HIV treatment strategies across Central, Eastern and Southeastern Europe: New times, old problems.

INTRODUCTION: In the last decade, substantial differences in the epidemiology of, antiretroviral therapy (ART) for, cascade of care in and support to people with HIV in vulnerable populations have been observed between countries in Western Europe, Central Europe (CE) and Eastern Europe (EE). The aim of this study was to use a survey to explore whether ART availability and therapies have evolved in CE and EE according to European guidelines. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group conducted two identical multicentre cross-sectional online surveys in 2019 and 2021 concerning the availability and use of antiretroviral drugs (boosted protease inhibitors [bPIs], integrase inhibitors [INSTIs] and nucleoside reverse transcriptase inhibitors [NRTIs]), the introduction of a rapid ART start strategy and the use of two-drug regimens (2DRs) for starting or switching ART. We also investigated barriers to the implementation of these strategies in each region. RESULTS: In total, 18 centres participated in the study: four from CE, six from EE and eight from Southeastern Europe (SEE). Between those 2 years, older PIs were less frequently used and darunavir-based regimens were the main PIs (83%); bictegravir-based and tenofovir alafenamide-based regimens were introduced in CE and SEE but not in EE. The COVID-19 pandemic did not significantly interrupt delivery of ART in most centres. Two-thirds of centres adopted a rapid ART start strategy, mainly in pregnant women and to improve linkage of care in vulnerable populations. The main obstacle to rapid ART start was that national guidelines in several countries from all three regions did not support such as strategy or required laboratory tests first; an INSTI/NRTI combination was the most commonly prescribed regimen (75%) and was exclusively prescribed in SEE. 2DRs are increasingly used for starting or switching ART (58%), and an INSTI/NRTI was the preferred regimen (75%) in all regions and exclusively prescribed in SEE, whereas the use of bPIs declined. Metabolic disorders and adverse drug reactions were the main reasons for starting a 2DR; in the second survey, HIV RNA <500 000 c/ml and high cluster of differentiation (CD)-4 count emerged as additional important reasons. CONCLUSIONS: In just 2 years and in spite of the emergence of the COVID-19 pandemic, significant achievements concerning ART availability and strategies have occurred in CE, EE and SEE that facilitate the harmonization of those strategies with the European AIDS Clinical Society guidelines. Few exceptions exist, especially in EE. Continuous effort is needed to overcome various obstacles (administrative, financial, national guideline restrictions) in some countries.

The Management of HIV Care Services in Central and Eastern Europe: Data from the Euroguidelines in Central and Eastern Europe Network Group.

INTRODUCTION: The COVID-19 pandemic has been challenging time for medical care, especially in the field of infectious diseases (ID), but it has also provided an opportunity to introduce new solutions in HIV management. Here, we investigated the changes in HIV service provision across Central and Eastern European (CEE) countries before and after the COVID-19 outbreak. METHODS: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of ID from 24 countries within the CEE region. Between 11 September and 29 September 2021, the group produced an on-line survey, consisting of 32 questions on models of care among HIV clinics before and after the SARS-CoV-2 outbreak. RESULTS: Twenty-three HIV centers from 19 countries (79.2% of all countries invited) participated in the survey. In 69.5% of the countries, there were more than four HIV centers, in three countries there were four centers (21%), and in four countries there was only one HIV center in each country. HIV care was based in ID hospitals plus out-patient clinics (52%), was centralized in big cities (52%), and was publicly financed (96%). Integrated services were available in 21 clinics (91%) with access to specialists other than ID, including psychologists in 71.5% of the centers, psychiatrists in 43%, gynecologists in 47.5%, dermatologists in 52.5%, and social workers in 62% of all clinics. Patient-centered care was provided in 17 centers (74%), allowing consultations and tests to be planned for the same day. Telehealth tools were used in 11 centers (47%) before the COVID-19 pandemic outbreak, and in 18 (78%) after (p = 0.36), but were represented mostly by consultations over the telephone or via e-mail. After the COVID-19 outbreak, telehealth was introduced as a new medical tool in nine centers (39%). In five centers (28%), no new services or tools were introduced. CONCLUSIONS: As a consequence of the COVID-19 pandemic, tools such as telehealth have become popularized in CEE countries, challenging the traditional approach to HIV care. These implications need to be further evaluated in order to ascertain the best adaptations, especially for HIV medicine.

Treatment initiation or switch to BIC/FTC/TAF - real-world safety and efficacy data from two HIV centers in Romania.

INTRODUCTION: Development of highly active antiretroviral therapy marked an important step forward in the management of people living with HIV and fixed dose combinations are now available to be used as modern antiretroviral regimens. The single-tablet regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was recently approved in Europe and included in international guidelines and recommendations. It became available in Romania in early 2021. We present the real-world results from a retrospective analysis of patients initiating BIC/FTC/TAF in two HIV centers in Romania. METHODS: This retrospective analysis included patients treated with BIC/FTC/TAF (first-line or switch) in two HIV centers in Romania, one in Bucharest and one in Iași. We collected data on baseline patient characteristics, reasons for initiation of BIC/FTC/TAF and preliminary clinical and laboratory efficacy, safety and tolerability data. All assessments had been performed according to local practice. Statistical analyses were mostly descriptive and association analysis was performed to assess changes in laboratory parameters from baseline to data cut-off (October 2021). RESULTS: In total, 122 patients were initiated on BIC/FTC/TAF in routine clinical practice from February to October 2021 in the two HIV centers, either as first-line or switch. The majority of patients were male (71%). The median age at baseline was 35.0 years (IQR 32.0-50.8 years). Overall, 91 patients (75%) were treatment-experienced and the most frequent reason for switch was treatment simplification (79%). The mean ± standard deviation follow-up duration on treatment with BIC/FTC/TAF was 101.6 ± 64.2 days until the cut-off date for this analysis. We found no significant changes in lipid values, blood glucose or liver enzymes, coupled with a significant decrease in viral load (p=0.001). A low number of adverse events occurred during the treatment period (n=4): two cases of fatigue and two gastrointestinal reactions. No patient discontinued BIC/FTC/TAF and the overall tolerability was good. CONCLUSIONS: The insights of the first report on BIC/FTC/TAF use in routine clinical practice in Romania provide an overview of effectiveness and safety to local clinicians treating this patient population.

Epidemiological characteristics and access to end-stage liver disease care for HIV-positive patients with HCV and/or HBV coinfections in Central/Eastern European and neighboring countries ­ data from the ECEE network

OBJECTIVES: There is currently an urgent need to harmonize hepatitis standards of care for HIV-positive patients across Europe. The HIV epidemic in Central and Eastern Europe has often been driven by injecting drug use, therefore a higher rate of co-infection with HCV and HBV is expected in this region. We have investigated the epidemiological prevalence and treatment availability for end-stage liver disease in HIV/HCV/HBV coinfections in countries represented in the ECEE Network Group. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group was initiated in February 2016 to compare standards of care regarding HIV infection in the region. Information about HIV/HCV/HBV co-infections and the availability for end-stage liver disease treatment for HIV-positive patients were collected through on-line surveys. The respondents were ECEE members from 16 countries of the region. The information on co-infection prevalence was sourced from WHO, national HIV programmes, articles published in international journals, single clinic reports, and personal information in ten of the participating countries (62.5%). RESULTS: The HIV/HCV co-infection rate was from 3% to 99%. The range of reported of HIV/HBV coinfection percentages was 2.3% to 40%. HIV/HCV/HBV co-infection ranged from 0% to 9%. Regarding treatment for end-stage liver disease, liver transplantation was an available option for HIV-positive patients in only three countries (19%). CONCLUSION: Our findings revealed only a limited number of treatment options for the end-stage liver disease in HIV-positive patients for the vast majority of Central and Eastern European countries. There are gaps in epidemiological surveillance in this region. It appears there are many differences in the number of co-infected patients among Central and Eastern European and neighboring countries, but there is no unification of information sources.

Epidemiological trends and therapeutic challenges of malignancies in adult HIV-1-infected patients receiving combination antiretroviral therapy in a tertiary hospital from Romania: An observational retrospective study.

BACKGROUND: Malignancies have become a leading cause of morbidity and mortality in people living with HIV (PLHIV). The primary endpoint of our study was to describe the epidemiology of acquired immunodeficiency syndrome (AIDS)-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Epidemiological disparities, mortality predictors and survival analysis within the two groups of patients were key secondary endpoints. METHODS: We retrospectively evaluated all adult PLHIV with histopathologically proven cancers registered from 2010 to 2016 in the "Matei Balș" National Institute for Infectious Diseases, Bucharest, Romania. RESULTS: 110 eligible patients have been included in the study. The incidence of ADCs decreased from 1.6% in 2010 to 0.3% in 2016, unlike NADCs which remained fairly stable over time (0.3%). The higher CD4 count and lower HIV-RNA level at the cancer diagnosis were associated with prolonged survival in ADCs group, but not in NADCs group. The mean CD4 count was 449/mm3 to survivors and 92/mm3 to non-survivors (p=0.017). The mean level of HIV-RNA was 64,671 copies/mL to survivors and 1,760,345 copies/mL to non-survivors (p=0.002). CONCLUSIONS: A good therapeutic control of HIV infection at the diagnosis of ADCs was associated with better survival, emphasizing the key role of the effective cART in the management of HIV-associated cancers.

Birth outcome in HIV vertically-exposed children in two Romanian centers.

BACKGROUND: The Romanian HIV epidemic is characterized by a high prevalence among children born in the late '80s, perinatally infected. The impact of long-term treatment on their offspring is unknown. We evaluated the influence of prenatal care on the rate of premature birth among the HIV-exposed children of heavily treated HIV-infected mothers in two Romanian centers. METHODS: We retrospectively analyzed data on all patients born by HIV-infected mothers between 2006 and 2012 followed up in two main regional centers. We compared the rate of premature birth and the differences between the sites regarding children and maternal demographic characteristics and antiretroviral exposure in pregnant women. RESULTS: A total of 358 children born to 315 women were enrolled between 2006-2012, 262 children from the National Institute for Infectious Diseases "Prof. Dr. Matei Bals" Bucharest (NIID) and 96 children from the Clinical Infectious Diseases Hospital Constanta (IDHC). Gender rate in newborns and mean age in mothers were similar. We recorded statistically significant differences between centers in the rate of HIV vertical transmission (16.8% vs. 6.2%, p=0.002) and prematurity (25.2 vs. 14.6%, p=0.023). The most used antiretroviral combination during pregnancy in IDHC was boosted lopinavir and fixed dose zidovudine-lamivudine (66% of cases), while in NIID a greater diversity of antiretrovirals were used. Women from IDHC were more frequently treated during pregnancy (83.3% vs. 68.6%, p=0.004). HCV coinfection and illegal drug use were associated with prematurity in the NIID cohort (p=0.037, p=0.024). CONCLUSION: We found a higher rate of premature birth and HIV infection in NIID. In IDHC we found a higher rate of low birth weight in children and a higher rate of heavily treated women. Prematurity was associated with hepatitis C infection and illegal drug use in the NIID cohort.

Enhanced HIV-1 surveillance using molecular epidemiology to study and monitor HIV-1 outbreaks among intravenous drug users (IDUs) in Athens and Bucharest.

BACKGROUND: A significant increase in HIV-1 diagnoses was reported among Injecting Drug Users (IDUs) in the Athens (17-fold) and Bucharest (9-fold) metropolitan areas starting 2011. METHODS: Molecular analyses were conducted on HIV-1 sequences from IDUs comprising 51% and 20% of the diagnosed cases among IDUs during 2011-2013 for Greece and Romania, respectively. Phylodynamic analyses were performed using the newly developed birth-death serial skyline model which allows estimating of important epidemiological parameters, as implemented in BEAST programme. RESULTS: Most infections (>90%) occurred within four and three IDU local transmission networks in Athens and Bucharest, respectively. For all Romanian clusters, the viral strains originated from local circulating strains, whereas in Athens, the local strains seeded only two of the four sub-outbreaks. Birth-death skyline plots suggest a more explosive nature for sub-outbreaks in Bucharest than in Athens. In Athens, two sub-outbreaks had been controlled (Re<1.0) by 2013 and two appeared to be endemic (Re∼1). In Bucharest one outbreak continued to expand (Re>1.0) and two had been controlled (Re<1.0). The lead times were shorter for the outbreak in Athens than in Bucharest. CONCLUSIONS: Enhanced molecular surveillance proved useful to gain information about the origin, causal pathways, dispersal patterns and transmission dynamics of the outbreaks that can be useful in a public health setting.

Characteristics of late presenters in Bucharest.

INTRODUCTION: Late presentation is associated with increased healthcare costs, rates of HIV transmission and poor outcome. In Romania, in 2012, one third of individuals with new HIV diagnosis were late presenters (LP). OBJECTIVE: The aim of the study was to evaluate the epidemiological and clinical characteristics associated with late presentation. METHODS: We retrospectively studied patients over 18 years old, notified in our institution between January 2012 and December 2013, including 499 out of 727 newly diagnosed patients in Bucharest. LP were defined as patients presenting with CD4 T-cell count below 350 cells/mm(3) or with an AIDS defining event. Patients with advanced HIV disease (AHD) were defined as persons with a CD4 T-cell count below 200 cells/mm(3). Differences between groups were analyzed using the Mann-Whitney U test for continuous variables and the chi-square test for dichotomous variables. Multivariable analysis was performed using binary logistic regression. RESULTS: Out of 499 patients included, 362 (72%) were male. The median age was 30 (IQR 26-36). A total of 302 (61%) were LP and 184 (37%) were patients with AHD. A total of 170 (34%) were asymptomatic and 114 (23%) presented with an AIDS-defining event. The median CD4 count was 293 cells/mm(3) (IQR 125-471) and the median HIV viral load was 100,191 copies/mL (IQR 34,560-272,936). Characteristics of LP compared with non-LP are shown in Table 1. Stage C disease has been shown by multivariable analysis to be associated with LP (p<0.001, OR=11.56, 95% CI 4.94-27.03). CONCLUSIONS: More than half of newly HIV diagnosed patients in Bucharest were LP. The proportion of LP was highest among heterosexually acquired cases. Although most our patients were young, late presentation was associated with age over 35 years. The lower proportion of LP among IVDU compared with those heterosexually infected could be explained by a higher proportion of HIV screening tests among IVDU.

ART management in children perinatally infected with HIV from mothers who experience behavioural changes in Romania.

INTRODUCTION: During the recent years the rate of HIV perinatally exposed children in Romania has increased as a consequence of the expanding number of HIV-infected women. These women belong to Romania's long-terms survivors, aged between 20 and 24 years and to the group of new HIV infection cases (20-24 years), acquired through unsafe sexual contact and use of new psychoactive substance (IV). MATERIALS AND METHODS: We focused on 396 HIV perinatally exposed children born between 2008 and 2013, under surveillance in National Institute for Infectious Diseases "Prof. Dr. Matei Bals," Bucharest. Of them, 43 acquired HIV through materno-foetal transmission. Our aim was to observe the characteristics in their evolution under antiretroviral treatment and to emphasize the causes of treatment failure. Children with perinatally acquired HIV infection were followed in a retrospective case series. We assessed maternal characteristics, HIV vertical transmission prophylaxis, timing of diagnosis, immunological and virologic status and features of the evolution under combined antiretroviral therapy (cART). RESULTS: The rate of mother-to-child HIV transmission was 10.8% versus the national rate registered in 2013, namely <5%. 16% of mothers belonged to the Romanian 1990s cohort and 84% were recently infected with HIV, through unprotected sexual contact (70%) or use of new psychoactive substances (14%). 51% of mothers were diagnosed postnatally as a consequence of their reluctance to access specific health services and in 57% CD4 value was <350 cell/mm. 41% of the monitored children were diagnosed with HIV infection at birth. Their median entry CD4 value was 23% and 49% had a CD4 >25%; median entry viral load was 7 log. 16 patients (37%) had undetectable viral load after six months of treatment. In 87.5% of them the virologic suppression was achieved and maintained with one single regimen (2 NRTIs+1 NNRTI or 2 NRTIs+1 PI/r). 15 children (35%) did not achieve suppression of viral load. 19 children (44%) faced special issues related to adherence to antiretroviral treatment, due to mothers' poor adherence to a basic set of cares destined for their children. CONCLUSIONS: Prevention programmes in Romania must be designed on the basis of the new economic context and emerging psychoactive substance use. Hence, women who use drugs should benefit from a wider access to medical and social services.

c-Kit expression in somatosensory nuclei of lower medulla oblongata.

Protein kinase signal-transduction pathways play critical roles in regulating nociception. The c-kit receptor contributes to pain regulation in the spinal cord and is present on both peripheral and central terminals. Expression of c-kit was demonstrated in human trigeminal and spinal ganglia. However, the brainstem expression of c-kit was overlooked. We aimed to evaluate it by immunohistochemistry, on eight samples of human lower medulla oblongata. We used two clones of CD117/c-kit antibodies, from different manufacturers, and neurofilament antibodies. Positive expression of CD117/c-kit was found within the spinal trigeminal nucleus, the gracilis, cuneate, and lateral cuneate nuclei, and within the olivary complex. CD117/c-kit positive interstitial networks of these nuclei were positively labeled with neurofilaments. CD117/c-kit labeled the olivary neurons, but not the magnocellular neurons of the trigeminal, gracilis and cuneate nuclei. c-kit interstitial systems of brainstem could play so an important role for the functional status along the somatosensory neural circuits.

What do we know about the situation of women living with HIV in Europe?

At present, women represent approximately one-third of new diagnoses of HIV in Europe - most are infected by heterosexual transmission. Some specific populations of women, such as migrants, sex workers and those who are intravenous drug users, may be at increased risk of HIV infection. Women living with HIV face a range of intersecting situations and challenges distinct from those faced by men. The most familiar of these is pregnancy and motherhood; however, family and social situations will also be different for women compared with men, and can affect how individuals access care and manage their disease. The stigma of HIV can be a particular problem for women in many communities. Improved surveillance of HIV and increased study of the situations facing women living with HIV will help to identify improved strategies to support the care of this patient population.

Phylodynamic and phylogeographic patterns of the HIV type 1 subtype F1 parenteral epidemic in Romania.

In the late 1980s an HIV-1 epidemic emerged in Romania that was dominated by subtype F1. The main route of infection is believed to be parenteral transmission in children. We sequenced partial pol coding regions of 70 subtype F1 samples from children and adolescents from the PENTA-EPPICC network of which 67 were from Romania. Phylogenetic reconstruction using the sequences and other publically available global subtype F sequences showed that 79% of Romanian F1 sequences formed a statistically robust monophyletic cluster. The monophyletic cluster was epidemiologically linked to parenteral transmission in children. Coalescent-based analysis dated the origins of the parenteral epidemic to 1983 [1981-1987; 95% HPD]. The analysis also shows that the epidemic's effective population size has remained fairly constant since the early 1990s suggesting limited onward spread of the virus within the population. Furthermore, phylogeographic analysis suggests that the root location of the parenteral epidemic was Bucharest.

Impact of highly active antiretroviral therapy on cytomegalovirus viraemia in the absence of specific anti-cytomegalovirus therapy.

OBJECTIVES: (1) to evaluate the effect of HAART on CMV viraemia in co-infected patients, in the absence of specific anti-CMV therapy; (2) to compare 2 molecular biology techniques for the detection and quantification of CMV-DNA in these patients. METHODS: We present the preliminary data of an ongoing prospective research grant on newly diagnosed HIV seropositives, in a tertiary care hospital, during June 2006- June 2008. Clinical, virological (HIV and CMV viraemia) and immunological (CD4) screening was performed every 3 months. The CMV viraemia was performed by RoboGene Human Cytomegalovirus Quantification kit (aj Roboscreen). We retested all undetectable CMV viremia found in patients with CD4 <50/mmc, by CMV PCR kit (Qiagen Diagnostics). Both PCR reactions were performed on ABI Prism 7000 (Applied Biosystems). RESULTS: Up to date, our study has included 105 HIV-infected subjects, who were seropositive for anti-CMV IgG antibodies. Average follow-up was 18 months. CMV viraemia was found detectable in 21 cases at first visit and in other 5 at the second visit. 22 cases had CD4 <50/mmc, among which 14 had undetectable CMV viraemia. The results of both molecular biology techniques were widely the same. HAART was prescribed to 86% of the patients; all the patients having detectable CMV viraemia received HAART, but not any specific anti-CMV therapy. Under HAART, all the detectable CMV loads which were retested in time became undetectable at next visits, after a median of 16.5 weeks from the introduction of therapy. CONCLUSIONS: CMV viraemia detection was useful in early diagnosis of asymptomatic CMV infection. As opposed to transplant cases, molecular biology techniques for the detection and quantification of CMV-DNA in HIV-patients have not been standardized yet. In our study, the two kits RoboGene Human Cytomegalovirus (HCMV) Quantification kit (aj Roboscreen) and CMV PCR kit (Qiagen Diagnostics) were comparable. HAART made the reduction of CMV viral load, without any specific anti-CMV therapy. As in the case of other opportunistic infections, undetectable natural history of CMV infection seemed to have been improved by controlling HIV infection.