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COMMON ACTION AGAINST HIV/TB/HCV ACROSS THE REGIONS OF EUROPE

Periodic Reporting for period 2 - CARE (COMMON ACTION AGAINST HIV/TB/HCV ACROSS THE REGIONS OF EUROPE)

Reporting period: 2020-01-01 to 2021-06-30

An estimated 2.3 million people are living with HIV in the WHO European Region today. The incidence of HIV in eastern Europe is growing, while ART coverage remains particularly low.
Although most HIV patients under modern antiretroviral therapy (ART) respond well to therapy, a minority still experience virological failure or have to change their successful regimen due to drug resistance, toxicity, drug-drug interactions or comorbidity.
Recently, the modern class of antivirals called “integrase strand transfer inhibitors” (InSTI) is being introduced into low/middle-income countries, requiring specific surveillance particularly in eastern Europe, where a specific viral population is present (including the HIV-1 A6 subsubtype).

TB causes 10.4 million new cases globally and is a major public health problem in the WHO European Region.
TB diagnosis is difficult and, more significantly, reliable prognostic markers (i.e. cure, relapse, failure) are missing. Multi-drug resistant TB (MDR-TB) requires long, expensive, often ineffective treatments. Patients from eastern Europe show specifically high rates of second-line MDR-TB.

The size of the HCV-infected population in the eastern region of Europe is around 14 million, and in combination with excessive alcohol consumption is a major cause of excess morbidity and mortality.
With the availability of direct acting oral anti-HCV drugs (DAA), communitywide eradication of HCV appears possible, but to define an optimal treatment strategy under public health perspective is necessary.

CARE activities will define tools, paradigms and interventions aiming at improving clinical care and treatment outcomes and reducing the burden of the three diseases in the short, medium and long term, with a specific focus on the European Region and the Russian Federation (Fig. 1).
CARE aimed at generating novel research findings with potential short term application as well as to implement the research infrastructure to allow the expansion of activities beyond the funding frame.
Infrastructure
The project partners (Fig. 2) put a tremendous and successful effort in building a powerful ethics and IT infrastructure that permits the full functioning of the project, with data and samples transfer across the European region.
This allowed the consortium to produce high level and novel scientific results in accordance with the objectives.
Participants enrolled in CARE
CARE has enrolled over 10 000 people living with HIV, tuberculosis and/or hepatitis C into various substudies as well as retrospective data on almost 60 000 DAA treated people with HCV infection.
In order to fully exploit the potential given by the cohorts infrastructure set-up, a plan for further long-term cooperation has been developed!

Major research results:

TB Diagnostics
With cohorts of patients from Russia and Lithuania, we identified and further evaluated at least 2 candidate urine biomarkers of response to treatment. If successful, this research will contribute to the development of reliable non-invasive TB diagnostics.
Also, our Extrapulmonary TB patients cohort allowed us to verify our hypothesis regarding the involvement of the Siglec‐1 gene in M tuberculosis extrapulmonary dissemination.
TB treatment management
We developed a beta version of Geno2Pheno TB tool for prediction of drug-resistance profiles from whole genome sequencing data of M tuberculosis, which favourably compares with a state-of-the-art mutation catalogue.
Also, we identified genomic variants implicated in Bedaquiline resistance, a new hallmark drug for the treatment of MDR-TB, and gained further insights into the population structure of MDR-TB strains and their resistance determinants in the region.

HIV epidemiology and treatment resistance
We achieved important scientific progress in the evaluation of drug resistance to INSTIs in the region.
Overall 2360 patients and 2472 sequences have been involved in the study. Several novel tools have been developed specific for the subsubtype A6: a high-throughput sequencing assay for HIV-1 A6; a Geno2pheno[] tool for A6 in beta version; a new consensus A6 sequence; and for the first time a full length reference A6 clone is being created.
Viruses expressing A6 integrase have been analyzed for in vitro phenotypic susceptibility to INSTIs and showed to be as susceptible as the reference subtype B to INSTIs.
For the first time in Russia, a statistically significant study of primary HIV drug resistance was carried out in the Moscow region. The prevalence of resistant viruses was 3.2% with a predominance of mutations to NNRTIs.
A Strategic Plan for pretreatment resistance (PDR) surveillance has been developed for Eastern Europe.

HIV host genomics and HCV
We enrolled a prospective cohort of over 6500 people with HIV and HIV/HCV coinfection, and established a biobank of whole blood samples from 4,299 participants, with host genomic analysis for 1500 participants. From the HIV substudy, we found that the target of 90% PLHIV on ART was achieved in Georgia and Ukraine but not in Russia, and the target of 90% on those on ART having viral suppression was achieved only in Georgia.
From the HIV/HCV substudy we found a striking inter- and intra-country differences in HCV-RNA testing (ranging from 4.9% to 88.3% in participating sites) and treatment (with cure proportion ranging from 0% to 19.4% across sites).
From the retrospective cohort of DAA treated people with HCV we found that the overall rate of sustained virologic response 12 weeks after end of treatment is 94.8% with similarly high rates in all four cohorts. A gradual decrease in SVR12 with increasing age and fibrosis stage was observed.

Training and dissemination
Training sessions, with Russian young researchers coming to Europe, have been held (Fig. 3).
14 scientific papers on project results have been published in international peer reviewed journals; 7 more are under preparation. 11 posters have been presented at international high-level conferences; 3 more have been submitted.
2 major conferences have been organized and co-organised with EU and Russian Federation Ministries to present project’s results (Figg. 4-7).
Despite its short duration and the overlap with the COVID-19 pandemics, CARE produced impactful novel results.
The novel findings in TB diagnostics and treatment strategies together with the groundbreaking innovative tool to support clinical choice have the potential to favorably impact the burden of the whole TB epidemic.
The study of HIV PDR showing that such resistance exists, also to INSTIs, the studies and novel tools on the subsubtype A6 are fundamental to evaluate the sensitivity for new INSTIs and to tailor clinical care in the region.
The Strategic Plan for PDR surveillance has the ambition to support targeted public health interventions.
Understanding the role of host genetic variants will allow for personalization of treatment approach as this area matures.
Overall CARE will contribute to decreasing the burden of HIV disease in Eastern Europe.
Comparative study of prioritisation strategies for HCV curative DAA medications allowed to outline the current gaps in HCV healthcare and are of the highest relevance for European healthcare policies in view of the HCV elimination goal.
Finally, CARE large cohorts and data collections have the potential to be exploited for prospective and retrospective studies, attracting funding and contributing to the European competitiveness.
Figure 7: Participants to the online meeting: “HIV-TB-HCV: EU-Russia cooperation results”
Figure 2: The project partners at the kick-off meeting
Figure 5: Presenters at the conference "Joint efforts against infectious diseases: HIV, TB, HCV"
Figure 4: The programme of the conference "Joint efforts against infectious diseases: HIV, TB, HCV"
Figure 1: The geographic distribution of CARE consortium.
Figure 3: Training in Siena
Figure 6: Programme of the online meeting: “HIV-TB-HCV: EU-Russia cooperation results”