Dissertation committee:
Δημήτριος Παρασκευής, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ, Επιβλέπων
Γεώργιος Δαΐκος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μήνα Ψυχογυιού, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Παγώνα Λάγιου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ελένη Γκόγκα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Σαμάρκος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Βασιλική-Αναστασία Σύψα, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Human Immunodeficiency Virus (HIV) has caused one of the most devastating pandemics in human history. In Greece, according to the national HIV/AIDS surveillance system (National Public Health Organization – NOPH), the total number of HIV-infected individuals was 17,389 in 2018. In addition, Greece has experienced one of the largest HIV-1 outbreaks among people who inject drugs (PWID) in Europe. The aim of the thesis was the investigation of the HIV-1 epidemic in Greece using molecular methods. In the context of the study, most of the available molecular data in Greece were analysed (high coverage). Specifically, the study population consisted of 4,856 unique HIV-1 nucleotide sequences sampled during 1999-06/2015 in Greece. The analysis was based on current state-of-the-art molecular epidemiology methods – phylogenetic, phylodynamic and phylogeographic analyses – which have proven to be powerful tools in public health. Subtyping analysis revealed that although subtype B (44.2%) and A1 (25.3%) are the most prevalent HIV-1 clades in Greece, the HIV-1 epidemic has a significant trend over time. Specifically, the prevalence of subtype B and non-B non-A1 subtypes was found to decrease over time. On the contrary, the prevalence of subtype A1 and CRFs shows an increasing trend. The investigation of the dispersal patters of the most prevalent HIV-1 subtypes in Greece revealed that 93.8% of subtype A1 sequences formed monophyletic clusters (regional dispersal). For subtype B the corresponding proportion was lower and equal to 77.1%. In addition, analysis showed that risk group (Men who have Sex with Men – MSM) and nationality (Greek) were associated with the regional clustering of subtype A1, while period of sampling (2011-2015) was associated with the regional clustering of subtype B. The molecular surveillance of the HIV-1 subepidemic among PWID in Athens (2011-2014) indicated that the majority of sequences from PWID fell within four local transmission networks – LTNs (subepidemics) (CRF14_BG, CRF35_AD, Β, A). In addition to sequences from PWID, a low number of sequences from non-PWID belonged to these networks, corresponding to cross-group transmissions. It was also found that subtype A1 and CRF35_AD subepidemics started around the same time period (December 2009 - May 2010), in contrast to subtype B and CRF14_BG subepidemics which started earlier (B: March 2006, CRF14_BG: July 2008). Furthermore, transmissions within subtype A1 and CRF35_AD LTNs increased sharply during the early stage of the outbreak, while transmissions within subtype B and CRF14_BG LTNs lasted for a longer time period. Focusing on the non-Greek PWID in Athens, analysis revealed that for 94.3% the origin of their HIV-1 infection was assumed to be in Greece (post-migration). Most of the non-Greek PWID had been infected within the PWID-LTNs (CRF14_BG, CRF35_AD, B, A1). Moreover, the recent PWID subepidemic in Athens was found to be a unique case, since for PWID infected within networks, HIV-1 transmissions occurred more frequently among non-Greeks than would be expected by chance. The exploration of associations between transmission links (as estimated by molecular analysis) and social network-based ties among PWID recruited into “TRIP” (Transmission Reduction Intervention Project – TRIP) showed that a high proportion of individuals (59.3%) in phylogenetic clusters had first-degree social ties with at least one member of their cluster. This means that more than half of the individuals with viral linkage were also socially linked, suggesting that during an HIV outbreak among PWID, transmissions occurred preferentially within socially linked individuals. Additionally, it was found that transmissions are more frequent among PWID with high viremia and that recently HIV-infected individuals are more likely to be the source of HIV-1 transmission within transmission pairs. The prevalence of resistance among treatment-naïve individuals during 2003–2015 was estimated 22.2% (HIVdb resistance interpretation algorithm). Resistance to NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors) was the most common (16.9%) and was found to increase over time. Analysis revealed that the dispersal patterns of the NRTI (Nucleoside Reverse Transcriptase Inhibitor) and NNRTI resistant strains differed significantly. Specifically, the most frequently observed NNRTI resistant mutations (E138A, K103N) were found to be transmitted within local networks (five subepidemics), suggesting regional dispersal, and, also, to be associated with MSM and subtype A1. Furthermore, it was found that three out of four E138A subepidemics started around the same time period (between 1995 and 1997) and that the number of transmissions within most of the E138A networks increased during 2011-2015. On the other hand, the origin of the K103N subepidemic was more recent (2007) and the number of transmissions within this network increased during 2008-2013. In conclusion, according to the leading national public health institute of the USA (Centers for Disease Control and Prevention – CDC), the investigation and characterization of an epidemic is of crucial importance for the control of the epidemic. Under this perspective, the current findings, which were based on an analysis of almost 5,000 HIV-1 sequences using innovative molecular epidemiology methods, produced evidence-based knowledge that could provide added value on the control of the HIV-1 epidemic in Greece.
Keywords:
HIV, Molecular epidemiology, Phylogenetic analysis, Phylodynamic analysis, Phylogeographic analysis, Dispersal patterns, Epidemiological parameters, HIV drug resistance
