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HIV molecular epidemiology and new treatment strategies in Russia and Eastern Europe

Leading partner: Karolinska Institute (Sweden)

Adopting a comprehensive approach to the management of HIV infection, CARE on one hand analyses the molecular epidemiology of the infection, including treatment efficacy and drug resistance; on the other hand, it prepares for the introduction of dolutegravir-based treatment, as recommended by the World Health Organisation.

CARE pursues the following specific objectives:

  • Characterization of HIV transmission clusters with different subtypes and recombinants, including molecular epidemiology of HIV/TB coinfection across Europe and the Russian Federation

  • Development of high throughput sequencing (HTS) protocols based on next generation sequencing for monitoring HIV drug resistance in a convenient and productive format

  • Analysis of the mechanisms of INSTI (integrase strand transfer inhibitor) drug resistance in the highly prevalent HIV-1 subtype A6, including the role of natural polymorphisms and off-target mechanisms based on mutations outside the integrase gene

  • Comparative analysis of time trends of pre-treatment drug resistance in Russia and estimation of its effect on upcoming dolutegravir-based therapy, based on both currently available data and a specific PDR surveillance program

  • Analysis of adverse events, tolerability, and treatment efficacy of DTG, including HIV drug resistance assessment, in a large cohort of patients from Europe and Russia including both HIV-monoinfected and HIV/TB coinfected patients

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Cohorts and DBs

Ongoing results

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The CARE Consortium has achieved important scientific progresses in experimental research, and cohort establishment for the evaluation of drug resistance to integrase strand inhibitors (INSTI).

Also, it has obtained knowledge about the impact of natural polymorphisms, pre-existing and off-target mutations on INSTI susceptibility in a limited number of HIV isolates from patients infected by subtypes/sub-subtypes highly prevalent in Russia and Eastern Europe but rare otherwise.

  • The Eastern European Database for molecular HIV-1 epidemiological analysis has been set-up aiming at enrolling 1100 patients in Russia, Georgia and Ukraine. So far, 1620 retrospective sequences and 859 prospective patients are included, with prospective samples and data collection ongoing.

  • Wild type in house integrase HIV+ sub-subtype A6 sequences have been obtained from Europe, Russia, and Georgia and a new consensus A6 sequence has been created.

  • Samples from HIV-1 A6 patients have been shipped from Russia and Ukraine to Europe and the creation of recombinant A6 viruses has started.

  • A high-through put sequencing assay for HIV-1 A6 strains has been established and validated on Swedish, German and Russian samples.

  • Sub-subtype A6 has been analyzed for its in vitro phenotypic susceptibility to integrase strand transfer inhibitors (INSTIs). The HIV-1 integrase coding region from twenty different A6 isolates was inserted into the HIV-1 NL4-3 backbone and showed to be as susceptible as the reference subtype B integrase to INSTIs, including dolutegravir, bictegravir, cabotegravir. While this data is reassuring, further analysis is ongoing to evaluate the genetic barrier of A6 isolates to INSTIs through in vitro drug resistance selection experiments.

  • When reanalysing the Swedish InfCareHIV database (>11.000), patients infected with A6 strains were identified for the first time with the first case from 1991 and a substantial increase in the numbers in the period 2007-2020.

  • In the prospective HIV drug resistance substudy real-life samples from failing patients are collected (target is 160) from Russia and Ukraine. As of October 2020, 208 samples from patients failing INSTIs have been collected.

 

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