Healthcare delivery for HIV-positive people with tuberculosis in Europe.

BACKGROUND: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). OBJECTIVES: To verify the differences in TB and HIV services in EE vs. WE. METHODS: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. RESULTS: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. CONCLUSION: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

A new health care index predicts short term mortality for TB and HIV co-infected people.

BACKGROUND: Using 2004-2007 TB:HIV Study data from Europe and Latin America, we previously generated a health care index (HCI) for TB and HIV co-infected people. With improvements in diagnostic and management practices, we have now updated the HCI with new data.METHODS: We evaluated nine aspects of health care in Cox proportional hazards models on time from TB diagnosis to death. Kaplan-Meier methods were used to estimate the probability of death by HCI quartile.RESULTS: Of 1396 eligible individuals (72% male, 59% from Eastern Europe), 269 died within 12 months. Use of rifamycin/isoniazid/pyrazinamide-based treatment (HR 0.67, 95% CI 0.50-0.89), TB drug susceptibility testing (DST) and number of active TB drugs (DST + <3 drugs (HR 1.09, 95% CI 0.80-1.48), DST + ≥3 drugs (HR 0.49, 95% CI 0.35-0.70) vs. no DST), recent HIV-RNA measurement (HR 0.64, 95% CI 0.50-0.82) and combination antiretroviral therapy use (HR 0.72, 95% CI 0.53-0.97) were associated with mortality. These factors contributed respectively 5, -1, 8, 5 and 4 to the HCI. Lower HCI was associated with an increased probability of death; 30% (95% CI 26-35) vs. 9% (95% CI 6-13) in the lowest vs. the highest quartile.CONCLUSION: We found five potentially modifiable health care components that were associated with mortality among TB-HIV positive individuals. Validation of our HCI in other TB cohorts could enhance our findings.

Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study.

OBJECTIVES: Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. METHODS: In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). RESULTS: A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5-74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. CONCLUSIONS: Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care.

Mitochondrial DNA D-loop haplogroup contributions to the genetic diversity of East European domestic chickens from Russia.

To elucidate geographical and historical aspects of chicken dispersal across Eastern Europe, we analysed the complete mitochondrial DNA D-loop sequence of 86 representatives from chicken breeds traditionally raised in the territory of the East European Plain (Orloff, Pavlov, Russian White, Yurlov Crower, Uzbek Game and Naked Neck). From the 1231-1232 bp D-loop sequence, 35 variable sites that defined 22 haplotypes were identified in modern chicken. All populations, except Uzbek Game, exhibited high values of haplotype and nucleotide diversity suggesting a wide variation in maternal diversity. Inclusion of mtDNA sequences from other European and Asian countries revealed representatives from this study belonging to haplogroups A, E1 and C1. We also assessed fossil chicken material dated to the 9th-18th century from archaeological sites in Northern and Eastern Europe. Three haplotypes found in the fossil specimens belonged to haplogroup E1, while one sample dated to the 18th century was assigned to the C1 haplogroup. This is the first report of the occurrence of the C1 haplogroup in European chicken populations prior to the 20th century based on the fossil material. These results provide evidence for a relatively recent introduction of all haplotypes other than E1 into the East European chicken gene pool with the significant impact of the C1 haplogroup mainly distributed in Southern China.

Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers.

The outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen "activity," host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4(+) T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4(+) T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

Chitosan as a Modifying Component of Artificial Scaffold for Human Skin Tissue Engineering.

We compared the structure and mechanical properties of scaffolds based on pure collagen, pure chitosan, and a mixture of these polymers. The role of the composition and structure of scaffolds in the maintenance of cell functions (proliferation, differentiation, and migration) was demonstrated in two experimental models: homogeneous tissue analogues (scaffold populated by fibroblasts) and complex skin equivalents (fibroblasts and keratinocytes). In contrast to collagen scaffolds, pure chitosan inhibited the growth of fibroblasts that did not form contacts with chitosan fibers, but formed specific cellular conglomerates, spheroids, and lose their ability to synthesize natural extracellular matrix. However, the use of chitosan as an additive stimulated proliferative activity of fibroblasts on collagen, which can be associated with improvement of mechanical properties of the collagen scaffolds. The effectiveness of chitosan as an additional cross-linking agent also manifested in its ability to improve significantly the resistance of collagen scaffolds to fibroblast contraction in comparison with glutaraldehyde treatment. Polymer scaffolds (without cells) accelerated complete healing of skin wounds in vivo irrespective of their composition healing, pure chitosan sponge being most effective. We concluded that the use of chitosan as the scaffold for skin equivalents populated with skin cells is impractical, whereas it can be an effective modifier of polymer scaffolds.

Major differences in organization and availability of health care and medicines for HIV/TB coinfected patients across Europe.

OBJECTIVES: The aim of the study was to investigate the organization and delivery of HIV and tuberculosis (TB) health care and to analyse potential differences between treatment centres in Eastern (EE) and Western Europe (WE). METHODS: Thirty-eight European HIV and TB treatment centres participating in the TB:HIV study within EuroCoord completed a survey on health care management for coinfected patients in 2013 (EE: 17 respondents; WE:21; 76% of all TB:HIV centres). Descriptive statistics were obtained for regional comparisons. The reported data on health care strategies were compared with actual clinical practice at patient level via data derived from the TB:HIV study. RESULTS: Respondent centres in EE comprised: Belarus (n = 3), Estonia (1), Georgia (1), Latvia (1), Lithuania (1), Poland (4), Romania (1), the Russian Federation (4) and Ukraine (1); those in WE comprised: Belgium (1), Denmark (1), France (1), Italy (7), Spain (2), Switzerland (1) and UK (8). Compared with WE, treatment of HIV and TB in EE are less often located at the same site (47% in EE versus 100% in WE; P < 0.001) and less often provided by the same doctors (41% versus 90%, respectively; P = 0.002), whereas regular screening of HIV-infected patients for TB (80% versus 40%, respectively; P = 0.037) and directly observed treatment (88% versus 20%, respectively; P < 0.001) were more common in EE. The reported availability of rifabutin and second- and third-line anti-TB drugs was lower, and opioid substitution therapy (OST) was available at fewer centres in EE compared with WE (53% versus 100%, respectively; P < 0.001). CONCLUSIONS: Major differences exist between EE and WE in relation to the organization and delivery of health care for HIV/TB-coinfected patients and the availability of anti-TB drugs and OST. Significant discrepancies between reported and actual clinical practices were found in EE.

[Generalized pneumocystosis in HIV infection].

The paper describes a rare case of rapidly progressive generalized pneumocystosis in HIV infection in a 43-year-old patient who died 4.5-5 months after disease onset. The specific feature of the case is that in pneumocystosis there was multiple organ dysfunction, as well as infiltrate decay to form small and large lung cavities similar to tuberculosis ones. Autopsy disclosed Pneumocystis-induced changes in the liver, spleen, lymph nodes, and the wall of the ileum. Pneumocystosis and HIV infection were diagnosed only posthumously. The specificity of organ diseases was immunohistochemically verified.

Health care index score and risk of death following tuberculosis diagnosis in HIV-positive patients.

OBJECTIVES: To assess health care utilisation for patients co-infected with TB and HIV (TB-HIV), and to develop a weighted health care index (HCI) score based on commonly used interventions and compare it with patient outcome. METHODS: A total of 1061 HIV patients diagnosed with TB in four regions, Central/Northern, Southern and Eastern Europe and Argentina, between January 2004 and December 2006 were enrolled in the TB-HIV study. A weighted HCI score (range 0-5), based on independent prognostic factors identified in multivariable Cox models and the final score, included performance of TB drug susceptibility testing (DST), an initial TB regimen containing a rifamycin, isoniazid and pyrazinamide, and start of combination antiretroviral treatment (cART). RESULTS: The mean HCI score was highest in Central/Northern Europe (3.2, 95%CI 3.1-3.3) and lowest in Eastern Europe (1.6, 95%CI 1.5-1.7). The cumulative probability of death 1 year after TB diagnosis decreased from 39% (95%CI 31-48) among patients with an HCI score of 0, to 9% (95%CI 6-13) among those with a score of ≥4. In an adjusted Cox model, a 1-unit increase in the HCI score was associated with 27% reduced mortality (relative hazard 0.73, 95%CI 0.64-0.84). CONCLUSIONS: Our results suggest that DST, standard anti-tuberculosis treatment and early cART may improve outcome for TB-HIV patients. The proposed HCI score provides a tool for future research and monitoring of the management of TB-HIV patients. The highest HCI score may serve as a benchmark to assess TB-HIV management, encouraging continuous health care improvement.

[Expression of early hematopoietic markers in cord blood and mobilized blood].

G-CSF mobilized peripheral blood and cord blood are major sources of hematopoietic progenitor cells. These cells are characterized by the expression of "early" antigens. We have evaluated the coexpression of hematopoietic cell markers CD34, CD133, CD90, CDCP1, CD117 and activation antigen CD38 using multicolor flow cytometry. We show that (1) cells being positive for every single antigen form a separate population. (2) Percentage of cells expressing each "early" antigen are twice more in the cord blood than in the mobilized blood. The content of cells with complex progenitor phenotype (CD34+/CD38-/CD117, CD133+/CD34+/CD38-, CDCP1+/CD34+/CD38- etc.) is equal in mobilized and cord blood. (3) There are strong positive correlations between the expression of CD34, CD133, CD117 and CDCP1 in both groups. Positive correlation exists for CD90 with CD34, CD133, CDCP1 and CD117 only in cord blood and is not significant in mobilized blood. The analyses of early antigens coexpression with activation marker CD38 revealed that hypothesis on sequential activation and loss of expression of the aforementioned antigens is not confirmed. We assume that there is global regulation of the expression of CD34, CD133, CDCP1 and CD117. Yet expression of CD38 could be reversibly abolished during maturation of the hemapoetic cells and CD117 could be expressed not only on myeloid cells.

[The use of cycloferon in the combined treatment of tuberculosis patients infected with HIV and viral hepatitis].

The study was designed to evaluate efficiency of 8-week treatment of 86 patients with tuberculosis and concomitant mild hepatitis B using cycloferon tablets. This therapy had beneficial effect on the symptoms of intoxication syndrome and respiratory manifestations of tuberculosis; in addition, it improved hemograms. By the end of the treatment the frequency of sputum abacillation was 4.9 times and positive X-ray dynamics (cavity closure) 2.2 times higher than in control. Therapy positively influenced hepatic function assessed from activity of cytolitic enzymes and bilirubin level; also, it improved serum levels of total protein.

[Combined cycloferon treatment of tuberculosis in patients infected with HIV].

Outcome of treatment of 102 patients co-infected with HIV and tuberculosis hospitalized at Second Municipal Tuberculosis Hospital (St. Petersburg) is analyzed. The median period of follow up was 8 weeks. In order to select the optimum treatment scheme, all patients were divided into three groups (I-III). Group I (51 patients) received, in addition to antituberculosis medications, cycloferon 600 mg tablets on alternate days. Group II (16 patients) received alpha and gamma interferons (Interal injection, 3 MU and Ingaron injection, 500,000 on alternate days) in combination with antituberculosis medications. Control group III (35 patients) received antituberculosis treatment plus placebo. Assessment of the outcome of TB treatment upon 8 weeks of follow up showed a remarkable improvement of clinical and immunological conditions in the patients who received interferons and cycloferon.

[Extrapulmonary tuberculosis in HIV-infected patients].

The authors analyze 143 cases of extrapulmonary and generalized tuberculosis in HIV-infected patients. There is a steady increase in the number of patients with multiple organ tuberculosis that frequently acquires the pattern of an acute generalized septic process. Generalized tuberculosis predominantly develops in HIV-infected patients with a considerable reduction in immunological parameters and it is, in these cases, of primary generalized nature. The efficiency of treatment is very low in patients with multiple organ tuberculosis. Despite therapy, the progression of the disease results in early death. However, the prospects for further inclusion of highly active antiretroviral therapy in multimodality treatment for comorbidity give hope for the solution of this problem.

[Analysis of death rates in patients with tuberculosis and HIV infection].

The proportion of those who died at a hospital in 2001 is 3.8% of the treated patients and that in 2002 is 4.2%. In 2003, mortality rates increased more than 3-fold and accounted for 13.4%. Patients with a long history of tuberculosis were found to have pulmonary tuberculosis without extrapulmonary foci. Generalized forms of tuberculosis were detectable in more than a third of the cases and more frequently encountered in patients with significant immunodeficiency for whom tuberculosis was opportunistic infection.

[Tuberculosis in the HIV-infected: early detection and prevention].

Tuberculosis in the HIV infected becomes an urgent problem the phthisiologists of Saint Petersburg face. The test using tuberculin in a dose of 2 TE remains the most informative method for determining Mycobacterium tuberculosis (MBT) infection in HIV-affected persons. It is a more information method than the Mantoux reaction using 5 TE. The diagnostic value of enzyme immunoassay employing tuberculous antigen is low in the persons infected MBT and HIV. There is evidence for the effectiveness of prophylactic double (isonizid and ethambutol) component courses against the development of tuberculosis for those infected with MBT and HIV.

[Use of regional lymphotropic therapy in the treatment of pulmonary tuberculosis in HIV-infected individuals]. / Primenenie regionarnoi limfotropnoi terapii v lechenii tuberkuleza legkikh u VICH-infitsirovannykh lits.

The efficiency of regional lymphotropic therapy (RLT) used to treat tuberculosis in HIV-infected patients was analyzed. With this treatment, the symptoms of intoxication are eliminated more rapidly. In shorter periods, bacterial isolation ceases and decay cavities close in the majority of patients. This chemotherapy is better tolerated and toxic reactions occur less frequently. Due to its absolute controllability, RLT is may be used in socially dysadapted patients.