Cornelia Feiterna-Sperling

Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants.

Objective:A prospective observational study to investigate hematologic alterations during the first 3 months of life in HIV-exposed uninfected infants subjected to antiretroviral medication before and after birth. Methods:Two hundred twenty-one consecutive uninfected infants born to HIV-positive mothers on antiretroviral medication during pregnancy were included. Perinatal transmission prophylaxis comprised zidovudine (ZDV) administered intravenously intrapartum and 10 days after birth. Blood counts and differentials were determined at birth and at 2, 4, 6, and 12 weeks of age, and hematologic toxicity was graded according to pediatric toxicity scales. Data were analyzed according to the kind of prenatal medication (ZDV alone or with another nucleoside reverse transcriptase inhibitor [NRTI] vs. highly active antiretroviral therapy [HAART]). Results:Median hemoglobin was significantly lower in HAART-exposed newborns from birth (P = 0.004) until day 28. During follow-up, 119 (53.8%) infants had anemia grade 2 or higher on at least 1 occasion; 16 (7.2%) received red blood cell transfusion at 23 (range: 1-56) days of age. Neutropenia grade 2 or higher occurred in 106 (48.0%) infants at least once; 8 infants had staphylococcal infections, and 2 infections were severe. After adjustment for possible confounders (prematurity, birth weight, ethnicity, gender, duration of maternal antiretroviral therapy, maternal Centers for Disease Control and Prevention stage, and maternal illicit drug use), HAART exposure was the only independent risk factor for anemia (odds ratio [OR] = 2.22, 95% confidence interval [CI]: 1.06 to 4.64; P = 0.034) and neutropenia (OR = 2.15, CI: 1.02 to 4.55; P = 0.045). Conclusions:Antiretroviral transmission prophylaxis is associated with significant anemia and neutropenia in HIV-uninfected infants during the first 3 months of life. Anemia was more profound in HAART-exposed infants.

An effective and safe protocol involving zidovudine and caesarean section to reduce vertical transmission of HIV-1 infection

ObjectiveTo investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. InterventionsElective caesarean section before labour, usually at 36–38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen). ResultsOf 179 mother–infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0–4.7] and 12.6% (6.4–19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6–8 weeks. ConclusionA much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.

S2k-Leitlinie: Tuberkulose im Erwachsenenalter

Since 2015 a significant increase in tuberculosis cases is notified in Germany, mostly due to rising numbers of migrants connected to the recent refugee crisis. Because of the low incidence in previous years, knowledge on tuberculosis is more and more limited to specialized centers. However, lung specialist and healthcare workers of other fields have contact to an increasing number of tuberculosis patients. In this situation, guidance for the management of standard therapy and especially for uncommon situations will be essential. This new guideline on tuberculosis in adults gives recommendations on diagnosis, treatment, prevention and prophylaxis. It provides a comprehensive overview over the current knowledge, adapted to the specific situation in Germany. The German Central Committee against Tuberculosis (DZK e. V.) realized this guideline on behalf of the German Respiratory Society (DGP). A specific guideline for tuberculosis in the pediatrics field will be published separately. Compared to the former recommendations of the year 2012, microbiological diagnostics and therapeutic drug management were given own sections. Chapters about the treatment of drug-resistant tuberculosis, tuberculosis in people living with HIV and pharmacological management were extended. This revised guideline aims to be a useful tool for practitioners and other health care providers to deal with the recent challenges of tuberculosis treatment in Germany.

Pandemic Influenza A (H1N1) Outbreak among 15 School-Aged HIV-1-Infected Children

Patients infected with human immunodeficiency virus type 1 (HIV-1) are considered to be at increased risk for 2009 H1N1 influenza-related complications. We performed an observational study after an outbreak of 2009 H1N1 influenza virus infection among a group of 15 HIV-1-infected school-aged children in Germany in October 2009. Clinical course, kinetics of viral shedding, and antibody response among children with CD4 cell counts >350 cells/μL and 2009 H1N1 influenza virus coinfection did not appear to differ from that among healthy children. Oseltamivir shortened the duration of viral shedding.

Granulysin-Expressing CD4 + T Cells as Candidate Immune Marker for Tuberculosis during Childhood and Adolescence

Background Granulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB. Methods Peripheral blood mononuclear cells (PBMC) from children and adolescents (1–17 years) with active TB, latent TB infection (LTBI), nontuberculous mycobacteria (NTM) infection and from uninfected controls were isolated and restimulated in a 7-day restimulation assay. Intracellular staining was then performed to analyze antigen-specific induction of activation markers and cytotoxic proteins, notably, granulysin in CD4+ CD45RO+ memory T cells. Results CD4+ CD45RO+ T cells co-expressing granulysin with specificity for Mycobacterium tuberculosis (Mtb) were present in high frequency in TB-experienced children and adolescents. Proliferating memory T cells (CFSElowCD4+CD45RO+) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype. PBMC from study participants after TB drug therapy revealed that granulysin-expressing CD4+ T cells are long-lived, and express several activation and cytotoxicity markers with a proportion of cells being interferon-gamma-positive. In addition, granulysin-expressing T cell lines showed cytolytic activity against Mtb-infected target cells. Conclusions Our data suggest granulysin expression by CD4+ memory T cells as candidate immune marker for TB infection, notably, in childhood and adolescence.

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents

Objectives:To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents. Design:Phase I, nonrandomized, open-label study in two stages. Methods:Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen. Results:Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration–time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses. Conclusion:Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Resolution of human immunodeficiency virus type 1 infection-related severe pulmonary hypertension in a very low-birth-weight infant.

Pulmonary arterial hypertension (PAH) affects approximately 0.5% of human immunodeficiency virus (HIV)-infected adults with poor prognosis. The effectiveness of highly active antiretroviral therapy for treatment of HIV-related PAH (HIV-PAH) remains controversial. Little is known about the incidence, clinical course, and therapy options for PAH in HIV-1-infected pediatric patients. Here, we report the case of a preterm infant with HIV-related life-threatening PAH, which resolved after initiation of highly active antiretroviral therapy.

Steady-state Pharmacokinetics of Nevirapine Extended-release Tablets in Hiv-1–infected Children and Adolescents: An Open-label, Multiple-dose, Cross-over Study

Background: To compare steady-state (ss) pharmacokinetic targets of nevirapine extended-release (NVP-XR) tablets once-daily (QD) with immediate-release (NVP-IR) tablet or oral suspension twice-daily in HIV-1–infected children and adolescents. Methods: Phase I, open-label, multidose, cross-over study with optional extension phase, in 85 patients 3 to <18 years of age, previously on an NVP-IR–based regimen for ≥18 weeks with baseline viral load <50 copies/mL. Patients were stratified by age, treated with NVP-IR twice-daily for 11 days, then NVP-XR QD for 10 days. Cpre,ss (steady-state, predose concentrations) was obtained from all, and 12-hour NVP-IR and 24-hour NVP-XR steady-state pharmacokinetic profiles were obtained in the pharmacokinetic substudy. Viral loads, CD4 counts and adverse events (AEs) were monitored. Results: Eighty patients completed the trial. Adjusted geometric mean (gMean) Cpre,ss for NVP-XR and NVP-IR exceeded the target of 3000 ng/mL, and the adjusted gMean NVP-XR:NVP-IR ratio (90% confidence interval) for QD normalized and un-normalized Cpre,ss were 91.2% (83.5–99.6%) and 91.8% (83.7–100.7%). gMean 24-hour area under the curve at steady-state NVP-XR:NVP-IR for un-normalized dose was 90.4% and un-normalized Cpre,ss NVP-XR:NVP-IR were 91.0%, 81.9% and 103.7% for the 3 age groups, 3 to <6, 6 to <12 and 12 to <18 years, respectively. gMean values indicated no exposure to subtherapeutic NVP concentrations and viral suppression was adequate and maintained in all QD groups. Most AEs were mild and similar between age groups. No serious or Division of AIDS Grade 4 AEs or AE related treatment discontinuations occurred. Conclusions: NVP-XR exhibited adequate trough concentrations with equivalent area under the curve at steady-state relative to NVP-IR. NVP-XR was well-tolerated and is a valuable treatment option for HIV-infected children and adolescents.

S2k-Leitlinie zur Diagnostik, Prävention und Therapie der Tuberkulose im Kindes- und Jugendalter. Eine Leitlinie unter Federführung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI) e. V.

Recently, epidemiological data shows an increase of childhood tuberculosis in Germany. In addition to this, drug resistant tuberculosis becomes more frequent. Therefore, diagnosis, prevention and therapy in childhood and adolescence remain a challenge. Adult guidelines do not work for children, as there are age specific differences in manifestation, risk of progression and diagnostic as well as therapeutic pathways.The German Society for Pediatric Infectious Diseases (DGPI) has initiated a consensus-based (S2k) process and completed a paediatric guideline in order to improve and standardize care for children and adolescents with tuberculosis exposure, infection or disease.Updated dosage recommendations take age dependant pharmacokinetics in the treatment of drug sensitive but also drug resistant tuberculosis in account. In addition to this, there is a detailed chapter on perinatal exposure and disease as well as extrapulmonary manifestations.

Nevirapine Extended-Release Formulation Tablets in HIV-1–Infected Children—Long-term Follow-up

In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to <18 years) received ≥48 weeks of treatment with extended-release nevirapine. By last visit, all patients had undetectable viral loads and no new safety signals, demonstrating the safety and efficacy of a once-daily antiretroviral regimen.