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.

Treatment outcomes of integrase inhibitors, boosted protease inhibitors and nonnucleoside reverse transcriptase inhibitors in antiretroviral-naïve persons starting treatment.

OBJECTIVES: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. METHODS: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12 ± 3 months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL < 200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4 count > 750 cells/µL or a 33% increase where the baseline CD4 count was ≥ 500 cells/µL. Poisson regression compared clinical failures (AIDS/death ≥ 14 days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. RESULTS: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged > 50 years, 2539 (49.4%) had CD4 counts < 350 cells/µL and 1891 (36.8%) had VL > 100 000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40-50 and > 50 years), CD4 count categories (≤ 350 vs. > 350 cells/µL) and VL categories at ART initiation (≤ 100 000 vs. > 100 000 copies/mL), with all investigated interactions being nonsignificant (P > 0.05). CONCLUSIONS: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

INCIDENCE OF TUBERCULOSIS AMONG HIV/HCV CO-INFECTED PATIENTS RECEIVING HEPATITIS C TREATMENT WITH PEGYLATED INTERFERON AND RIBAVIRIN IN GEORGIA.

Treatment of hepatitis C is necessary for ensuring higher life expectancy among HIV/HCV co-infected patients. However antiviral treatment for chronic HCV infection with Pegylated interferon (PEG-IFN) and Ribavirin (RBV) is associated with a variety of side effects. In Georgia up to 22% of HIV-infected patients were found to have active Tuberculosis (TB) and 22.4 to 32.6% had latent TB. The objective of this study was to describe the characteristics and clinical outcomes of tuberculosis in HIV/HCV co-infected patients receiving hepatitis C treatment with pegylated interferon and ribavirin and calculate incidence rate of TB. A retrospective study was conducted among HIV/HCV co-infected patients receiving antiviral treatment for chronic HCV infection at the Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia from December 2011 to May, 2015. A total of 420 HIV/HCV co-infected patients received HCV therapy with PEG-IFN and RBV during study period. Six of 420 patients developed TB while receiving PEG IFN + RBV therapy. These patients were on Antiretroviral treatment. Baseline HIV RNA load was <34 copies/ml and CD4+ cell counts >350 cells/mm3. No opportunistic infections were observed in all cases. Three of 6 patients had a previous positive tuberculin skin test (TST) result and had completed isoniazid chemoprophylaxis several years before TB diagnosis. In 2 patients TST was not performed. Only one patient had experienced a previous episode of TB and had completed the anti-TB therapy 1 year before hepatitis C treatment. In all patients TB was diagnosed during the PEG IFN + RBV therapy. Hepatitis C treatment was immediately stopped in all patients. The incidence rate of TB was 1.4 cases per 100 person-years (95% CI=0.58-2.97). Our study emphasizes the necessity of screening for latent TB prior to the initiation of chronic hepatitis C treatment with PEG IFN and RBV.

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.

Safety and efficacy of systematic administration of Filgrastim to prevent neutropenia and infections in patient with hepatitis C.

The aim of 36 months follow up study was to assess the safety and efficacy of Filgrastim (Neupogen) for preventing neutropenia and bacterial infection during combination therapy of chronic HCV infection with pegilated interferon alfa and ribavirin. Study enrolled 64 patients with chronic active hepatitis C, aged 20-65. Among them 49 were male and 15 female). Among 64 patients: 5 patients had HCV genotype 1a, 24 patients HCV genotype 1b, 17 patients HCV genotype 2a/2c and 18 patients HCV genotype 3a. Treatment regimen for chronic hepatitis C patients was as follows: Pegylated interferon alfa 2a (Pegasys) 180 micro kg or alfa 2b (PegIntron) 1,5 micro g/kg. and ribavirin (RBV). RBV daily dose was adjusted by body weight- 1000/1200 mg. Treatment duration was 48 weeks for HCV genotype 1 patient and 24 weeks for HCV non 1 genotype accordingly. The patients were divided into two groups: 29 patients (1st group) besides combination antiviral therapy (pegilated interferon alfa plus ribavirin) systematically received Filgrastim and other 35 patients (2nd group) - same antiviral therapy without administration of Filgrastim. Selection of patients was performed by computerized randomization method. HCV antibodies were detected by ELISA and RIBA. HCV RNA by Real time PCR. HCV genotype- by Inno-Lipa. Among 2nd group 35 patients (without Filgrastim administration) during antiviral therapy 8 patients (22.8%) developed different bacterial infections.(3 patients- urinary tract infection, 2 patients- pneumonia, 1 patient- bronchitis, 1 patients - sinusitis and 1 patient-gingivitis/stomatitis). 7 patients required interferon dose modification (dose reduction) and in 5 patients treatment stopped due to severe neutropenia. Among 1st group patients (with filgrastim administration) only one patient developed bacterial infection (urinary tract infection). None of patients, due to neutropenia, required neither stoppage of therapy, nor interferon dose reduction. The quality of life of 1st group patients was better in comparison of 2nd group patients. Filgrastim was safe and effective for prevention neutropenia and bacterial infections in Hepatitis C patients with Peg-INF/RBV combination antiviral therapy. Filgrastim was well tolerated by patients. It gives possibility to maintain interferon dose during treatment period and significantly improves the patient's quality of live.

Antiretroviral treatment in Georgia.

HIV infection is the major public health, social and economic problem in Georgia. The aim of this study is to evaluate effectiveness of ARV treatment system in Georgia. Study included 1052 people living with HIV/AIDS in Georgia registered at Infectious Disease, AIDS and Clinical Immunology Research Center since 2004. To ensure universal access to ARV therapy all HIV/AIDS individuals included in the study were investigated by special algorithm, all identified patients requiring ARV therapy were offered treatment and monitored during therapy on treatment effectiveness and side effects. Detection of HIV antibodies was performed by ELISA with further confirmation by Western Blot Assay. HIV-1 RNA in plasma was measured by quantitative Polymerase Chain Reaction. For determination of percentages and absolute count of T lymphocyte subpopulations single-platform immunophenotyping technique using the Becton-Dickinson FACSCalibur flow cytometer was applied. For resistance testing TRUGENE HIV-1 Genotyping Kit with the OpenGene DNA Sequencing System (Siemens) was used. Treatment was offered to 595 HIV/AIDS patients. 594 patients started treatment, 1 patient refused. Out of treated 594 HIV/AIDS patients 22 patients discontinued, 111 patients died and 461 patients are currently on ARV treatment. Out of treated patients 406 adults and 21 children are receiving first-line treatment, 31 adults and 2 children are on second-line treatment and 1 adult is receiving salvage regimen. Treatment failure was defined in 55 cases. Among them immunological failure was observed in 7 cases, clinical failure in 1 case and virologic failure in 47 cases. Prevalence of drug resistance among virologic failure cases accounted for 72% and inadequate adherence for 28% cases. Majority of death cases among ARV treated patients was due to non-AIDS related or incurable conditions, while deaths due to AIDS related conditions mainly were associated to the delayed referral of patients in already advanced stage of disease. It's worth to mention that highest number of death cases was due to liver failure in HIV/HCV and/or HBV co-infected patients.

Neurological complications in patients with HIV/AIDS.

The aim of the study was to determine the prevalence of HIV-related neurological disorders in HIV positive patients and its relationship to CD4 cell counts in Georgia. This study included 388 HIV/AIDS patients (302 men and 86 women), who have been admitted to the in-patient Department of Infectious Diseases, AIDS and Clinical Immunology Research Center (IDACIRC) of Georgia since 2006. Diagnosis of neurological disorders was made based on clinical symptoms and instrumental-laboratory investigations. CNS Neurological complications were detected in 76 patients; 13 patients had two or more neurological complications. Tuberculosis meningitis were the most common neurological disorders 26 (34%), followed by CNS toxoplasmosis 17 (22%), cryptococcal meningitis 11 (15%), presumed CMV encephalitis 5 (7%), PML 4 (5%), primary CNS lymphoma 4 (5%) and bacterial meningitis 3 (4%). AIDS related dementia was detected in 18 patients (24%). The median CD4+ T lymphocyte count was 47 cells/mm(3) (range: 2-183 cells/mm(3)) in HIV patients with neurological complications. There was correlation between the CD4 T lymphocyte count and type of neurological manifestation. Namely, in the patients with HIV related dementia median CD4 T lymphocyte count was 164 cells/mm(3), in the patients with CNS toxoplasmosis median CD4 count was 83 cells/mm(3), in the patients with cryptococcal meningitis median CD4 T lymphocyte count was 34 cells/mm(3) and in the patients with CMV encephalitis median CD4 T lymphocyte count was 26 cells/mm(3). Some neurological disorders such as TB meningitis and bacterial meningitis can occur at any CD4 level. PML and primary CNS lymphoma occurred when CD4 T lymphocyte count < 50 cells/mm(3). The most common clinical manifestations of neurological disorders in HIV infected patients were headache (91%), fever (75%), focal neurological deficits (61%), speech disturbances (42%), cognitive dysfunction (41%), visual disturbances (36%), impaired coordination (29%) and seizures (15%). The study provide convincing evidence that neurological disorders with HIV infection might serve as an indicator for advanced HIV infection, immunosuppression and decreased CD4 cell counts. Our data have shown correlation between the type of neurological manifestations of HIV infection and CD4 T lymphocyte count.

IFN/RBV treatment induced neutropenia and its correction with neupogen in patients with hepatitis C.

The aim of the study was to observe the frequency of neutropenia during Pegylated Interferon/Ribavirin therapy in patient with chronic hepatitis C; to compare the efficacy of two strategies of management of neutropenia--with Interferon dose modification and with Neupogen administration; to compare the effectiveness rate of sustained viral response (SVR) in patients with Pegylated Interferon dose modification and in patients treated by using granulocyte colony-stimulating factor G-CSF-filgrastim. (Neupogen). Study enrolled 47 patients with chronic active hepatitis C, aged 23-64. (38 male and 9 female). All patients had HCV genotype 1b. Significant neurtopenia (ANC<750 mm3) and severe neurtopenia (ANC<500 mm3) developed in 41 of 47 patients (87%). 41 patients with neurtopenia were randomized into two groups. The first group--22 patients who received granulocyte colony-stimulating factor (G-CSF, or filgrastim) 300 mcg s/c weekly for correction of neutropenia and the second group--19 patients treated either with Interferon dose reduction or temporarily inhibit of Interferon treatment. In all 22 patients of the first group neutropenia was normalized without reduction and/or inhibit of Pegylated interferon. Neupogen was well tolerated and in all 22 patients the improvement of quality of life (QOL) was observed. It was concluded that dose reduction or temporary inhibit of Pegylated Interferon in the second group negatively acts on antiviral treatment response in patients with HCV genotype 1. In patients with PEG-IFN/RBV therapy Neupogen effectively manages neutropenia and gives opportunity to maintain interferon dose (without reduction). Neupogen has the potential to improve adherence rates, which may in turn improve SVR.

Comparison of erythrocyte aggregability changes during ischemic and hemorrhagic stroke.

The aim of this work was to perform a comparative investigation of erythrocyte aggregability changes in the peripheral and cerebral circulation during ischemic and hemorrhagic stroke. Subjects of the present study were patients with ischemic brain infarcts (14 patients) and with hemorrhagic stroke (21 patients) from the Intensive Care Unit of the Institute of Neurology and Neurosurgery. The blood samples were obtained from the following blood vessels: the common carotid artery carrying blood to the primarily damaged brain hemisphere, both jugular veins carrying blood from the primarily damaged and the contralateral hemispheres, as well as from the cubital vein to obtain specimens of the systemically circulating blood. Erythrocyte aggregation was evaluated by using the "Georgian technique". We found that the RBC aggregation indices increased in both the regional as well as the systemic circulation of the hemorrhagic stroke patients as compared to ischemic stroke patients. The results of the present study demonstrate different changes of erythrocyte aggregation in ischemic and hemorrhagic stroke patients. Therefore, the role of blood rheological properties in their pathogenesis seems also to be different.

Peculiarities of herpes zoster in immunocompetent and immunocompromised hosts.

The aim of five years (2000-2005) study was to investigate the peculiarities of Herpes Zoster in immunocompromised and immunocompetent patients. For this purpose we have investigated the clinical course of Herpes Zoster, disease duration, complications of disease, as in acute phase as well as postherpetic neuralgia in 74 HIV positive (1st group) and 74 HIV negative (2nd group) groups of patients. In both group of patients we have studied the prevalence of the following complications: 1. Acute complications of Herpes Zoster: a) Neurological: motor neuropathy, cranial neuritis, meningoencephalitis, transverse myelitis. b) Ophthalmic: keratitis, iritis, retinitis, visual impairment c) Cutaneous: bacterial superinfection, scarring, disfigurement. d) Visceral: pneumonitis, hepatitis. e) Multidermatomal. 2. The complications of after resolution of infection: a) Postherpetic neuralgia and various duration of pain associated with postherpetic neuralgia such as : < month, 1-6 months, 6-12 months and >1 year durations. b) Recurrent herpes zoster. Herpes Zoster infection was diagnosed based on clinical symptoms and by detection of VZV specific IgM and IgG by ELISA. HIV infection was diagnosed by ELISA method and was confirmed by Western Blot. We found that Herpes Zoster may develop as in HIV positive as well as HIV negative population. Study showed that severe cases of disease (Herpes Zoster), long duration and rate of complications are much higher in HIV/AIDS than in HIV negative group patients. Rate of hospitalization is also higher in HIV/AIDS patients with Herpes Zoster than in HIV negative patients with Herpes Zoster. Frequency of recurrent Herpes Zoster is much higher in HIV/AIDS patients than in HIV negative patients. The postherpetic neuralgia is very frequent complication for both group (HIV positive and HIV negative) Herpes Zoster patients, but its duration longer in HIV/AIDS patients in comparison HIV negative group. There were no significant difference in disease severity, duration and complications among male and female patients.

Blood rheological properties and lipid peroxidation in cerebral and systemic circulation of neurocritical patients.

The present study was aimed at investigating the red blood cell (RBC) aggregation and the parameters of lipid peroxidation - malondialdehyde (MDA) and MDA + 4-hydroxyalkenals (HAE) - in the blood of critically deteriorated stroke patients (brain infarcts, parenchymatous and subarachnoid hemorrhages) and in the control group. Measurements were made in blood samples from the common carotid artery, the both internal jugular and cubital veins. The RBC aggregation index was found to increase by about 80 per cent in both the cerebral and systemic circulation as compared to the control blood samples. MDA content appeared also significantly higher in the blood flowing out of the damaged hemisphere of the neurocritical patients as compared to the control group. In the blood flowing out of the damaged hemisphere of the neurocritical patients MDA as well as MDA + HAE content significantly exceeded the values found in blood samples of the jugular vein of the contralateral hemisphere, carotid artery and the cubital vein. The results of this study suggest a certain interdependence between the blood plasma lipid peroxidation and the RBC aggregation in the brain vessels following its damage.

About spread of local cerebral hemorheological disorders to whole body in critical care patients.

PURPOSE: The aim of the present pathophysiological studies was elucidation of the feasible mechanism of spread of the blood rheological disorders from the cerebral to systemic circulation, and vice versa. METHODS: The investigation was carried out in the critical care patients with the brain tissue damage related to stroke (cerebral ischemic infarcts as well as parenchymatous and subarachnoid hemorrhages). The applied diagnostic techniques provided us with valid and quantitative data revealing the degree of the red blood cell aggregability, the value of local hematocrit, and the blood plasma viscosity in the cerebral and systemic circulation. In addition, rabbits experiments were carried out for analysis of the hemorheological disorders associated with the brain damage. RESULTS: Despite the local character of the patients primary brain damage, the hemorheological disorders were found regularly spread not only over the cerebral hemispheres, but even also the systemic circulation. Under such conditions they might cause the generalized brain tissue damage and play significant role in the subsequent damage-cascade of the whole brain. In addition, the rabbits experiments demonstrated pronounced hemorheological disorders in the cerebral cortex capillaries: increase of their numbers with RBC enhanced aggregation and blood stasis, as well as with lowering of the RBC deformability in the narrow capillary lumina. These changes befell simultaneously with increase of water contents in the cerebral tissue evidencing for edema development in the brain. CONCLUSION: Local cerebral hemorheological disorders might spread over the whole brain via the systemic circulation, thus promoting a generalized brain damage and being responsible for the critical state of the patients.

Lipid peroxidation in the erythrocytes under condition of their increased aggregation.

The aim of the present study was investigation of the lipid peroxidation changes within the erythrocytes under conditions of increased RBC aggregation. This latter was produced both in the in vitro and in vivo conditions by the addition of Dextran T-500. For the in vitro studies blood samples were taken from the cubital veins of 15 healthy subjects. During the in vivo studies 10 ml of the 10 percent Dextran T-500 solution was administered intravenously in six chinchilla rabbits. Another six animals were treated with rheopolyglucyne. The RBC aggregation in blood was investigated with the "Georgian technique". The malondialdehyde (the end product of lipid peroxidation) was determined in all cases by its reaction with thiobarbituric acid. We found that in the in vitro conditions, as well as in the in vivo studies, the lipid peroxidation was significantly increased in the erythrocytes during the enhanced RBC aggregation induced by addition of Dextran T-500. Therefore we suppose that the elevated RBC aggregation cause an increase of cell's lipid peroxidation and it is possible to think that appropriate prooxidant: antioxidant balance is shifted toward the pro-oxidants in the erythrocytes.