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PURPOSE: Neutralizing antibodies can reduce SARS-CoV-2 cellular entry, viral titers, and pathologic damage. CT-P59 (regdanvimab), a SARS-CoV-2 neutralizing monoclonal antibody, was examined in 2 randomized, double-blind, placebo-controlled, single ascending dose, Phase I studies. METHODS: In study 1.1, healthy adults were sequentially enrolled to receive CT-P59 10, 20, 40, or 80 mg/kg or placebo. In study 1.2, adult patients with mild SARS-CoV-2 infection were enrolled to receive CT-P59 20, 40, or 80 mg/kg or placebo. Primary objectives of both studies were safety and tolerability up to day 14 after infusion. Secondary end points included pharmacokinetic properties. Study 1.2 also measured virology and clinical efficacy. FINDINGS: Thirty-two individuals were randomized to study 1.1 (6 per CT-P59 dose cohort and 8 in the placebo cohort). By day 14 after infusion, adverse events (AEs) were reported in 2 individuals receiving CT-P59 20 mg/kg (headache and elevated C-reactive protein levels) and 1 receiving CT-P59 40 mg/kg (pyrexia) (all Common Terminology Criteria for Adverse Events grade 1). In study 1.2, 18 patients were randomized (5 per dose cohort and 3 in the placebo cohort). Sixteen AEs were reported in 10 patients receiving CT-P59. No AEs in either study led to study discontinuation. Greater reductions in viral titers were reported with CT-P59 than placebo in those with maximum titers >105 copies/mL. Mean time to recovery was 3.39 versus 5.25 days. IMPLICATIONS: CT-P59 exhibited a promising safety profile in healthy individuals and patients with mild SARS-CoV-2 infection, with potential antiviral and clinical efficacy in patients with mild SARS-CoV-2 infection. ClinicalTrials.gov identifier: NCT04525079 (study 1.1) and NCT04593641 (study 1.2).

Background We report a case of post-coronavirus disease (COVID) immune hepatitis occurring in a young male with no pre-existing comorbidities. Case summary A previously healthy 21-year-old male patient was admitted to our hospital with mild COVID-19. During the course of in-hospital isolation and monitoring, he developed an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase, with the enzymes peaking at day 24 (ALT 15 times the upper normal limit), with preserved liver function. The liver enzyme increase occurred 20 d after the complete clinical remission of COVID-19, and ALT dynamics paralleled the increase in total antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case was interpreted as post-COVID immune hepatitis, with extensive laboratory investigations excluding other potential causes. The hepatocytolysis remitted 20 d after the peak ALT, without further intervention, with complete recovery, but the total anti-SARS-CoV-2 antibodies continued to increase the next 5 mo following the acute infection. Conclusion Close attention should also be paid to young patients with mild forms of disease, and a high index of suspicion should be maintained for post-COVID complications.

Introduction. Antiretroviral therapy (ART) is used in human immunodeficiency virus (HIV)-infected patients, to suppress viral replication and slow disease progression. The side effects of ART, milder or more serious, frequently occur, thus the main challenge for specialists is to find a balance between the benefits of long-term viremia suppression and the risks of toxicity. The objective of the study was to compare the frequency of mild side effects after administration of a regimen containing darunavir (DRV) boosted with ritonavir (RTV) (DRV/r 600 mg/100 mg, twice daily), vs DRV boosted with cobicistat (COBI) (DRV/c – 800 mg/150 mg, once a day) and perform a profile of the patient at risk of developing these types of adverse reactions during ARV treatment. Materials and methods. 462 patients were enrolled in the study and divided into two groups: 384 received DRV/r, and 78 DRV/c. This was a retrospective, non-interventional study using the database of the National Institute of Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Romania. The self-declared mild side effects were collected from patients’ medical files and a comparison between the frequency of these in the two groups have been made. The main self-declared mild side effect was statistically correlated with the characteristic parameters of the cohort. Results. The statistical description of the most frequent self-declared mild side effects in the two groups showed that all parameters were found in a greater proportion in DRV/r group than in DRV/c group, with a statistically significant difference of p

OBJECTIVES: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. DESIGN: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). METHODS: Virologic response rates (HIV-1 RNA

Aims To evaluate the kinetics of inflammatory biomarkers in septic patients in order to identify the most reliable predictor of unfavorable outcome. Methods A prospective analysis of septic patients was performed. Median levels of neutrophil/lymphocyte count ratio, fibrinogen, C-reactive protein and procalcitonin were dynamically assessed and comparatively analyzed. Results Seventy-seven patients were included. Descendent kinetic patterns were registered for all biomarkers, except C-reactive protein. At 24 hours, neutrophil/lymphocyte count ratio significantly decreased in 42.85% of cases, procalcitonin in 37.33%, C-reactive protein in 16.12% and fibrinogen in 1.58% of cases. At 72 hours, procalcitonin decreased to one-half in 70% of cases and neutrophil/lymphocyte count ratio in 67.53% of cases. Conclusions Neutrophil/lymphocyte count ratio and procalcitonin significantly decreased in the first 72 hours, while C-reactive protein increased in the first 24 hours. The proportions of patients with major decrease of baseline values were higher for neutrophil/lymphocyte count ratio and procalcitonin.

Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study.This randomised, controlled, double-blind, multicentre, non-inferiority, phase 3 study was undertaken at 125 clinical centres in 15 countries. Eligible participants were adults (aged ≥18 years) infected with HIV-1 who were naive to antiretroviral therapy, with a plasma HIV-1 RNA concentration of 1000 copies per mL or higher at screening, and no known resistance to any of the study drugs. Participants were randomly assigned (1:1) using an interactive voice and web response system, stratified by baseline HIV-1 RNA concentration and background nucleoside reverse transcriptase inhibitor therapy, to doravirine (100 mg per day) or ritonavir-boosted darunavir (100 mg ritonavir and 800 mg darunavir per day), both with investigator-selected nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. Participants and investigators were masked to treatment assignment until week 96. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here we report the key secondary efficacy endpoint of the proportion of participants who achieved this concentration by week 96, assessed in all participants who received at least one dose of any study drug, regardless of whether it was their randomly assigned treatment. We used a US Food and Drug Administration snapshot approach and a margin of 10 percentage points to define the non-inferiority of doravirine to ritonavir-boosted darunavir at 96 weeks. Key safety endpoints were change in fasting serum lipid concentrations, the incidence of adverse events, and time to discontinuation due to an adverse event, assessed in all participants who received at least one dose of any study medication. This study is registered with ClinicalTrials.gov, NCT02275780, and is closed to accrual.Between Dec 1, 2014, and Oct 20, 2015, 1027 individuals were screened, of whom 769 participants were randomly assigned to doravirine (n=385) or ritonavir-boosted darunavir (n=384), and 383 in both groups were given at least one dose of their allocated treatment. Most participants were male (645 [84%] of 766) and white (560 [73%]), with a mean age of 35·2 years (SD 10·6). 292 participants in the doravirine group and 273 in the darunavir group completed 96 weeks of treatment. At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3). Frequencies of adverse events were similar between groups. No significant treatment difference (log-rank nominal p=0·063) through week 96 was observed in time to discontinuation due to an adverse event. The most common adverse events (week 0-96) were diarrhoea (65 [17%] in the doravirine group vs 91 [24%] in the ritonavir-boosted darunavir group), nausea (45 [12%] vs 52 [14%]), headache (57 [15%] vs 46 [12%]), and upper respiratory tract infection (51 [13%] vs 30 [8%]). Two participants, one in each group, died during treatment; neither death was considered to be related to study medication.These results through 96 weeks support the efficacy and safety results reported previously for doravirine at 48 weeks, supporting the use of doravirine for the long-term treatment of adults with previously untreated HIV-1 infection.Merck.

CT-P59, a monoclonal antibody with potent neutralizing activity against severe acute respiratory syndrome coronavirus 2, may ameliorate symptoms and prevent hospitalization in outpatients with mild-to-moderate disease. We report findings from part one of a two-part randomized, placebo-controlled, double-blind study (NCT04602000; EudraCT: 2020-003369-20). Outpatients with mild-to-moderate COVID-19 received a single dose of CT-P59 40 mg/kg (n=101), CT-P59 80 mg/kg (n=103), or placebo (n=103). Median (95% confidence interval [CI]) time to conversion to negative RT-qPCR result (coprimary endpoint) was 12.8 days (9.00–12.84) with CT-P59 40 mg/kg, 11.9 days (8.94–12.91) with CT-P59 80 mg/kg, and 12.9 days (12.75–13.99) with placebo. Median (95% CI) time to clinical recovery (coprimary endpoint) was 5.4 days (3.97–6.78) with CT-P59 40 mg/kg, 6.2 days (5.53–7.85) with CT-P59 80 mg/kg, and 8.8 days (6.72–11.73) with placebo. The proportion (95% CI) of patients requiring hospitalization or oxygen therapy was lower with CT-P59 40 mg/kg (4.0% [1.6–9.7%]) and CT-P59 80 mg/kg (4.9% [2.1–10.9%]) versus placebo (8.7% [4.7–15.8%). CT-P59 was well tolerated and no serious treatment-emergent adverse events or deaths occurred. In summary, CT-P59 accelerated viral and clinical recovery from COVID-19 and was well tolerated in patients with mild-to-moderate infection.

Introduction. The digestive tract is invariably affected in HIV-infected patients and should be investigated especially in patients with longer disease duration. The significance of decreasing CD4+ cell counts as a predictive factor for the existence and severity of upper gastrointestinal lesions has been previously evaluated in some studies, that demonstrated a link between this parameter and the frequency or extent of esophageal or gastric lesions. The objective of the study was to investigate the upper digestive tract infections in HIV-infected patients and to establish the link between endoscopic changes (type and location) and the peripheral CD4+ cell counts. Material and methods. This is a retrospective cohort study. 88 HIV-infected patients, hospitalized for clinical and biological evaluation between November 2015 and July 2018 in the National Institute for Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Romania, were investigated by upper digestive endoscopy. In all patients, CD4+ T-lymphocyte values were determined. Results. Our study emphasizes a greater probability of developing lesions of the upper digestive tract and a greater frequency of esophagitis in HIV-infected patients with low CD4+ T-lymphocyte values compared to patients with normal values. The most commonly involved segment is the esophagus. The most common gastric lesion is gastritis, which in patients with lymphocytic depletion affects the entire gastric mucosa. Conclusions. The results of the study support the necessity of routine evaluation by upper digestive endoscopy of HIV-infected patients with low CD4+ T-lymphocyte values, irrespective of the presence or absence of symptoms specific for upper digestive tract lesions, both for diagnostic and epidemiological purposes.

Background Young, non-obese adults are considered at low risk for cardiometabolic diseases, although markers of an unhealthy metabolic state are not uncommon findings in this population. Adipose tissue dysfunction, evaluated by the adipokine profile, significantly influences lipid and glucose metabolism and low-grade systemic inflammation. Aims To determine the relation between adipose tissue dysfunction and the already confirmed cardiometabolic risk indicators, including the atherogenic index of plasma, lipid accumulation product, homeostatic model assessment of insulin resistance, and the low-grade inflammation markers, namely, interleukin 6 and high-sensitivity C-reactive protein. Study design Cross-sectional study. Methods We recruited 93 non-obese, healthy young adults. Anthropometric, lipid profile, inflammatory markers, and adipokines were measured. An abnormal adipokine profile (high leptin-to-adiponectin ratio) was considered as a marker of a dysfunctional adipose tissue. The correlation between the leptin-to-adiponectin ratio and the anthropometric measurements, atherogenic index of plasma, lipid accumulation product, homeostatic model assessment of insulin resistance, interleukin 6, and high-sensitivity C-reactive protein was determined. Results We found a direct correlation between the abnormal adipokine profile and the cardiometabolic risk indicators mentioned above, except for the low-grade inflammatory markers. In the regression model derived from our data, the leptin-to-adiponectin ratio was best correlated with the unfavorable plasma lipid profile, as estimated by the atherogenic index of plasma (r=0.097, confidence interval=0.015-0.180, p=0.021). A significantly higher leptin-to-adiponectin ratio was found in the insulin-resistant group (p=0.012) and in the highest lipid accumulation product quartile (p=0.032). Conclusion In a non-obese young population, the high rate of leptin-adiponectin may be a good predictor of cardiovascular and metabolic risk assessment.

Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA

Background and Aims: The 12-week regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (OPrD) has shown high efficacy and tolerability in clinical trials for the treatment of chronic hepatitis C virus (HCV). The shorter 8-week regimen has been recently incorporated into clinical guidelines and on-label indications, but real-world evidence on its use is limited. Given this knowledge gap, the AMETHYST study aimed to evaluate the effectiveness of the 8- and 12-week regimens of OPrD in treatment-naive patients with HCV with mild to moderate liver fibrosis in Romanian clinical practice. Methods: This was a secondary data collection study analyzing data from a 1-year Patient Support Program in HCV in Romania. Patients received OPrD treatment for 8 or 12 weeks. The effectiveness endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results: A total of 1,835 treatment-naive patients with HCV with mild or moderate fibrosis were included in the study. Of these, 426 and 1,375 completed the 8-week and 12-week regimens, respectively. SVR12 was 98.1% in the 8-week treatment group and 98.7% in the 12-week treatment group. Conclusion: The study provides real-world evidence that 8-week and 12-week treatment regimens of OPrD are highly effective in treatment-naive patients with HCV with mild to moderate liver fibrosis.

INTRODUCTION: Vitamin D (VD) deficiency is highly prevalent worldwide. AIM: To assess the prevalence of hypovitaminosis D in HIV-positive Romanian patients compared to controls. METHODS: Serum 25OHD concentration was measured in HIV-infected patients and a control sample, matched by age, sex and menopausal status. The 25OHD status was defined as: deficiency < 20 ng/mL (severe deficiency 30 ng/mL. RESULTS: We evaluated 118 HIV-positive patients (72 males, 46 females), aged 36.9±12.2 years. 98.14% of them were on complex antiviral regimens. The B/C hepatitis coinfection rate was 9.3%. The control sample consisted of 119 subjects, (74 males, 45 women). The median and interquartile range for serum 25OHD concentration in patients was 17.6 (9.7, 26.9) ng/mL and 23.7 (18.4, 27.5) ng/mL in controls (p=0.001). Only 15.96% of HIV-positive cases and 12.71% of controls had normal VD status. The percentage of cases with severe VD deficiency was significantly higher in HIV positive cases (23.52%) compared to HIV-negative controls (4.2%, p=0.001). CONCLUSIONS: Hypovitaminosis D was identified in 84.04% of HIV-infected patients, but the serum 25OHD concentration was not associated with specific HIV-related factors in our sample. Clinical guidelines regarding VD status determination and supplementation in HIV patients are needed.

Background Seasonal influenza causes a considerable burden to healthcare services every year. To better measure the impact of severe influenza cases in Romania, we analyzed active surveillance data collected during the 2017–2018 season from patients admitted for influenza-like illness (ILI) at a tertiary care hospital in Bucharest. Methods Patients admitted for acute ILI were included if they were resident in the Bucharest-Ilfov region, had been hospitalized for at least 24 h, and had onset of symptoms within 7 days before admission. Patient demographics, healthcare use, vaccination status, and outcome data were collected by questionnaire or by searching clinical records. Respiratory swabs were also obtained from each patient to confirm influenza A (A/H1 and A/H3 subtypes) or influenza B (Yamagata and Victoria lineages) infection by real-time reverse-transcription polymerase chain reaction assay. Results The study included 502 patients, many (45.2%) of whom were aged n = 259, 51.6%) were positive for influenza. Most influenza cases were caused by B viruses (172/259, 66.4%), which were mostly of the B/Yamagata lineage (85 of 94 characterized, 90.4%). Most of the subtyped A viruses were A/H1 (59/74, 79.7%). A/H1 viruses were frequently detected in influenza-positive admissions throughout the 2017–2018 season, whereas the predominant B/Yamagata viruses were detected around the middle of the season, with a peak in cases at week 7 of 2018. Eleven patients were admitted to an intensive care unit; of these, one patient with confirmed B/Yamagata infection died. Conclusions These results show that seasonal influenza results in considerable hospitalization in Bucharest-Ilfov, Romania and suggest vaccine coverage should be extended, especially to the youngest age groups. The data from this study should help inform and optimize national influenza healthcare policies.

INTRODUCTION: Patients with diabetes may be at a higher risk of developing complicated influenza. We report the characteristics of influenza in hospitalized elderly patients with and without diabetes, in three consecutive influenza seasons. METHODS: The study included patients admitted for severe acute respiratory infection (SARI) in the National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, Bucharest, during a three-year active epidemiological surveillance study (2015/16, 2016/17, 2017/18), in the I-MOVE+ hospital network. RESULTS: A total of 349 patients were tested by PCR over the duration of the study. The percentage of patients with diabetes was comparable throughout the seasons: 34.7%, 28.3% and 30.4% (p=0.587). Influenza A was the main viral type circulating in 2015/16 and 2016/17 (100% and 97.6%) in our study population, while in 2017/18, B viruses predominated (90.0%). Diabetics presented a higher median number of comorbidities (3 vs. 2) p

Context In HIV+ patients, several factors related to patient and antiretroviral therapy (ART) could determine early onset of bone mineral density (BMD) disturbances. Objective Evaluation of bone quality according to gender in patients from the HIV Romanian cohort. Design A cross-sectional study in "Prof. Dr. Matei Bals" National Institute for Infectious Diseases, Bucharest between 2016-2018. Subject and methods We collected data regarding HIV infection, ART history, viral hepatitis co-infections and we calculated patients body mass index (BMI). CD4 cell count, HIV viral load (VL), vitamin-D levels were determined. Dual-energy X-ray absorptiometry (DXA) scans were used to evaluate BMD. Results We enrolled 97 patients with the median age of 26 years. According to the DXA T-scores, 10 males and 8 females had osteopenia and 4 males and 4 females had osteoporosis. According to Z-scores 2 males and 1 female had osteoporosis. Hip DXA T-scores revealed osteopenia in 6 males and 9 females, whereas T and Z-scores showed osteoporosis in 2 males and 3 females. Lumbar spine (LS) T-score diagnosed osteopenia in 9 males and 6 females, while T and Z-scores revealed osteoporosis in 3 males and females. In males, low T-scores were associated with decreased BMI; low LS DXA Z-scores with low vitamin-D levels; low T and Z-scores and LS-BMD with high VL. Conclusions Evaluating bone quality in patients with a long history of HIV infection, multiple factors should be taken into account.

Background & Aims JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection. Methods We performed a double-blind study of 57 treatment-naive patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period. Results Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed. Conclusions In a phase 1 study of treatment-naive patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712

The management of the side effects caused by the antiretroviral therapy is one of the main problems facing clinicians. The patient’s tolerability and safety influence the success of the therapy. This retrospective study assesses the tolerability and impact on metabolic profiles of antiretroviral regimens containing darunavir/ritonavir (DRV/r) versus those containing darunavir/cobicistat (DRV/c), in routine clinical practice. The database of Prof. Dr Matei Bals of the National Institute of Infectious Diseases (INBI MB) was studied for the period 2017–2020, allowing the inclusion in the study of 462 HIV-infected patients who received the current regimen at least three months before evaluation. The following parameters were collected and analyzed: significant medical history, associated diseases, serum levels for profile evaluation: carbohydrate, lipidic, serum level of liver and pancreatic enzymes, serum markers of cardiac function, coagulation, and renal function. DRV/c (800 mg/150 mg, once daily) administrated in combination with other antiretroviral (ARV) in HIV-1 infected subjects proved to be better tolerated and with a lower impact on metabolic profile than DRV/r (600 mg/100 mg, twice daily). Patients in DRV/r group are significantly more at risk of developing, over time, side effects and metabolic impairments than those in DRV/c group, in all body functions studied, with statistically significant differences (p &lt, 0.05) between the two groups. Laboratory data were correlated with patient’s demographic and clinical characteristics and statistically significant outcomes have been found, proving that a personalized regimen is needed to minimize the ART side effects and to maximize the success of therapy. The results of the study showed that DRV/c, associated with other antiretroviral drugs in the regimens of Romanian HIV infected subjects, have a more favorable metabolic profile than those containing DRV/r.

Background In aesthetic breast augmentation, especially by the transareolar approach, there is increasing concern regarding the occurrence of capsular contracture and its potential correlation with intraoperative implant contamination from putative endogenous breast flora of the nipple and lactiferous ducts. However, detectable bacteria cannot be considered synonymous with established resident microflora. Objectives The authors sought to elucidate the existence of endogenous breast flora and assess the microbiologic safety of transareolar breast augmentation. Methods In this prospective study (BREAST-MF), the authors collected microbiologic samples from the breast skin, ductal tissue, and parenchyma of 39 consecutive female patients who underwent breast procedures in a plastic surgery clinic. Swabs collected pre-, intra-, and postoperatively were processed for bacterial and fungal growth. Positive cultures underwent identification through VITEK and MALDI-TOF, as well as antimicrobial susceptibility testing. Results Staphylococcus species accounted for 95 of 106 (89.6%) positive results from native breast skin, 15 of 18 (83.3%) positive results from decontaminated breast skin, and 4 of 4 (100%) positive results from the breast parenchyma. Methicillin resistance was present in 26.4% of S. epidermidis , 25.3% of S. hominis , and 71.4% of S. haemolyticus strains. Conclusions During transareolar breast augmentation, in the nipple-areola region it is more likely to find bacteria populating the skin, rather than endogenous breast flora, as previously considered. Appropriate preoperative decontamination is essential for minimizing the risk of postoperative infections. Level of Evidence: 3 ![Graphic][1] Risk [10.1093/asj/sjv108][2] [1]: /embed/inline-graphic-1.gif [2]: /lookup/doi/10.1093/asj/sjv108

Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection.This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load10,000IU/ml were randomized to receive 12weeks of EBR/GZR 50mg/100mg once daily (n=129) or sofosbuvir (400mg once daily) plus PR (n=128). Primary efficacy objective was sustained virologic response 12weeks after the end of therapy (SVR12, HCV RNA15IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event.The majority of patients were non-cirrhotic (83.1%), treatment-naïve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6-15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than -10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, -35.5% to -19.6%; p0.001]).EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR.The combination of elbasvir/grazoprevir for 12weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations.Clinical trials.gov Identifier: NCT02358044.

Introduction: Understanding the intersection of HIV, aging and health is crucial due to the increasing number of people aging with HIV. Objective: The objective of the study was to assess the prevalence of, and risk factors for individual comorbidities and multi-morbidity in people living with HIV with similar duration of HIV infection, notwithstanding a 25-year difference at the time of HIV acquisition. Methods: In a cross-sectional multicentre retrospective study, we compared three match-control age groups. The “Young” were selected from Romania and included HIV-positive patients prenatally infected and assessed at the age of 25-30 years. The “Old” and the “Geriatric” were selected from Italy. These respectively included subjects infected with HIV at the age of 25 years and assessed at the age of 50-55 years, and those infected at the age of 50 years and assessed at the age of 75-80 years. Each group was sex and age matched in a 1:5 ratio with controls selected from the CINECA ARNO database from Italy. We described non-infectious comorbidities (NICM), including cardiovascular disease, hypertension, dyslipidaemia, diabetes, chronic kidney disease, and multi-morbidity (MM≥ 3 NICM). Results: MM prevalence in the “Young” group compared to controls was 6.2% vs 0%, while in the “Geriatric” was “68.2% vs 3.6%. Using “Young” as a reference, in multivariate analyses, predictors for MM were as follows: HIV serostatus (OR=47.75, IQR 14.78-154.25, p

Background: Severe acute hepatitis B (SAHB) is an insufficiently described clinical entity, with relatively scarce data on anti-viral therapy available in field literature. Methods: We performed an open-label study to evaluate specific anti-viral therapy in SAHB in Bucharest, Romania, during 2005-2009. Patients were allocated to two treatment groups and one control group: Group 1 - lamivudine 100 mg/day, Group 2 - entecavir 0.5 mg/day and Group 3 - standard of care, without anti-viral therapy. The primary endpoint was hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (anti-HBs) seroconversion by 24 weeks. Additional analyses included assessment of HBsAg clearance and hepatitis B e antigen (HBeAg) to hepatitis B e antibody (anti-HBe) seroconversion. Results: In Group 1, 7/69 patients (10.14%, P = 0.032) reached HBsAg/Ab seroconversion by 24 weeks, compared with 9/21 (42.85%, P = 0.053) in Group 2 and 25/110 (22.72%) in Group 3. HBsAg clearance by 24 weeks: 16/69 patients (23.18%, P = 0.027) in Group 1, 11/21 (52.38%, P = 0.256) in Group 2 and 43/110 (39.09%) in Group 3. HBeAg/Ab seroconversion: 46/61 (75.40%, P = 0.399) in Group 1, 9/19 (47.36%, P = 0.001) in Group 2 and 74/100 (74.00%) in Group 3. Conclusion: Anti-viral therapy can be considered for managing selected cases of SAHB. Biochemical as well as virological parameters need to orient the choice of the anti-viral agent. Lamivudine displayed a greater decrease in viral load compared to controls, but it was associated with lower levels of HBsAg to anti-HBs seroconversion. Patients treated with entecavir showed a better response in terms of HBs seroconversion by 24 weeks.

It is unknown whether peginterferon (PEG-IFN) add-on to entecavir (ETV) leads to more HBsAg decline compared to PEG-IFN monotherapy or combination therapy, and whether ETV therapy may prevent HBsAg increase after PEG-IFN cessation. We performed a post hoc analysis of 396 HBeAg-positive patients treated for 72 weeks with ETV + 24 weeks PEG-IFN add-on from week 24 to 48 (add-on, n = 85), 72 weeks with ETV monotherapy (n = 90), 52 weeks with PEG-IFN monotherapy (n = 111) and 52 weeks PEG-IFN + lamivudine (combination, n = 110) within 2 randomized trials. HBsAg decline was assessed at the end of PEG-IFN (EOP) and 6 months after PEG-IFN (EOF) discontinuation. Differences in baseline characteristics were accounted for using inversed probability of treatment weights. At EOP, a HBsAg reduction of >= 1log(10) IU/mL was more frequently achieved for patients in the add-on or combination therapy arms (both 36%), compared to PEG-IFN mono (20%) or ETV (8%) (add-on vs PEG-IFN mono P = 0.050). At EOF, the HBsAg reduction >= 1log(10) IU/mL was only sustained in patients treated with ETV consolidation (add-on vs combination and PEG-IFN mono: 40% vs 23% and 18%, P = 0.029 and P = 0.003, respectively). For add-on, combination, PEG-IFN mono and ETV, the mean HBsAg-level change at EOF was -0.84, -0.81, -0.68 and -0.33 log(10) IU/mL, respectively (P > 0.05 for PEG-IFN arms). HBeAg loss at EOF was 36%, 31%, 33% and 20%, respectively (P > 0.05). PEG-IFN add-on for 24 weeks results in more on-treatment HBsAg decline than does 52 weeks of PEG-IFN monotherapy. ETV therapy may maintain the HBsAg reduction achieved with PEG-IFN.

Background & AimsTelaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV.MethodsTreatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12–36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.ResultsThree hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0–1% and 8–11%, respectively, p

The risk of developing secondary infections in immunocompromised patients due to hematological malignancies and the treatments for such conditions is very well known. Fever can be the only manifestation of a serious infection among this category of patients. The degree and duration of neutropenia is directly related to the risk of multiple infectious complications. When we are dealing with severely impaired host defenses virtually any microorganism can become invasive, bacteria (gram-positive pathogens, but gram-negative as well), being the greatest immediate threat. Multiple pathogens isolated from an immunocompromised host can represent a major challenge for the clinician, especially when we have to face multidrug resistant (MDR) microorganisms, also called “superbugs”. Besides, when we confront such a patient with many comorbidities and a high risk for MDR pathogens infection, we also confront with a lot of limitations in terms of treatment options. We present a complicated case of glycopeptide-resistant Enterococcus faecium sepsis secondary to Clostridium difficile colitis in a 63 years old female patient with B-cell non-Hodgkin Lymphoma (NHL) during the R-CHOP therapy.

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. Keywords: AIDS, HIV, Cancer, Kaposi sarcoma, Epidemiology, Romania

Background The recently updated EASL Guidelines for Management of HBV Infection (2017) recommend the use of TAF as an alternative to TDF in patients with risk factors unfavourable to TDF use. We, therefore, performed an evaluation of the efficacy and safety of TAF compared with TDF in patients considered to be at risk for adverse bone and/or renal effects from TDF. Methods In two Phase 3 studies, patients (HBeAg-positive [n=873] and HBeAg-negative [n=425]) were randomised 2:1 to TAF or TDF. Antiviral efficacy (HBV DNA 60 years, osteoporosis of hip or spine by t-score, eGFRCG 30 mg/g, or serum phosphorus Results Of 1298 patients randomised and treated in the 2 studies, 239 (18%; 151 TAF and 88 TDF) patients had at least 1 risk factor for TDF use. Baseline demographics were similar between groups. At Week 96, similar antiviral efficacy (HBV DNA Conclusions In CHB patients considered to be at risk for TDF toxicity, TAF showed significantly less impact on bone and renal parameters while efficacy was maintained in this subgroup through 96 weeks.

Background The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. Methods This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. Results Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. Conclusions AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.

BACKGROUND: Leptin is an adipokine with complex metabolic, neuroendocrine and immune functions. Our objective was to evaluate leptin serum levels in a cohort of Romanian HIV-infected patients undergoing antiretroviral therapy in relation to their immune-virological status, lipid and glucose metabolic abnormalities and the presence of metabolic syndrome (MS). METHODS: We enrolled consecutive non-diabetic HIV-infected patients aged 18 and over on stable cART for at least 6 months. Blood samples were tested for: leptin, CD4 T cells count, HIV viral load and lipid panel. RESULTS: A total of 90 HIV-infected patients were included in the study: 50 males (55.6%) with a mean age of 33.3 years and 40 females with a mean age of 30.4 years. Most patients (74.4%) had HIV viral load below the limit of detection and the median CD4 count for the cohort was 476 (410) cells/cmm. More than one third of the patients (41.1%) had hypoleptinemia. The prevalence of MS was 13.3%. Hypoleptinemia was significantly more frequent in men. In a subset of patients with undetectable HIV viral load, the median leptin value was 0.6 (6.07) ng/mL in patients with poor immune recovery (CD4 count ≤ 200/cmm) compared to 2 (3.07) ng/mL for those with better immune response (CD4 count > 200/cmm), without statistical significance. The median values of leptin were similar for persons with and without MS criteria. HDL-cholesterol values were positively correlated to leptin values in a linear regression model. CONCLUSION: A significant proportion of patients in our study presented low levels of leptin; this finding was not associated with immune and virological parameters or the presence of MS. Hypoleptinemia was significantly correlated with lower levels of HDL-cholesterol, a key cardiovascular risk factor.

Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA

There is little information regarding the extent to which difficult to cure patients with advanced liver fibrosis, due to hepatitis C virus genotype-1 (HCV-1) can successfully and safely be treated with triple therapy with telaprevir (TVR), pegylated interferon alpha (P) and ribavirin (R). In the TVR early access program HEP3002 we aimed to explore treatment safety and efficacy, and identify predictors of sustained virological response at week 24 (SVR24).1078 patients with bridging fibrosis (n=552) or cirrhosis (n=526) diagnosed by either liver biopsy or non-invasive markers, with compensated bone marrow (neutrophils1500/mm(3), Hb12/13 g/dl) and liver function (Albumin3.3g/dl, Platelets90,000/ml) received TVR PR for 12 weeks, followed by a PR tail according to label.Overall, 614 (57%) achieved SVR24 by intention-to-treat analysis. The SVR24 rate was 68% in 221 treatment naïve patients (62.8% F4), 72% in 356 prior relapsers (64.4% F4), 55% in 139 partial responders (53.2% F4), and 34% in 294 null responders (28.6% F4). The SVR24 rate to response-guided therapy (24 weeks treatment duration if undetectable viremia at weeks 4 and 12) was 84% in 222 naïve/relapser F3 patients. Independent predictors of response were: (A) F3 (odds ratio (OR)=1.51, 95% CI 1.31-2.00, p=0.005), (B) subtype 1b (OR=1.63, 95% CI 1.18-2.24, p=0.0029), (C) alpha-fetoprotein10 ng/ml (OR=2.50, 95% CI 1.87-3.36, p0.0001) and (D) any prior response other than null (OR=3.29, 95% CI 2.40-4.52, p0.0001). SVR24 rose for patients who had more of these predictive factors: 6/32 (19%) for none, 38/139 (27%) for 1, 129/260 (50%) for 2, 202/329 (61%) for 3, and 194/235 (83%) for 4 factors. Grade 2-4 treatment-related adverse events (AE) were experienced by 719 (67%) patients; 169 (16%) discontinued therapy for AE and 7 (0.6%) died during the PR tail.Naïve and experienced patients with advanced fibrosis or cirrhosis due to HCV-1 who have compensated bone marrow and liver function, can effectively and safely be treated by TVR triple therapy. Baseline predictors of outcome have been identified to optimize pre-treatment counselling.

Background The Romanian HIV cohort has certain particularities that render it unique in Europe. We have performed a study to evaluate the prevalence of bone and kidney impairment in this particular group of HIV-infected patients. Methods We performed dual-energy X-ray absorptiometry (DXA) evaluation of the lumbar vertebrae and the femur, as well as laboratory tests including standard serum panels, bone-related markers and urinalysis in patients from the Romanian HIV cohort. Results The study included 72 patients, of which 46 (58.3 %) were males. The median (IQR) age was 38 (18) years and the median (IQR) time from HIV infection diagnosis was 9 (13) years. Most patients (55.6 %) were non-smokers, but a relatively high proportion (37.5 %) was currently smoking. Only a small percentage of patients (20.8 %) did not present any comorbidities, while 40.3 % had one comorbidity, the most frequent being dyslipidemia (present in 25 patients, 38.5 %). Only 6 patients had a medical history suggestive for renal disease and 3 for bone-related abnormalities. The median (IQR) glomerular filtration rate was 97.5 (33.0) mL/min/1.73sqm. We diagnosed 21 patients (29.6 %) with stage 2 chronic kidney disease and one patient (1.4 %) with stage 3 chronic kidney disease. Proteinuria was present in 9 (12.7 %) patients. The estimated glomerular filtration rate was significantly lower in patients with cardiac comorbidities (p = 0.013). Vitamin D was significantly lower in smokers compared with non-smokers, with a mean value of 15 vs. 21 ng/mL and a moderate effect size (Cohen’s d = −0.5) (p = 0.046). Lumbar osteopenia and osteoporosis were diagnosed in 33.3 and 13.7 % of patients, while femoral osteopenia and osteoporosis were diagnosed in 37.3 and 7.8 %, respectively. Lower nadir CD4 cell counts were found in patients with bone-related comorbidities (p = 0.000). Conclusions We identified a relatively high prevalence of chronic kidney disease in the Romanian HIV cohort, and a fairly low prevalence of osteopenia and osteoporosis, compared with other European countries. In this category of patients smoking should be avoided altogether, as it may be an indirect risk factor for kidney disease (associating cardiac comorbidities) and it may impair bone metabolism by altering serum levels of hydroxy-vitamin D.

Introduction Vitamin D (VD) deficiency is highly prevalent among HIV-infected patients and has been associated with a worse disease prognosis. Aim To determine the prevalence of hypovitaminosis D in a cohort of HIV-positive Romanian patients compared to healthy controls Methods Plasma samples for the determination of serum 25OHD concentration were collected from HIV-infected patients and healthy controls. 25OHD status was defined as: deficiency 30 ng/mL. Clinical and laboratory parameters were retrospectively extracted from patients'files (CD4+ cell count, CD4+ nadir, HBV/HCV co-infection, ART). Results We evaluated 118 HIV-positive patients, (72 males, 46 females, aged 36.9±12.2 years). 106 patients (98.14 %) were on complex ART regimens. 9.3% had B/C hepatitis coinfection. We also 119 healthy controls matched by age, sex and menopausal status. The mean serum 25OHD concentration in the HIV-positive patients was significantly lower (19.36 ±11.34 ng/ml) compared to controls (23.74±8.32 ng/ml; p=0.001). Normal VD status was determined in only 15.96% of patients and 12.71% of controls. Severe VD deficiency was found in a higher percentage of HIV positive patients (23.52%) compared to controls (4.2%, p=0.001). The serum 25OHD level in patients was not significantly correlated with gender, age, menopausal status in women, number of years of previous ART treatment or nadir CD 4 positive cell-count. Conclusions Low levels of 25OHD are present in a significantly higher percentage in HIV-positive patients compared to healthy controls. The serum 25OHD concentration was not correlated with any particularities of the treatment regimen or disease characteristics in our sample. Clinical guidelines related to the VD status in HIV-positive patients are needed.

Summary Background Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. Methods In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than −10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. Findings Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI −1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one ( Interpretation In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. Funding Merck & Co.

INTRODUCTION The aim of the study was to assess the safety and efficacy of darunavir (Prezista(®)) used in subtype F human immunodeficiency virus - type 1 (HIV-1) infected, antiretroviral therapy (ART)-experienced patients in Romania in routine clinical practice. METHODS This was a post-authorization, open-label, one-cohort, non-interventional, prospective study conducted at multiple sites in Romania to assess efficacy (CD4 cell count, viral load, and treatment compliance) and safety ([serious] adverse events, clinical laboratory evaluation, and vital signs) of darunavir in combination with low-dose ritonavir (DRV/r) and other antiretroviral (ARV) medications in subtype F HIV-1 infected subjects in naturalistic settings. Seventy-eight subjects were recruited by 9 investigational sites and received 600/100 mg DRV/r twice daily. RESULTS Treatment with DRV/r administered with other ARV medications resulted in the expected, statistically relevant improvement of CD4 cell count and viral load in subjects eligible for such treatment. In addition, adherence to treatment was high and the treatment-emergent safety profile observed during this study was consistent with the established safety profile of darunavir. CONCLUSION DRV/r administered in combination with other ARV medications in subtype F HIV-1 infected subjects in naturalistic settings proved to be an effective and safe treatment in Romania. TRIAL REGISTRATION NCT01253967.

Impaired production of adipocytokines is a major factor incriminated in the occurrence of lipodystrophy (LD).To evaluate LD prevalence and subtypes in HIV treatment-multiexperienced patients, and to determine the correlations between adipocytokines and LD subtypes.Cross-sectional study in a Romanian tertiary care hospital, between 2008 and 2010, in HIV-positive patients, undergoing cART for ≥6 months. LD diagnosis, based on clinical and anthropometric data, was classified into lipoatrophy (LA), lipohypertrophy (LH) and mixed fat redistribution (MFR). Blood samples were collected for leptin, adiponectin and resistin assessments.We included 100 patients, 44 % with LD, among which LA had 63 %. LA patients had sex ratio, median age, treatment duration and median number of ARV regimens of 1, 20, 93 and 3.5 compared to non-LD patients: 1.65, 31, 44 and 1. LH and MFR patients were older and had higher total and LDL cholesterol versus non-LD patients. For both overall group and female group, LA was associated in univariate and multivariate analysis with increased resistin (p = 0.02 and 0.04) and number of ARV regimens (p0.001). Determination coefficient (Nagelkerke R (2)) of increased resistin and the number of ARV combinations in the presence of LA was 33 % in overall group and 47 % in female patients.In our young HIV-positive population, LD had high prevalence with predominance of LA subtype. LA was associated with high resistin levels and greater number of ARV regimens in overall group and female subgroup. Resistin could be used as a marker of peripheral adipose tissue loss and might be used as a target for new anti-LD therapeutic strategies.

Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1)., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA

Case report A 35 year-old male patient presented to our clinic in May 2014 for progressive malaise, low-grade fever and nausea. His medical history revealed chronic glomerulonephritis and renal failure with hemodialysis from 2005 to 2010; kidney transplant in 2010, with transplant rejection and positive CMV-IgM in March 2014. He also presented arterial hypertension, ischemic heart disease and left ventricular hypertrophy since 2010, multiple episodes of sepsis and pneumonia with Klebsiella spp. through digestive microbial translocation (colonic ulcerations), and a double aortocoronary bypass in March 2014. The thoracotomy incision had healed almost completely, but the right calf incision presented signs of infection. His concomitant therapy included anti-hypertensive agents, antiplatelet therapy, ganciclovir, immune-suppression therapy with mycophenolic acid, and prednisone (10 mg/day). On admission, the clinical exam was normal, except for bilateral lower limb edema and inflammation of the right calf incision area, with multiple patches of exposed soft tissue and suppuration. Biologically, he presented pancytopenia (WBC 2,100 cells/μL, hemoglobin 6.8 g/dL, thrombocytes 137,000 cells/μL), nitrogen retention syndrome (urea 147.4 mg/dL, creatinine 4.4 mg/dL). The patient’s reactivity was quite low given the concomitant immune-suppressive treatment, with ESR 38 mm/1h, fibrinogen 351 mg/dL, and CRP 10 mg/L. Urine cultures, repeated blood cultures and procalcitonin were negative, but the smear from the right calf incision wound identified inflammatory cells and Gramnegative coccobacilli, and CLED cultures grew smooth, yellow, lactose-fermenting colonies. Microscan (Siemens, Munich, Germany) identified carbapenemase-producing Klebsiella pneumoniae (KPC) and the strain was subcultured and grew a smooth, grey, non-lactose-fermenting colony, identified on VITEK (bioMerieux, Paris, France) as Acinetobacter baumannii. Both strains were resistant to all tested drugs except for colistin and tigecycline. As both strains initially grew in a single isolated culture, with homogenous morphology, it took repeated cultures to separate the two strains. The patient’s evolution was favorable under treatment with tigecycline and local instillations of colistin.

Results We assessed 21 patients with chronic HCV infection, with a male-to-female ratio of 0.6:1. The mean age was 51.4 ± 11.9 years. The mean duration of HCV infection was 5.2 ± 5.5 years (range: 0-20 years). The predominant HCV genotype was 1b (in 16 patients – data not available for 5 patients), and the predominant IL28-B genotype was CT (9 patients), followed by TT (7 patients) and CC (3 patients) – IL28-B data were not available for 2 patients. Most (17, 81.0%) of the patients had received prior anti-HCV therapy with peg-interferon+ribavirin (PR) or direct-acting antivirals (DAA)-based treatment, and 13 of them displayed SVR (12 with DAA-based therapy and one with PR – the patient had an IL28-B genotype CC), while 4 displayed non-response to PR (IL28-B genotypes CT and TT). Eight of the patients (38.1%) had a previously diagnosed thyroid dysfunction, and 4 of them (19.0%) were under thyroid substitution treatment at the time of evaluation. Five of the patients (23.8%) presented thyroid nodules on ultrasound examination. The mean liver SWE was 9.6 ± 4.2 kPa and the mean thyroid SWE was 25.1 ± 10.4 kPa overall, and 26.2 ± 11.3 kPa for the left thyroid lobe and 24.7 ± 13.0 kPa for the right thyroid lobe.

Infectious diseases represent an ever-changing field of practice. Virtually each week brings new information, some with the potential to adjust or reinvent the current clinical practice. It is our task as clinicians to browse through field literature, through reports of randomized controlled trials, excerpts of conference proceedings, and to choose relevant scoops with high applicability in patient management. This supplement brings together four articles relevant to four different areas of medical practice, from HIV infection to Gram-negative bacilli such as Acinetobacter baumannii and Pseudomonas aeruginosa, and interdisciplinary studies on infectious acute maxillary sinusitis. Non-infectious comorbidities are of utmost importance in the management of HIV infection, as occurrence of kidney impairment, or fractures following decrease in bone mineral density, can significantly impact the quality of life and/or even life expectancy. The study presented at the 11th Edition of the Scientific Days of the National Institute for Infectious Diseases “Prof. Dr. Matei Balș” describes the epidemiology of chronic kidney disease and bone demineralization in HIV-positive patients from the Romanian HIV cohort, patients who acquired HIV infection at an early age, in infancy and childhood, in the late ‘80s, and who have since have tried all available therapeutic options. The prevalence of chronic kidney diseases is reported at 29.6 % for stage 2 and 1.4 % for stage 3 chronic kidney disease. The prevalence of lumbar osteopenia and osteoporosis was 33.3 % and 13.7 %, respectively, and that of femoral osteopenia and osteoporosis was 37.3 % and 7.8 %, respectively. An in-depth study of the virulence factors expressed by Pseudomonas aeruginosa revealed that virulence genes are highly prevalent in strains isolated from patients treated in a Dermatology department in Bucharest, Romania, namely ExoT (100 %), AlgD (92.3 %), genes codifying for phospholipases (84.6 % each) and genes coding for protease IV (61.5 %). A study performed by oromaxillofacial and dentoalveolar surgeons revealed an incidence of 4.3 % acute maxillary sinusitis in patients undergoing sinus lift procedures, and identified certain grafting materials which may be correlated with higher incidences. This study can pave the way for new therapeutic guidelines for the interdisciplinary management of acute sinusitis, which is currently treated by dental surgeons, ear-nose-throat practitioners, and infectious diseases specialists, alike. The last study included in the volume evaluated the patterns of antimicrobial susceptibility of Acinetobacter baumannii strains isolated from patients in intensive care, and reported a worrisome prevalence of carbapenem resistance: 94.6 % to imipenem and 86.5 % to meropenem. The authors conclude that there is dire need for new therapeutic options, as carbapenems are considered last-resort antibiotics, and the only antimicrobial to which Acinetobacter strains still displayed satisfactory susceptibility was colistin, with resistance reported in 9/37 strains (24.3 %) in this study.

INTRODUCTION Several studies have reported that cytokines secreted by adipose tissue (adipokines) may be linked to HIV replication. The aim of the study was to evaluate the relationship between HIV replication and serum levels of adipokines, in a Caucasian HIV-infected population of men and women undergoing complex antiretroviral therapy. METHODS A cross-sectional study was conducted in an unselected sample of 77 HIV-1-positive patients. Serum adipokines levels were measured including circulating adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Patients were divided into two groups: Group 1 - with undetectable viral load and Group 2 - with persistent HIV viral replication. Differences between groups ? were tested using independent-sample t-test for Gaussian variables and Mann-Whitney-Wilcoxon test for non-parametric variables. Pearson's chi-squared test was used for correlation analysis. RESULTS A total of 77 patients (age range: 17-65, mean: 32.5 years) including 44 men (57.1% men, age range: 17-63 years, mean: 34.1 years) and 33 women (42.9% women age range: 19-65 years, mean: 30.3 years) were included in the study. TNF-alpha had significantly higher serum levels in patients with detectable viral load (16.89 vs. 9.35 pg/mL), (p=0.043), but correlation analysis lacked statistical significance. Adiponectin had median serum levels of 9.22 ig/mL in Group 1 vs. 16.50 ig/mL in Group 2 but the results lacked statistical significance (p=0.059). Higher leptin, IL-6 and resistin serum levels were noted in patients with undetectable HIV viral load, without statistical significance. CONCLUSIONS The present study reported higher TNF-alpha serum levels in patients with persistent HIV viral load. We found no statistically significant correlations between adiponectin, leptin, resistin and IL-6 and HIV viral load in our Caucasian HIV-positive study population, undergoing antiretroviral therapy.

Background The noninvasive assessment of liver fibrosis in chronic hepatitis C patients is very important as it dictates the disease prognosis and the indication for therapy, narrowing down the use of the liver biopsy. Standardized scores (FibroTest, FibroMax) and imaging techniques (FibroScan) have been validated in this respect. As for the noninvasive prediction of the sustained viral response (SVR), GenoFibroTest and Prometheus are two indexes that may be used. This study’s aim is to compare several biological scores with these standardized scores for evaluating fibrosis and the two indexes for prediction of SVR.

Portal interstitial cells of Cajal (PICCs), acting as vascular pacemakers, were previously only identified in nonhumans. Moreover, there is no evidence available about the presence of such cells within the liver. The objective of the study is to evaluate whether or not PICCs are identifiable in humans and, if they are, whether or not they are following the scaffold of portal vein (PV) branches within the liver. We obtained extrahepatic PVs and liver samples from six adult human cadavers, negative for liver disease, in accordance with ethical rules. They were stained with hematoxylin-eosin (HE) and Giemsa, and then we performed immunohistochemistry on formalin-fixed paraffin-embedded specimens for CD117/c-kit, a marker of the Cajal's cells. Immune labeling was also performed for S-100 protein, desmin, glial fibrillary acidic protein (GFAP), neurofilaments, α-smooth muscle actin (α-SMA), and CD34. c-kit-Positive PICCs were identified within the extrahepatic PV, in portal spaces, and septa. On adjacent sections, these PICCs were negative for all the other antibodies used. In conclusion, our study confirms the presence of extrahepatic PICCs on humans, which may act as a possible intrinsic pacemaker in the human PV. However, the intrahepatic PICCs, which were evidenced here for the first time, are in need for further experimental studies to evaluate their functional role. A promising further direction of the study is the PICCs role in the idiopathic portal hypertension.

Treatment-related toxicities frequently limit antiretroviral therapy for patients with HIV-1 infection. This study evaluated the changes in treatment-limiting toxicities when the primary toxicity-causing agent was replaced with enfuvirtide.Adult patients with HIV-1 infection (N = 91) with antiretroviral treatment-limiting toxicities were enrolled in this multicenter, open-label, single-arm, 24-week study. Enfuvirtide 90 mg bid was administered instead of a single toxicity-causing component of the previous antiretroviral regimen. Changes in severity of antiretroviral toxicity, safety, tolerability, and maintenance of efficacy of the enfuvirtide regimen were evaluated at baseline and at 4, 8, 12, and 24 weeks.Eighty-four percent of participants completed the study. Injection site reactions with enfuvirtide caused premature withdrawal in 5 participants (5%); a further 10 participants (11%) also withdrew early. Overall antiretroviral-related, treatment-limiting toxicities improved or resolved in 53% of participants switching to enfuvirtide, remained unchanged in 43%, and worsened in 3%. At Week 24, 66% of participants (60/91; intent-to-treat population) maintained or improved their viral load category and 73% of participants (66/91) maintained or improved their CD4 cell counts.Replacing a toxicity-causing antiretroviral with enfuvirtide may reduce toxicity without compromising the efficacy of different antiretroviral regimens.