Prevalence of HIV drug resistance at antiretroviral treatment failure across regions of Russia.

BACKGROUND: This study aimed to investigate mutations associated with, the causes of, and the conditions that contribute to HIV drug resistance (DR). This research provides crucial insights into the mechanisms through which HIV evades antiretroviral drugs and suggests strategies to counter this phenomenon. Our objective was to assess the prevalence and structure of DR in HIV-1 across various regions in Russia and identify the primary factors influencing the development of HIV DR. METHODS: The study used nucleotide sequences from the HIV-1 pol gene obtained from 1369 patients with a history of therapy and virological failure between 2005 and 2019 to analyze the frequency and structure of DR and the factors associated with it. RESULTS: The analysed HIV-1 genotypes included viruses resistant to nucleoside reverse transcriptase inhibitors (NRTIs; 11.8%), non-nucleoside reverse transcriptase inhibitors (NNRTIs; 6.4%), and NRTIs + NNRTIs (31.7%). The mutations M184V/I and G190A/S/E were the most prevalent, accounting for 54.5% and 26.6%, respectively. The dominance of multiple DR persisted throughout the entire observation period. The likelihood of encountering drug-resistant variants was increased among men, patients in the late stage of infection, and those with a viral load <30 000 RNA copies/mL. Injection drug use was not associated with DR. CONCLUSION: This study has yielded new insights into HIV DR in Russia, offering valuable information to identify clinical or programmatic events warranting closer attention and support.

Factors Associated with Fatal COVID-19 Outcomes among People Living with HIV: A Cohort Study.

BACKGROUND: People living with HIV (PLHIV) are at increased risk of COVID-19 death. However, information about whether factors related to the HIV-infection influence the COVID-19 outcome still remains conflicting. OBJECTIVE: Here, we evaluate the risk factors for fatal COVID-19 in a cohort of PLHIV from the Moscow region, aged >18 years and diagnosed with COVID-19 between March 2020 and December 2021. METHODS: Demographic, clinical and laboratory data were compared between different COVID-19 outcomes. To analyze the risk factors associated with COVID-19 death, we employed the logistic regression method. A total of 566 PLHIV were included in the analysis. RESULTS: The majority of individuals, 338 (59.7%), were male; 194 (34.3%) were on antiretroviral therapy; 296 (52.3%) had a comorbidity; 174 (30.7%) of patients had drug and/or alcohol dependence; 160 (33.1%) patients had CD4 counts <200 cells/µl; 253 (51.9%) had undetectable viral load. Our analysis revealed that PLHIV >55 years old (OR, 12.88 [95% CI, 2.32-71.62]), patients with a viral load of more than 1000 copies/ml (OR, 2.45 [95%CI, 1.01-5.98]) and with CD4 counts <200 cell/µl (OR, 2.54 [95%CI, 1.02-6.28]), as well as with a history of cachexia (OR, 3.62 [95%CI, 1.26-10.39]) and pneumocystis pneumonia (OR, 2.47 [95%CI, 1.03-5.92]), and drug/alcohol dependence (OR, 2.70 [95%CI, 1.36-5.39]) were significantly more likely to die from COVID-19. CONCLUSION: These data show that people with advanced HIV-1 infection have an increased risk of fatal COVID-19 outcomes and that there is a need to improve this population's access to health services and, hence, increase their survival rates.

Alarming Rise of Primary HIV Drug Resistance in Major Regions of Russia.

OBJECTIVE: The study aimed to compare the prevalence of surveillance HIV drug resistance mutations (SDRMs) across the main federal districts of Russia. METHODS: A pooled analysis was conducted to examine data on HIV primary drug resistance (HIV PrimDR). The analysis was based on published results primarily from Russian regional clinical and scientific laboratories, covering a span of 20 years. RESULTS: The findings indicate that three surveyed regions, namely Central, Far Eastern, and Volga, exhibit a low level of HIV PrimDR prevalence (not exceeding 5%), and this prevalence does not show a tendency to increase. In contrast, three major regions, namely Northwestern, Southern, and Siberian, demonstrate a significant and progressive increase in HIV PrimDR prevalence, with recent values surpassing 10%. CONCLUSION: Consequently, it was concluded that a change in the HIV treatment strategy in these regions is imperative, emphasizing the need to expedite the transition to the utilization of secondgeneration integrase inhibitors.

Recombinant Forms of HIV-1 in the Last Decade of the Epidemic in the Russian Federation.

Currently, HIV-1 displays a substantial level of genetic diversity on a global scale, partly attributed to its recombinant variants. This study seeks to identify and analyze HIV-1 recombinants in Russia during the last decade of the epidemic. A comprehensive examination was conducted, encompassing 3178 partial pol sequences. Subtyping was achieved through various programs including COMET, the Stanford Database, REGA, jpHMM, RIP, and RDP4 for recombination analysis. The study also involved phylogenetic analysis to trace the origins of the identified recombinants. Primary resistance (PrimDR) prevalence and Drug Resistance Mutations (DRMs) were assessed. The study uncovered an overall proportion of recombinants at 8.7%, with a statistically significant increase in their frequency observed over time (p < 0.001). The Northwestern (18.5%) and Siberian (15.0%) Federal Districts exhibited a high prevalence of recombinants, while the Volga (1.9%) and Ural (2.8%) Federal Districts had a lower prevalence. Among HIV-1 recombinants, a PrimDR prevalence of 11.4% was identified. Notably, significant differences in DRMs were observed, with a higher prevalence of M184V in sub-subtype A6 (p = 0.018) and K103N in CRF63_02A6 (p = 0.002). These findings underscore the increasing HIV-1 genetic diversity and highlight a substantial prevalence of PrimDR among its recombinant forms, emphasizing the necessity for ongoing systematic monitoring.

Features of Tat Protein in HIV-1 Sub-Subtype A6 Variants Circulating in the Moscow Region, Russia.

Tat, the trans-activator of transcription, is a multifunctional HIV-1 protein that can induce chronic inflammation and the development of somatic diseases in HIV-infected patients. Natural polymorphisms in Tat can impact the propagation of the inflammatory signal. Currently, Tat is considered an object for creating new therapeutic agents. Therefore, the identification of Tat protein features in various HIV-1 variants is a relevant task. The purpose of the study was to characterize the genetic variations of Tat-A6 in virus variants circulating in the Moscow Region. The authors analyzed 252 clinical samples from people living with HIV (PLWH) with different stages of HIV infection. Nested PCR for two fragments (tat1, tat2) with subsequent sequencing, subtyping, and statistical analysis was conducted. The authors received 252 sequences for tat1 and 189 for tat2. HIV-1 sub-subtype A6 was identified in 250 samples. The received results indicated the features of Tat1-A6 in variants of viruses circulating in the Moscow Region. In PLWH with different stages of HIV infection, C31S in Tat1-A6 was detected with different occurrence rates. It was demonstrated that Tat2-A6, instead of a functional significant 78RGD80 motif, had a 78QRD80 motif. Herewith, G79R in Tat2-A6 was defined as characteristic amino acid substitution for sub-subtype A6. Tat2-A6 in variants of viruses circulating in the Moscow Region demonstrated high conservatism.

Reconstructing the Temporal Origin and the Transmission Dynamics of the HIV Subtype B Epidemic in St. Petersburg, Russia.

The HIV/AIDS epidemic in Russia is among the fastest growing in the world. HIV epidemic burden is non-uniform in different Russian regions and diverse key populations. An explosive epidemic has been documented among people who inject drugs (PWID) starting from the mid-1990s, whereas presently, the majority of new infections are linked to sexual transmission. Nationwide, HIV sub-subtype A6 (previously called AFSU) predominates, with the increasing presence of other subtypes, namely subtype B and CRF063_02A. This study explores HIV subtype B sequences from St. Petersburg, collected from 2006 to 2020, in order to phylogenetically investigate and characterize transmission clusters, focusing on their evolutionary dynamics and potential for further growth, along with a socio-demographic analysis of the available metadata. In total, 54% (107/198) of analyzed subtype B sequences were found grouped in 17 clusters, with four transmission clusters with the number of sequences above 10. Using Bayesian MCMC inference, tMRCA of HIV-1 subtype B was estimated to be around 1986 (95% HPD 1984-1991), whereas the estimated temporal origin for the four large clusters was found to be more recent, between 2001 and 2005. The results of our study imply a complex pattern of the epidemic spread of HIV subtype B in St. Petersburg, Russia, still in the exponential growth phase, and in connection to the men who have sex with men (MSM) transmission, providing a useful insight needed for the design of public health priorities and interventions.

Molecular Epidemiology of HIV-1 in Eastern Europe and Russia.

The HIV epidemic in Eastern Europe and Russia is large and not well-controlled. To describe the more recent molecular epidemiology of HIV-1, transmitted drug resistance, and the relationship between the epidemics in this region, we sequenced the protease and reverse transcriptase genes of HIV-1 from 812 people living with HIV from Ukraine (n = 191), Georgia (n = 201), and Russia (n = 420) before the initiation of antiretroviral therapy. In 190 Ukrainian patients, the integrase gene sequence was also determined. The most reported route of transmission was heterosexual contact, followed by intravenous drug use, and men having sex with men (MSM). Several pre-existing drug resistance mutations were found against non-nucleoside reverse transcriptase inhibitors (RTIs) (n = 103), protease inhibitors (n = 11), and nucleoside analogue RTIs (n = 12), mostly polymorphic mutations or revertants. In the integrase gene, four strains with accessory integrase strand transfer inhibitor mutations were identified. Sub-subtype A6 caused most of the infections (713/812; 87.8%) in all three countries, including in MSM. In contrast to earlier studies, no clear clusters related to the route of transmission were identified, indicating that, within the region, the exchange of viruses among the different risk groups may occur more often than earlier reported.

Identifying HIV-1 Transmission Clusters in Uzbekistan through Analysis of Molecular Surveillance Data.

The CRF02_AG and sub-subtype A6 are currently the predominant HIV-1 variants in the Republic of Uzbekistan, but little is known about their time-spatial clustering patterns in high-risk populations. We have applied molecular evolution methods and network analyses to better understand the transmission patterns of these subtypes by analyzing 316 pol sequences obtained during the surveillance study of HIV drug resistance. Network analysis showed that about one third of the HIV infected persons were organized into clusters, including large clusters with more than 35 members. These clusters were composed mostly of injecting drug users and/or heterosexuals, with women having mainly high centrality within networks identified in both subtypes. Phylogenetic analyses of the 'Uzbek' sequences, including those publicly available, show that Russia and Ukraine played a role as the main sources of the current subtype A6 epidemic in the Republic. At the same time, Uzbekistan has been a local center of the CRF02_AG epidemic spread in the former USSR since the early 2000s. Both of these HIV-1 variants continue to spread in Uzbekistan, highlighting the importance of identifying transmission networks and transmission clusters to prevent further HIV spread, and the need for HIV prevention and education campaigns in high-risk groups.

Pre-existing singleton E138A mutations in the reverse transcriptase gene do not affect the efficacy of first-line antiretroviral therapy regimens using rilpivirine in human immunodeficiency virus-infected patients.

General consensus suggests that even singleton E138A mutations in HIV reverse transcriptase at baseline are associated with resistance to rilpivirine (RPV). We detected 11 pre-existing E138A carriers treated with RPV in the pan European EuResist database. However, all 11 patients presented with full virological efficacy for first-line RPV-based ART regimens.

Correction: Prevalence and spatiotemporal dynamics of HIV-1 Circulating Recombinant Form 03_AB (CRF03_AB) in the Former Soviet Union countries.

[This corrects the article DOI: 10.1371/journal.pone.0241269.].

Prevalence of Antiretroviral Drug Resistance Mutations Among Pretreatment and Antiretroviral Therapy-Failure HIV Patients in Uzbekistan.

To evaluate the national prevalence of antiretroviral therapy (ART)-resistant HIV-1 viruses among both ART-initiators (pretreatment drug resistance, PDR) and ART-failure HIV patients in Uzbekistan. A nation-wide, cross-sectional active HIV-1 PDR surveillance was conducted in Uzbekistan from 2015 to 2016. In total, 713 blood plasma samples from adults were collected, including samples from ART-naive patients initiating ART and ART-failure HIV patients. HIV-1 genome polregion viral sequences were obtained from 309 patients, of those 106 on ART and 203 on ART-initiators. Analysis of HIV-1 subtypes and drug resistance mutations (DRMs) to HIV protease and reverse transcriptase inhibitors was performed. Among all the viruses studied, HIV-1 CRF 02_AG recombinant was the most common-57% (176/309). The second major group was represented by A1-40.5% (125/309). Two viruses were found to be recombinants formed by subtypes A1 and CRF02_AG sequences. ART-naive cohort I (PDR) included six samples that contained at least one surveillance drug resistance mutation (SDRM) (2.96%), with the most common being K103N mutation (4/6). In ART-experienced patients, cohort II, 77.4% (82/106) of viruses contained at least one mutation against PIs, NRTIs, or NNRTIs, with the most common mutations of M184V/I (49.1%; 52/106), K65R (18.9%; 20/106), K103N (23.6%; 25/106), and G190S (22.6%; 24/106). The significant difference in frequency of mutations was found between two dominant subtypes, A1 and CRF02_AG. The molecular epidemiological profile of HIV infection in Uzbekistan has changed toward a predominance of CRF02_AG viruses. In the first national-scale study of the PDR prevalence, it was found to be relatively low (2.96%). The DR mutations in failure patients correspond to the main therapy regimens (NRTI/NNRTI) adopted in the country. The observations provide new evidence for differences in ART efficacy and resistance profiles for different subtypes.

Prevalence and spatiotemporal dynamics of HIV-1 Circulating Recombinant Form 03_AB (CRF03_AB) in the Former Soviet Union countries.

BACKGROUND: HIV-1 circulating recombinant forms (CRFs) infections has been increasing in Former Soviet Union (FSU) countries in the recent decade. One is the CRF03_AB, which circulated in the region since late 1990s and probably became widespread in northwestern FSU countries. However, there is not much information provided about the dissemination of this recombinant. Here, we examine the prevalence, evolutionary dynamics and dispersion pattern of HIV-1 CRF03_AB recombinant. METHODS: We analyzed 32 independent studies and 151 HIV-1 CRF03_AB pol sequences isolated from different FSU countries over a period of 22 years. Pooled prevalence was estimated using a random effects model. Bayesian coalescent-based method was used to estimate the evolutionary, phylogeographic and demographic parameters. RESULTS: Our meta-analysis showed that the pooled prevalence of CRF03_AB infection in northwestern FSU region was 5.9% [95%CI: 4.1-7.8]. Lithuania (11.6%), Russia (5.9%) and Belarus (2.9%) were the most affected by CRF03_AB. We found that early region wide spread of HIV-1 CRF03_AB originated from one viral clade that arose in the city of Kaliningrad in 1992 [95%HPD: 1990-1995]. Fourteen migration route of this variant were found. The city of Kaliningrad is involved in most of these, confirming its leading role in CRF03_AB spread within FSU. Demographic reconstruction point to this is that CRF03_AB clade seems to have experienced an exponential growth until the mid-2000s and a decrease in recent years. CONCLUSION: These data provide new insights into the molecular epidemiology of CRF03_AB as well as contributing to the fundamental understanding of HIV epidemic in FSU.

Molecular Surveillance of HIV-1 Infection in Krasnoyarsk Region, Russia: Epidemiology, Phylodynamics and Phylogeography.

BACKGROUND: The information about the dynamics of the viral population and migration events that affect the epidemic in different parts of the Russia is insufficient. Possibly, the huge size of the country and limited transport accessibility to certain territories may determine unique traits of the HIV-1 evolutionary history in different regions. OBJECTIVE: The aim of this study was to explore the genetic diversity of HIV-1 in the Krasnoyarsk region and reconstruct spatial-temporal dynamics of the infection in the region. METHODS: The demographic and virologic data from 281 HIV-infected individuals in Krasnoyarsk region collected during 2011-2016 were analyzed. The time to the most recent common ancestor, evolutionary rates, population growth, and ancestral geographic movements was estimated using Bayesian coalescent-based methods. RESULTS: The study revealed moderate diversity of the HIV-1 subtypes found in the region, which included A6 (92.3%), CRF063_02A (4.3%), B (1.1%), and unique recombinants (2.5%). Phylogenetic reconstruction revealed that the A6 subtype was introduced into Krasnoyarsk region by one viral lineage, which arose around 1996.9 (1994.5-1999.5). The phylogeography analysis pointed to Krasnoyarsk city as the geographical center of the epidemic, which further spread to central neighboring districts of the region. At least two epidemic growth phases of subtype A6 were identified which included exponential growth in early-2000s followed by the decline in the mid/late 2010s. CONCLUSION: This study demonstrates a change in the genetic diversity of HIV-1 in the Krasnoyarsk region. At the beginning of the epidemic, subtype A6 prevailed, subtypes B and CRF063_02A appeared in the region later.

Human Immunodeficiency Virus-1 Diversity in the Moscow Region, Russia: Phylodynamics of the Most Common Subtypes.

This study analyzes the HIV-1 subtype diversity and its phylodynamics in Moscow region, which is the most densely populated area of Russia characterized by high rates of internal and external migration. The demographic and viral data from 896 HIV-infected individuals collected during 2011-2016 were analyzed. The study revealed broad diversity in the HIV-1 subtypes found in Moscow, which included A6 (85.1%), B (7.6%), CRF02_AG (1.2%) and URF_A6/B recombinants (4.2%). Other HIV-1 subtypes were detected as single cases. While A6 was most prevalent (>86.0%) among heterosexuals, injecting drug users and cases of mother-to-child transmission of HIV, subtype B (76.3%) was more common in men who have sex with men. Phylogenetic reconstruction revealed that the A6 sequences were introduced into the epidemic cluster that arose approximately around 1998. Within the subtype B, six major epidemic clusters were identified, each of which contained strains associated with only one or two dominant transmission routes. The date of origin of these clusters varied between 1980 and 1993, indicating that the HIV-1 B epidemic began much earlier than the HIV-1 A6 epidemic. Reconstruction of the demographic history of subtypes A6 and B identified at least two epidemic growth phases, which included an initial phase of exponential growth followed by a decline in the mid/late 2010s. Thus, our results indicate an increase in HIV-1 genetic diversity in Moscow region. They also help in understanding the HIV-1 temporal dynamics as well as the genetic relationships between its circulating strains.

Analysis of the env gene variability of the IDU-A HIV-1 variant in the outbreak of the HIV infection epidemic in Perm region of Russia (1996-2011).

In the present work, a total of 132 HIV-1 env gene C2-V3-C3 sequences belonging to the IDU-A genetic variant were analyzed. The variants were obtained from the viruses circulating among IDUs and heterosexuals in the Perm region at different periods. It was shown that the rate of the divergence of the IDU-A HIV-1 viruses from a common ancestor increased 4.3 times (p < 0.001) in 2011 as compared with the onset of the epidemics. The rate of the HIV-1 evolution was different in the two risk groups of the infection. The mean genetic distance of HIV-1 variants circulating among heterosexuals was 1.3 times longer (p = 0.008) than that among IDUs. The accumulation rate of the nucleotide (including nonsynonymous) substitutions in the C2-V3-C3 HIV-1 env gene region among individuals infected by heterosexual contacts was 1.7 times higher than that among IDUs. The differences in the positions of the codons subjected to positive selection were demonstrated depending on the infection risk group tested.