Polymorphisms and Mutational Covariation Associated with Death in a Prospective Cohort of HIV/AIDS Patients Receiving Long-Term ART in China

Abstract

BackgroundHIV 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.MethodsIn 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.ResultsThis 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.ConclusionsSome 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.

HIV drug resistance in patients in China’s national HIV treatment programme who have been on first-line ART for at least 9 months

“…Data collected through the Chinese National HIVDR Surveillance and Monitoring Network since 2003 were analyzed using a retrospective method to assess HIVDR and associated program factors in populations of patients on ART. The database included annual cross-sectional surveys of HIV drug resistance from 2003 to 2015 in China which were described in the previous studies [9,10,14,[16][17][18]. and the methodology was endorsed by WHO for HIVDR Monitoring Survey [6,19].…”

“…However, throughout the period of increasing implementation of ART, China's National Free Antiretroviral Treatment Program (NFATP) has been largely successful, with an overall reduction in virological failure and HIV drug resistance since 2008 [9]. Although there is limited access to many antiretrovirals (ARVs) in China, data from the NFATP study prove that understanding the scientific basis and clinical implications of HIVDR is useful in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases [9][10][11][12].…”

Natural polymorphisms in HIV-1 CRF01_AE strain and profile of acquired drug resistance mutations in a long-term combination treatment cohort in northeastern China

“…The HIV-1 strain HXB2 was used as the reference sequence of location. Positively selected mutations (PSMs) were determined using selection pressure (Ka/Ks ratio), with Ka/Ks > 1 and log odds ratio (LOD) > 2 [29]. Conditional selection pressure (conditional Ka/Ks, cKa/ Ks) was used to measure the correlation between PSMs, with cKa/Ks > 1 and LOD > 2 indicating the presence of directional co-variation.…”

Natural polymorphisms in HIV-1 CRF01_AE strain and profile of acquired drug resistance mutations in a long-term combination treatment cohort in northeastern China

“…Positively selected mutations (PSMs) were determined using selection pressure (Ka/Ks ratio), with Ka/Ks >1 and log odds ratio (LOD) >2 [29]. Conditional selection pressure (conditional Ka/Ks, cKa/Ks) was used to measure the correlation between PSMs, with cKa/Ks >1 and LOD >2 indicating the presence of directional co-variation.…”