within the patients HIV quasispecies(1-20%)in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger.Due to lack of TAMs by Sanger,AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success.Conclusions:Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second-and third-line treatment failures.展开更多
Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this numbe...Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.展开更多
基金F.K.was funded by a scholarship from the NIH Fogarty International Center grants D43-TW000011 and D43-TW009780.E.J.A.was funded by NIAID/NIH AI49170holds the Canada Research Chair in HIV-1 Pathogenesis and Viral Control.M.E.Q-M was partially supported by the CWRU/UH Center for AIDS Research(P30 AI036219)by funding from University Hospitals Cleveland Medical Center(UHCMC)for the University Hospitals Translational Laboratory(UHTL).
文摘Background:Thymidine analogs,namely AZT(Zidovudine or Retrovir^(TM))and d4T(Stavudine or Zerit^(TM))are antiretroviral drugs still employed in over 75%of first line combination antiretroviral therapy(cART)in Kampala,Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events.For this study,we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda,a low-income country.Methods:We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T,which represents approximately 5%of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment.Next generation sequencing(DEEPGEN^(TM)HIV)and multiplex oligonucleotide ligation assays(AfriPOLA)were then performed on a subset of patient samples to detect low frequency drug resistant mutations.CD4 cell counts,viral RNA loads,and treatment changes were analyzed in a cohort of treatment success and failures.Results:Over 80%of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC(Lamivudine)and non-nucleoside RT inhibitors(NNRTIs)in the treatment regimen but only 45%had resistance AZT/d4T associated resistance mutations(TAMs).TAMs were however detected at low frequency within the patients HIV quasispecies(1-20%)in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger.Due to lack of TAMs by Sanger,AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success.Conclusions:Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second-and third-line treatment failures.
文摘Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.
