title: Polymorphisms and Mutational Covariation Associated with Death in a Prospective Cohort of HIV/AIDS Patients Receiving Long-Term ART in China.
abstract: BACKGROUND
  HIV drug resistance is associated with faster clinical progression of AIDS. However, the effect of significant polymorphisms and mutational covariation on mortality among HIV/AIDS patients receiving long-term antiretroviral therapy (ART), have rarely been studied.
  
  
  METHODS
  In this prospective cohort study from December 2003 to December 2014, we present a new computational modelling approach based on bioinformatics-based models and several statistical methods to elucidate the molecular mechanisms involved in the acquisition of polymorphisms and mutations on death in HIV/AIDS patients receiving long-term ART in China.
  
  
  RESULTS
  This study involved 654 ART-treated patients, who had been followed for 5473.4 person-years, a median of 9.8 years, and 178 died (25.2%, 3.3/100 person-years). The first regimens included AZT/d4T + NVP+ ddI (78.9%) or AZT/d4T + NVP+ 3TC (20.0%). We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that 20 polymorphisms (E6D, Q18H, E35D, S37N, T39A, K43E, S68N, L74I, I93L, K103N, V106A, E169D, Y181C, G190A, Q197K, T200V, T200E, T215I, E224D and P225H) were strongly associated with AIDS related deaths. Among them, 7 polymorphisms (L74I, K103N, V106A, Y181C, G190A, T215I and P225H) were known to be drug resistance mutations, 7 polymorphisms (E6D, E35D, S37N, I93L, E169D, T200V and T200E were considered to be potential drug resistance mutations, and 6 polymorphisms (T39A, K43E, S68N, Q197K, T200V and E224D) were newly found to have an association with drug resistance mutations, which formed a complex network of relationships.
  
  
  CONCLUSIONS
  Some polymorphisms and mutational covariation may be the important influencing factors in the failure of treatment. Understanding these mechanisms is essential for the development of new therapies, designing optimal drug combinations, and determining effective clinical management of individual patients.
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Pengtao
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Anhui Center for Disease Control and Prevention, Hefei, Anhui Province, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Henan Center for Disease Control and Prevention, Zhengzhou, Henan Province, China.
authors.forename: Suian
authors.initials: S
authors.lastname: Tian
authors.affiliation: Anhui Center for Disease Control and Prevention, Hefei, Anhui Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
authors.affiliation: Henan Center for Disease Control and Prevention, Zhengzhou, Henan Province, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Lingjie
authors.initials: L
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xing
authors.affiliation: Weifang Medical University, Weifang, Shandong Province, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: You
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Ruan
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000401:mortality / Q000821:virology; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D002681:China; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase