The value of some genetic factors for prediction of chronic hepatitis C antiviral treatment effectiveness

Aim: To determine the value of gene polymorphisms of interleukin-28B (IL28B), RNase L, HLA DRB1*1101 and HLADQB1*03 alleles as predictors of antiviral treatment efficacy in patients with chronic hepatitis C (CHC).Material and methods. A total of 156 in-patients with chronic hepatitis C (65.4% men, 62.4% had genotype 1 hepatitis C virus – HCV) were studied. The results of treatment with interferon (IFN) and ribavirin (RBV) were analyzed in 74 patients. Polymerase chain reaction identified single nucleotide polymorphisms (SNP) of the gene IL28B 39743165T>G (rs8099917), SNP 39738787C> T (rs12979860), RNase L gene (1385G>A), HLA DRB1*1101 and HLA-DQB1*03 alleles.Results. In patients with HCV genotype 1 mutant alleles were more common in SNP 39743165T>G (p=0.001) and 39738787C>T (p=0.0002) than in patients with other genotypes. Response to therapy IFN/RBV was higher in those with “favorable” TT variant (SNP 39743165T>G) and CC (SNP 39738787C>T), in those with their combination virologic response ffect were found according to genes IL28B and RNase L SNP variants, DRB1*1101 and HLA-DQB1*03 alleles.Conclusion. Testing for SNP 39738787C>T of IL28B gene is recommended before starting therapy IFN / RBV for all patients with genotype 1 HCV as a predictor of treatment response. Testing SNP 1385G>A gene RNase L and DRB1*1101, HLA-DQB1*03 alleles has no apparent prognostic value for patients with CHC antiviral therapy

ЗНАЧЕНИЕ НЕКОТОРЫХ ГЕНЕТИЧЕСКИХ ФАКТОРОВ ДЛЯ ПРОГНОЗА ЭФФЕКТИВНОСТИ ПРОТИВОВИРУСНОГО ЛЕЧЕНИЯ ХРОНИЧЕСКОГО ГЕПАТИТА С

Aim: To determine the value of gene polymorphisms of interleukin-28B (IL28B), RNase L, HLA DRB1*1101 and HLADQB1*03 alleles as predictors of antiviral treatment efficacy in patients with chronic hepatitis C (CHC).Material and methods. A total of 156 in-patients with chronic hepatitis C (65.4% men, 62.4% had genotype 1 hepatitis C virus – HCV) were studied. The results of treatment with interferon (IFN) and ribavirin (RBV) were analyzed in 74 patients. Polymerase chain reaction identified single nucleotide polymorphisms (SNP) of the gene IL28B 39743165T>G (rs8099917), SNP 39738787C> T (rs12979860), RNase L gene (1385G>A), HLA DRB1*1101 and HLA-DQB1*03 alleles.Results. In patients with HCV genotype 1 mutant alleles were more common in SNP 39743165T>G (p=0.001) and 39738787C>T (p=0.0002) than in patients with other genotypes. Response to therapy IFN/RBV was higher in those with “favorable” TT variant (SNP 39743165T>G) and CC (SNP 39738787C>T), in those with their combination virologic response ffect were found according to genes IL28B and RNase L SNP variants, DRB1*1101 and HLA-DQB1*03 alleles.Conclusion. Testing for SNP 39738787C>T of IL28B gene is recommended before starting therapy IFN / RBV for all patients with genotype 1 HCV as a predictor of treatment response. Testing SNP 1385G>A gene RNase L and DRB1*1101, HLA-DQB1*03 alleles has no apparent prognostic value for patients with CHC antiviral therapy.Цель: определение значения полиморфизмов гена интерлейкина 28B (ИЛ-28В) и рибонуклеазы L (РНКазы L), а также аллелей HLA DRB1*1101 и HLA-DQB1*03 для прогноза эффективности противовирусного лечения хронического гепатита С (ХГС).Материалы и методы. Обследовано 156 стационарных пациентов с ХГС (65,4% мужчины; 62,4% с генотипом 1 вируса гепатита С – ВГС). Результаты лечения препаратами интерферона (IFN) и рибавирина (RBV) проанализированы у 74 пациентов. Методом полимеразной цепной реакции определялись единичные нуклеотидные полиморфизмы (SNP) гена ИЛ-28B 39743165T>G (rs8099917), SNP 39738787C>T (rs12979860) и гена РНКазы L (1385G>A), а также аллели HLA DRB1*1101 и HLA-DQB1*03.Результаты. У пациентов с генотипом 1 ВГС чаще встречаются мутантные аллели в SNP 39743165T>G (р=0,001) и 39738787C>T (р=0,0002), чем у больных с иными генотипами вируса. Ответ на терапию IFN/RBV был выше при «благоприятных» вариантах ТТ (SNP 39743165T>G) и СС (SNP 39738787C>T), при их сочетании вирусологический ответ составляет 70,6%. Различий в эффективности терапии у лиц в зависимости от вариантов полиморфизма 6552G>A (rs486907) гена РНКазы L и носительства аллелей HLA-DRB1*11 и HLA-DQB1*03 не выявлено.Заключение. Обследование на SNP 39738787C>T гена ИЛ-28B рекомендуется перед началом терапии IFN/RBV всем пациентам с генотипом 1 ВГС в качестве прогностического фактора ответа на лечение. SNP 1385G>A гена РНКа-зы L и носительство аллелей HLA-DRB1*11 и HLA-DQB1*03 не имеют прогностического значения при терапии ХГС

Диагностическое значение непрямых маркеров фиброза печени у пациентов с хроническим гепатитом В

Aim of investigation: The aim of the present study was to evaluate the possibility using of indirect liver fibrosis markers for the estimation of fibrosis severity and timely prescribing of antiviral therapy in patients with chronic hepatitis B.Materials and methods: We examined 130 patients with chronic hepatitis B (mean age 41,8±13,5 years, 70% of men) having known liver fibrosis stage based on fibroelastography or liver biopsy. The age of patients, 9 parameters of biochemical blood analysis, complete blood count and coagulogram along with 7 indices calculated on their base were considered. Their prognostic values were estimated by means of ROC analysis.Results: According to increase of liver fibrosis stage albumin, prothrombin index, platelet count, cholesterol reduce and aspartate aminotransferase, international normalized ratio, gamma-glutamyl transpeptidase, alanine aminotransferase, alkaline phosphatase levels rise (p<0,01). All of the laboratory parameters and indices were significantly different (p<0,01) in patients with minimal (F0–F1) and advanced (F2–F4) fibrosis. For patients with chronic hepatitis B the most significant predictors of advanced liver fibrosis (F2–F4) were: GUCI and King’s score indices as well as eLIFT scale. Index GUCI had the best diagnostic performance (area under the receiver operating characteristic curve 0,866) with 89,5% sensitivity and 78,0% specificity at cut off ≥0,7/ Conclusion: The assessment of indirect liver fibrosis markers in patients with chronic hepatitis B can be easily performed at any stage of medical care; they are quite informative and can be used for the estimation of fibrosis severity and timely conducting antiviral therapy.Цель: оценить возможность использования непрямых маркеров и рассчитанных на их основе индексов при определении выраженности фиброза печени для проведения динамического мониторинга прогрессирования фиброза и своевременного назначения противовирусной терапии пациентам с хроническим гепатитом В. Материалы и методы: обследовано 130 пациентов с хроническим гепатитом В (средний возраст 41,8±13,5 лет, 70% мужчин) с известной степенью выраженности фиброза на основании фиброэластометрии либо биопсии печени. Учитывались возраст пациентов, 9 показателей биохимического анализа крови, гемограммы и коагулограммы, а также 7 индексов, рассчитанных на их основе. Прогностическая значимость непрямых показателей фиброза и индексов оценивалась с помощью ROC-анализа.Результаты: с нарастанием стадии фиброза печени в периферической крови снижается уровень альбумина, протромбинового индекса, тромбоцитов, холестерина, повышается уровень аспартатаминотрансферазы, международного нормализованного отношения, гаммаглутамилтранспептидазы, аланинаминотрансферазы, щелочной фосфатазы (p<0,01). Все лабораторные показатели и индексы значимо различаются у пациентов с минимальным (F0–F1) и выраженным (F2–F4) фиброзом печени (р<0,01). Наиболее прогностически значимы для определения выраженного фиброза печени индексы GUCI, King’s score и шкала eLIFT, а наиболее информативным (площадь под характеристической кривой 0,866) с чувствительностью 89,5% и специфичностью 78,0% при точке разделения ≥0,7 является индекс GUCI. Заключение: исследование непрямых маркеров фиброза печени легко выполнимо на любом этапе оказания медицинской помощи и может использоваться для проведения динамического мониторинга прогрессирования фиброза и определения показаний к противовирусной терапии у пациентов с хроническим гепатитом В

РАННЯ ДІАГНОСТИКА АЛКОГОЛЬНОЇ ЗАЛЕЖНОСТІ В ПРАКТИЦІ СІМЕЙНОГО ЛІКАРЯ

SUMMARY. Early diagnosis of alcohol dependence is one of the most important and urgent problems of modernaddiction narcology. Attraction of family practice doctors to this problem allows them to identify potential cohort ofpersons with symptoms of alcohol dependence. Prompt medical consultation of narcologist will provide an opportunityto confirm or exclude the presence of narcopatology, determine the treatment program. The study involved 255 patientswith hepatic disorders, seeking medical care in somatic hospitals. On the basis of clinical interview, psycho-diagnostictesting, laboratory research complex algorithm designed to identify alcohol dependence in patients with chronic liverdiseases.KEY WORDS: early diagnosis, alcohol abuse, family doctor.РЕЗЮМЕ. Рання діагностика алкогольної залежності є однією з найважливіших і найактуальніших завданьсучасної наркології. Залучення до вирішення цієї проблеми лікарів сімейної практики дозволить на етапіобстеження пацієнтів з гепатопатичною патологією виявити потенційну когорту осіб, які мають симптомиалкогольної залежності. Своєчасна консультація лікаря нарколога дасть можливість підтвердити або виключитинаявність наркопатології, визначити лікувальну програму. Обстежено 255 пацієнтів з гепатопатичними розладами,які звернулися за медичною допомогою в загальносоматичні лікувальні установи. На основі даних клінічногоінтерв'ю, психодіагностичного тестування, лабораторного дослідження розроблено комплексний алгоритмвиявлення алкогольної залежності у пацієнтів з хронічними захворюваннями печінки.КЛЮЧОВІ СЛОВА: рання діагностика, алкогольна залежність, сімейний лікар

Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression: A prospective cohort study

Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR 50 copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50 copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL ≤50 copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure

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

Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression : A prospective cohort study

Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant.We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR 50copies/mL.We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL 50copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL 50copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon.A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.Peer reviewe

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens

Objectives: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. Methods: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. Results: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95–1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37–2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84–1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90–1.61) and 0.83 (95% CI 0.70–0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47–1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65–1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53–1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76–1.72 for RALvs. CONC). Conclusions: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.Peer reviewe

РЕЗУЛЬТАТЫ ИСПОЛЬЗОВАНИЯ СОФОСБУВИРА В КОМБИНАЦИИ С ЛЕДИПАСВИРОМ ИЛИ ДАКЛАТАСВИРОМ ДЛЯ ЛЕЧЕНИЯ ХРОНИЧЕСКОГО ГЕПАТИТА С В РЕСПУБЛИКЕ БЕЛАРУСЬ

To evaluate the efficacy of therapy with sofosbuvir in combination with ledipasvir or daclatasvir, the results of treatment of 299 patients with chronic hepatitis C, including 128 non-responders to combined interferon plus ribavirin therapy, who have prognostically unfavorable single nucleotide polymorphisms 39743165T> G (rs8099917) and 39738787C> T (rs12979860) of interleukin-28B gene, were analyzed. 57 people had liver cirrhosis. 80,9% (242) had genotype 1 of hepatitis C virus, 5% (15) – genotype 2, 13,7% (41) – genotype 3, and 0,4% (1) – genotype 4.All 299 patients, who adhered to the recommendations of the European Association for the Study of the Liver 2016 and the American Association for the Study of the Liver Disease 2017, achieved a sustained virologic response 12 weeks after the end of therapy. The clinical case of treatment failure, associated with the lack of confirmation of the elimination of hepatitis C virus by means of highly sensitive polymerase chain reaction methods and with the later identified amino acid substitution in position Y93H of NS5A (resistance to NS5A inhibitors), is shown.It is necessary to carry out monitoring of effectiveness of therapy only by means of highly sensitive polymerase chain reaction (from 10 ME/ml). If the virus elimination delays in patients with advanced stages of liver fibrosis it is needed to use the prolonged schemes of treatment. Repeated treatment of patients with existence of a mutation of Y93H requires the use of new NS5A inhibitors or combined drugs.С целью оценки эффективности терапии препаратами софосбувир в комбинации с ледипасвиром или даклатасвиром были проанализированы исходы лечения 299 пациентов с хроническим гепатитом С, включая 128 ранее неудачно пролеченных интерферонами и рибавирином, а также имеющих прогностически неблагоприятные однонуклеотидные полиморфизмы 39743165T>G (rs8099917) и 39738787C>T (rs12979860) гена интерлейкин-28В. У 57 пациентов был диагностирован цирроз печени, 128 пациентов были ранее неудачно пролечены интерферонами и рибавирином. У 80,9% (242) был первый генотип вируса, у 5% (15) – второй, у 13,7% (41) – третий, у 0,4% (1) – четвертый.В результате исследования было отмечено, что все 299 пациентов, которые придерживались рекомендаций European Association for the Study of the Liver 2015, 2016 и American Association for the Study of the Liver Disease 2017, достигли устойчивого вирусологического ответа через 12 недель после окончания терапии. Приведен клинический случай неудачного лечения, связанный с отсутствием подтверждения элиминации вируса гепатита С при помощи высокочувствительных методов полимеразной цепной реакции и с позднее выявленной аминокислотной заменой в позиции Y93H NS5A (резистентность к ингибиторам NS5A).Мониторинг эффективности терапии необходимо проводить только при помощи высокочувствительных методик полимеразной цепной реакции (от 10 МЕ/мл) и при задержке элиминации вируса у пациентов с продвинутыми стадиями фиброза печени использовать пролонгированные схемы лечения. Для повторного лечения пациентов с наличием мутации Y93Н необходимы новые препараты ингибиторов NS5A или комбинированных препаратов.

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\u201374.1) 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