HLA class II DRB1, DQA1, DQB1 loci in patients with HIV infection and tuberculosis in a Latvian cohort group.

Introduction: Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death among people infected with HIV. Tuberculosis incidence in Latvia has decreased by 25% during the last 30 years, but the mortality level of TB remains significant. The HLA class II genes are responsible for antigen presentation and regulation of immune responses, which plays an important role in individual susceptibility to infection disease. Whether or not differential HLA polymorphism contributes to TB with HIV infection and TB without HIV infection in Latvian patients is unknown. Material and methods: For the detection of HLA class II DQA1, DQB1, and DRB1 alleles a total of 616 subjects were enrolled, including 80 primary active TB (PATB) patients, 168 HIV-1/TB patients, 168 HIV-1 patients and 200 HC individuals. Results: For immunodeficiency caused by TB, HIV-1 or HIV-1/TB coinfection, alleles DRB1*12:01, 14:01, 16:01, DQA1*01:02, 01:03, 02:01, 06:01, DQB1*03:03, 06:01 are identified as protective, but DRB1*07:01, 11:01, 15:01, DQA1*02:01, 03:01, DQB1*03:01, 05:01 are identified as risk alleles. Conclusions: The results of our experimental pilot studies demonstrated that HLA class II genes may contribute to the genetic risk of TB and HIV-1/TB co-infection, possibly by reducing the presentation of protective Mycobacterium tuberculosis antigens to T-helpers. It is necessary to conduct repetitive, multicentre, and large sample studies in order to draw more scientific conclusions and to confirm the relationship between TB, HIV and HIV-1/TB co-infection susceptibility and gene polymorphisms.

Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe: associated factors and effect on mortality-a multicentre prospective cohort study.

BACKGROUND: Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). METHODS: PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan-Meier estimates and Cox models. FINDINGS: 480/740 patients (64.9%; 95% CI 61.3-68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. < 50 years, aOR = 2.51; 1.18-5.32; p = 0.016), injecting drug use (IDU) (vs. non-IDU aOR = 1.66; 1.21-2.29; p = 0.002), being ART naïve (aOR = 1.77; 1.24-2.54; p = 0.002), disseminated TB (vs. pulmonary TB, aOR = 1.56, 1.10-2.19, p = 0.012), and presenting with weight loss (vs. no weight loss, aOR = 1.63; 1.18-2.24; p = 0.003) were associated with delayed diagnosis. PLWH with a delayed diagnosis were at 36% increased risk of death (hazard ratio = 1.36; 1.04-1.77; p = 0.023, adjusted hazard ratio 1.27; 0.95-1.70; p = 0.103). CONCLUSION: Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

Association of HLA class II gene polymorphisms and expression levels of ORAI1/STIM1 genes in HIV-1‒positive patients with HIV-related dermatoses in Latvia.

INTRODUCTION: This study explores the immunogenetic associations of human leukocyte antigens (HLA) and the calcium release-activated calcium modulator 1 (ORAI1) and stromal interaction molecule 1 (STIM1) genes in HIV-1‒positive patients with HIV-related skin disorders. METHODS: This study assessed the distribution of variants of HLA class II alleles and expression levels of ORAI1 and STIM1 genes in the blood between HIV-1‒positive patients with HIV-related skin disorders and the control group with no HIV within the Latvian population. RESULTS: The research group comprised 115 HIV-1‒positive patients with HIV-related skin disorders, and the control group included 80 healthy individuals. Risk alleles (HLA- DQB1*02:01-0301 and HLA-DQA1*01:01-0501) and protective alleles (HLA-DRB1*07-13, DRB1*01-13, DRB1*04-11, and HLA-DQA1*05:01-0501) showed statistical significance in the groups. In 38 out of 115 patients, higher expression levels of ORAI1 and STIM1 genes were detected in the blood at the beginning of treatment. A significantly higher level of the microribonucleic acid (mRNA) ORAI1 gene was also found in the control group. CONCLUSIONS: The results demonstrate that HLA class II alleles are associated with a trend toward risk/protection concerning HIV-related skin disorders in HIV-1‒positive patients. It was also shown that a low level of ORAI1 mRNA and the risk allele HLA-DQB1*0201-0301 were simultaneously present in the research group.

Hepatitis A virus subgenotypes in Latvia, 2008-2021.

BACKGROUND: In Latvia outbreaks of the HAV were observed between 2008 and early 2010 and again in 2017-2018. However, the risks of introducing and spreading infection still exist, as the virus spreads easily when personal hygiene is not followed. METHODS: To determine the spread of HAV subgenotypes in the territory of Latvia the VP1/P2A genomic region of HAV was amplified and sequenced for 259 case serum samples. The study carried out a molecular biological investigation and molecular epidemiological investigation. Demographic data (sex, age), disease data (hepatitis symptoms, hospitalization, vaccination) and epidemiology data (part of the outbreak, possible source of infection, recent travel) were collected. Based on the obtained sequences, the phylogenetic tree was built and analyzed for the homology and belonging to different isolated HAV clusters from other countries. RESULTS: From the obtained data, it was concluded that HAV subgenotype IA had 13 clusters and 12 sporadic cases, HAV subgenotype IB had eight clusters and 11 sporadic cases, HAV subgenotype IIIA had one cluster and nine sporadic cases. It was found that the sources of infection among the investigated cases were different, they were mostly associated with contact with a patient with HAV, travel, as well as between persons who inject drugs and men who have sex with men, and the prevalence of HAV similar sequences was observed in different years. It was concluded that patients with HAV subgenotype IA had the longest hospitalization duration and averaged 9.3 days, while patients with subgenotype IB - 7.3 days, subgenotype IIIA - 7.7 days. Analyzing the data on vaccination, it was found that mostly all were not vaccinated or had an unknown vaccination status. CONCLUSIONS: All of this has led to the conclusion that the application of molecular biological methods of the HAV and a careful analysis of epidemiological data can help to better understand the ways of spreading the infection, investigate local outbreaks, detect cases of imported infection and track the recirculation of the virus.

Long-term outcomes after tuberculosis for people with HIV in eastern Europe.

BACKGROUND: Eastern Europe has a high burden of tuberculosis (TB)/HIV coinfection with high mortality shortly after TB diagnosis. This study assesses TB recurrence, mortality rates and causes of death among TB/HIV patients from Eastern Europe up to 11 years after TB diagnosis. METHODS: A longitudinal cohort study of TB/HIV patients enrolled between 2011 and 2013 (at TB diagnosis) and followed-up until end of 2021. A competing risk regression was employed to assess rates of TB recurrence, with death as competing event. Kaplan-Meier estimates and a multivariable Cox-regression were used to assess long-term mortality and corresponding risk factors. The Coding Causes of Death in HIV (CoDe) methodology was used for adjudication of causes of death. RESULTS: Three hundred and seventy-five TB/HIV patients were included. Fifty-three (14.1%) were later diagnosed with recurrent TB [incidence rate 3.1/100 person-years of follow-up (PYFU), 95% confidence interval (CI) 2.4-4.0] during a total follow-up time of 1713 PYFU. Twenty-three of 33 patients with data on drug-resistance (69.7%) had multidrug-resistant (MDR)-TB. More than half with recurrent TB ( n  = 30/53, 56.6%) died. Overall, 215 (57.3%) died during the follow-up period, corresponding to a mortality rate of 11.4/100 PYFU (95% CI 10.0-13.1). Almost half of those (48.8%) died of TB. The proportion of all TB-related deaths was highest in the first 6 ( n  = 49/71; 69%; P  < 0.0001) and 6-24 ( n  = 33/58; 56.9%; P  < 0.0001) months of follow-up, compared deaths beyond 24 months ( n  = 23/85; 26.7%). CONCLUSION: TB recurrence and TB-related mortality rates in PWH in Eastern Europe are still concerningly high and continue to be a clinical and public health challenge.