HIV drug resistance among patients experiencing antiretroviral therapy failure in Russia, 2019-2021.

Increasing HIV drug resistance is an important public health concern. The current study aimed to assess HIV drug resistance among people who live with HIV (PLWH) experiencing virological failure. Blood samples and epidemiological characteristics were collected in four Siberian regions from PLWH experiencing ART failure. Partial pol gene sequences were obtained for the study individuals. Drug resistance mutations (DRMs) were predicted using the Stanford HIVdb Program. The association of HIV DRM with epidemiological characteristics was estimated using logistic regression analysis. Further analysis was performed for children (0-14 y old) and adults (≥15 y old) separately. In total, 815 (89.4%) patients were included in the final dataset. Overall, 501 (61.5%) patients had DRM detected. NRTI DRM was more common in children, while NRTI+NNRTI DRM was more frequent in adults (P < 0.001). Krasnoyarsk region, male sex and high viral load were positively associated with the presence of DRM in adults, while higher CD4 cell count and PI/INSTI-based ART had a negative association. No association between epidemiological characteristics and DRM was identified in children. The remaining 38.5% of patients with virological failure had no DRM detected; those patients were likely to have insufficient ART adherence. Most (55.5%) patients had HIV CRF63_02A6, followed by sub-subtype A6 (39.2%). This study revealed poor ART adherence as a main factor driving ART failure among PLWH in the Siberian region. DRM was detected in over 60% of PLWH experiencing ART failure. The current results highlight an urgent need for the introduction of special programs focusing on ART adherence improvement.

Spatiotemporal dynamics of HIV-1 CRF63_02A6 sub-epidemic.

HIV-1 epidemic in Russia is one of the fastest growing in the world reaching 1.14 million people living with HIV-1 (PLWH) in 2021. Since mid-1990s, the HIV-1 epidemic in Russia has started to grow substantially due to the multiple HIV-1 outbreaks among persons who inject drugs (PWID) leading to expansion of the HIV-1 sub-subtype A6 (former Soviet Union (FSU) subtype A). In 2006, a local HIV-1 sub-epidemic caused by the distribution of novel genetic lineage CRF63_02A6 was identified in Siberia. In this study, we used a comprehensive dataset of CRF63_02A6 pol gene sequences to investigate the spatiotemporal dynamic of the HIV-1 CRF63_02A6 sub-epidemic. This study includes all the available CRF63_02A6 HIV-1 pol gene sequences from Los Alamos National Laboratory (LANL) HIV Sequence Database. The HIV-1 subtypes of those sequences were conferred using phylogenetic analysis, and two automated HIV-1 subtyping tools Stanford HIVdb Program and COMET. Ancestral state reconstruction and origin date were estimated using Nextstrain. Evolutionary rate and phylodynamic analysis were estimated using BEAST v 1.10.4. CRF63_02A6 was assigned for 872 pol gene sequences using phylogenetic analysis approach. Predominant number (n = 832; 95.4%) of those sequences were from Russia; the remaining 40 (4.6%) sequences were from countries of Central Asia. Out of 872 CRF63_02A6 sequences, the corresponding genetic variant was assigned for 75.7 and 79.8% of sequences by Stanford and COMET subtyping tools, respectively. Dated phylogenetic analysis of the CRF63_02A6 sequences showed that the virus most likely originated in Novosibirsk, Russia, in 2005. Over the last two decades CRF63_02A6 has been widely distributed across Russia and has been sporadically detected in countries of Central Asia. Introduction of new genetic variant into mature sub-subtype A6 and CRF02_AGFSU epidemics could promote the increase of viral genetic diversity and emergence of new recombinant forms. Further HIV-1 studies are needed due to a continuing rapid virus distribution. Also, the implementation of HIV-1 prevention programs is required to reduce HIV-1 transmission. This study also highlights the discrepancies in HIV-1 subtyping approaches. The reference lists of HIV-1 sequences implemented in widely used HIV-1 automated subtyping tools need to be updated to provide reliable results.

Characterization of HIV-1 Epidemic in Kyrgyzstan.

Kyrgyzstan has one of the highest rates of HIV-1 spread in Central Asia. In this study, we used molecular-epidemiological approaches to examine the HIV-1 epidemic in Kyrgyzstan. Samples were obtained from HIV-positive individuals who visited HIV/AIDS clinics. Partial pol gene sequences were used to identify HIV-1 subtypes and drug resistance mutations (DRMs) and to perform phylogenetic analysis. Genetic diversity and history reconstruction of the major HIV-1 subtypes were explored using BEAST. This study includes an analysis of 555 HIV-positive individuals. The study population was equally represented by men and women aged 1-72 years. Heterosexual transmission was the most frequent, followed by nosocomial infection. Men were more likely to acquire HIV-1 during injection drug use and while getting clinical services, while women were more likely to be infected through sexual contacts (p < 0.01). Heterosexual transmission was the more prevalent among individuals 25-49 years old; individuals over 49 years old were more likely to be persons who inject drugs (PWID). The major HIV-1 variants were CRF02_AG, CRF63_02A, and sub-subtype A6. Major DRMs were detected in 26.9% of the study individuals; 62.2% of those had DRMs to at least two antiretroviral (ARV) drug classes. Phylogenetic analysis revealed a well-defined structure of CRF02_AG, indicating locally evolving sub-epidemics. The lack of well-defined phylogenetic structure was observed for sub-subtype A6. The estimated origin date of CRF02_AG was January 1997; CRF63_02A, April 2004; and A6, June 1995. A rapid evolutionary dynamic of CRF02_AG and A6 among Kyrgyz population since the mid-1990s was observed. We observed the high levels of HIV-1 genetic diversity and drug resistance in the study population. Complex patterns of HIV-1 phylogenetics in Kyrgyzstan were found. This study highlights the importance of molecular-epidemiological analysis for HIV-1 surveillance and treatment implementation to reduce new HIV-1 infections.

Immunogenicity, safety, and reactogenicity of combined reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine administered as a booster vaccine dose in healthy Russian participants: a phase III, open-label study.

As vaccine-induced immunity and protection following natural pertussis infection wane over time, adults and adolescents may develop pertussis and become transmitters to unprotected infants. In Russia, diphtheria and tetanus but not pertussis-containing vaccines are registered for older children, adolescents, or adults. The reduced-antigen-content diphtheria toxoid, tetanus toxoid, and acellular pertussis (dTpa) vaccine (Boostrix, GSK) was developed for booster vaccination of children ≥4 years of age, adolescents, and adults. A phase III, open-label, non-randomized study was performed in eight centers in Russia between January and July 2018. The objective of this study was to assess immunogenicity, reactogenicity and safety of a single dose of dTpa vaccine in healthy Russian participants ≥4 years of age (age categories 4-9 years, 10-17 years, 18-64 years, and ≥65 years). At 1 month post-booster vaccination, across all age groups, >99.0% of participants were seroprotected against diphtheria and tetanus and >96.0% of participants were seropositive for anti-pertussis antibodies. For all antibodies across all age groups, antibody GMCs increased from pre- to 1 month post-booster vaccination and booster responses to diphtheria (in 71.5% of participants), tetanus (85.3%), and pertussis antigens (≥85.6%) were observed. One serious adverse event that was not causally related to the study vaccine was reported. No fatal cases were reported throughout the study period. In conclusion, administration of the dTpa vaccine as a booster dose in healthy Russian participants induced a robust immune response to all vaccine antigens and was generally well tolerated across all age groups.

Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course and a booster dose in healthy children in Russia: a phase III, non-randomized, open-label study.

We assessed the immunogenicity and safety of the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in children in Russian Federation aiming to support the registration of the vaccine in Russia. In this phase 3, non-randomized, open-label study (NCT02858440), healthy children received three primary doses at 3, 4.5, and 6 months of age (N = 235) and a booster dose at 18 months of age (N = 225). Seroprotection rates against diphtheria, tetanus, Hib, and poliovirus 1-3, seropositivity rates against pertussis antigens, and antibody geometric mean concentrations/titers for all antigens were evaluated one month post-primary and post-booster vaccinations. Solicited local and general adverse events (AEs) were collected during a 4-day period and unsolicited AEs during a 31-day period post-vaccination. Serious AEs were recorded throughout the study. At post-primary vaccination, all infants were seroprotected against diphtheria, tetanus, and poliovirus 1 and 2, 99.3% against poliovirus 3, and 98.4% against Hib. At least 98.9% of participants were seropositive for the three pertussis antigens. At post-booster vaccination, all toddlers were seroprotected/seropositive against all vaccine components. The most frequent local and general solicited AEs were redness, reported for 52.6% and 44.9% of children, and irritability, reported for 64.7% and 39.1% of children, post-primary and post-booster vaccination, respectively. Unsolicited AEs were reported for 20.4% (post-primary) and 5.8% of children (post-booster vaccination). Most AEs were mild or moderate in intensity. Six serious AEs were reported in three (0.4%) children; none were fatal or assessed as vaccination-related. DTPa-IPV/Hib proved immunogenic and well tolerated in the Russian pediatric population.

The management of acute myocardial infarction in the Russian Federation: protocol for a study of patient pathways.

BACKGROUND: Death rates from cardiovascular disease in Russia are among the highest in the world. In recent years, the Russian government has invested substantially in the healthcare system, with a particular focus on improving access to advanced technology, especially for acute myocardial infarction (AMI). This protocol describes a study to understand the management of AMI in different Russian regions, investigating the role of patient, clinical, and health system characteristics. METHODS: A prospective observational study has recruited a representative sample of AMI patients from 16 hospitals in 13 regions across Russia. Criteria for inclusion are being aged 35-70 years with a confirmed diagnosis of AMI and surviving until the day after admission. Information being collected includes health system contacts and features of clinical management prior to the event and in the 12 months following discharge from hospital. Following initial exploration of the data to generate hypotheses, multilevel modelling will be applied to assess the role of these characteristics in both treatment decisions and any delays in time critical interventions. Between June 2015 and August 2016, 1,122 patients have been recruited at baseline and follow-up to 12 months post-discharge is scheduled to be completed by autumn 2017. The study is unique in examining patient factors, clinical management prior to admission and in hospital in the acute phase and throughout the critical first year of recovery across a diverse range of geographies and facilities. It uses standardized instruments to collect data from patients and health care providers and includes regions that are diverse in terms of geography and development of cardiology capacity. However, given the limited health services research capacity in the Russian Federation, it was not possible to obtain a sample that was truly nationally representative.

The safety of two Bacillus probiotic strains for human use.

Probiotics based on Bacillus strains have been increasingly proposed for prophylactic and therapeutic use against several gastro-intestinal diseases. We studied safety for two Bacillus strains included in a popular East European probiotic. Bacillus subtilis strain that was sensitive to all antibiotics listed by the European Food Safety Authority. Bacillus licheniformis strain was resistant to chloramphenicol and clindamycin. Both were non-hemolytic and did not produce Hbl or Nhe enterotoxins. No bceT and cytK toxin genes were found. Study of acute toxicity in BALB/c mice demonstrated no treatment-related deaths. The oral LD(50) for both strains was more than 2 x 10(11) CFU. Chronic toxicity studies were performed on mice, rabbits, and pigs and showed no signs of toxicity or histological changes in either organs or tissues. We demonstrated that while certain risks may exist for the B. licheniformis strain considering antibiotic resistance, B. subtilis strain may be considered as non-pathogenic and safe for human consumption.