Hans Reinhard Brodt

HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy.

Summary: Postmortem neuropathologic reports for a consecutive series of 436 HIVseropositive patients who died between 1985 and 1999 were matched with clinical data for 371 of them. Cases were divided into four groups depending on the date of death. The chosen time periods reflected the type of antiretroviral therapy available: before 1987 (before zidovudine); 1987‐1992, the period of monotherapy (nucleoside analog reverse transcriptase inhibitors [NRTIs]); 1993‐1995, the era of the use of dual NRTI combinations; and 1996‐1999, the era of highly active antiretroviral therapy (HAART) containing protease inhibitors. Fifty‐seven percent of our cases in this group had been prescribed HAART. In our study population, accessibility to the latest antiretroviral therapy was widespread. The total number of HIV autopsies declined after the advent of combination therapy. The prevalence of opportunistic infections—cytomegalovirus, toxoplasmosis, cryptococcosis, and central nervous system lymphoma—decreased over time. Cerebral tuberculosis, aspergillosis, herpes, and progressive multifocal leukoencephalopathy showed a downward trend, but the numbers were too low for statistical analyses. The incidence of HIV encephalopathy increased over time (p = .014). The rising prevalence of HIV encephalopathy at time of death may reflect a longer survival time after initial HIV infection in the HAART era. Although combination therapies decrease overall mortality and prevalence of CNS opportunistic infections, these therapies may be less active in preventing direct HIV‐1 effects on the brain.

Immune Response after Two Doses of the Novel Split Virion, Adjuvanted Pandemic H1N1 Influenza A Vaccine in HIV-1–Infected Patients

BACKGROUND To determine the rate of seroconversion after 2 doses of a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in human immunodeficiency virus type 1 (HIV-1)-infected patients (ClinicalTrials.gov NCT01017172). METHODS Diagnostic study of adult HIV-1-infected patients scheduled for H1N1 influenza A vaccination. Blood samples where taken before and 21 days after the first dose and 21 days after the second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer ≤ 1:10 before and ≥ 1:40 after or ≥ 1:10 before and a ≥ 4-fold increase in AB titer 21 days after vaccination. RESULTS One hundred thirty-five patients received 2 doses of the H1N1 vaccine and were analyzed. The rate of seroconversion was 68.2% (95% confidence interval, 59.6-75.9) after the first dose and 91.9% (95% confidence interval, 85.9-95.9) after the second dose. Patients who did not seroconvert had a lower mean nadir CD4 cell count (± standard deviation; 81 ± 99 vs 190 ± 148 cells/μL; P = .006), had a longer duration of HIV infection (± standard deviation; 13.1 ± 5.9 vs 8.8 ± 6.8 years; P = .04), and were more likely to have an AB titer ≥ 1:40 before vaccination (4% vs 55%; P < .001) when compared with patients with seroconversion. No other differences were found between the 2 groups, including AIDS status, highly active antiretroviral therapy status, HIV RNA - polymerase chain reaction load <50 copies/mL, CD4 cell count, sex, body mass index, and chronic hepatitis. CONCLUSION Among HIV-infected patients, the rate of seroconversion after the first dose of an adjuvanted H1N1 influenza A vaccine was 68% and increased to 92% after a second doses.

Low rate of seroconversion after vaccination with a split virion, adjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected patients.

Objective:To determine rates of seroconversion after single vaccination with a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HIV-1-infected patients (ClinicalTrials.gov Identifier: NCT01017172). Design:Single center diagnostic study. Setting:Institutional HIV outpatient department of an urban university clinic. Participants:Adult HIV-1-infected individuals. Intervention:Serum samples were taken before and 21 days after vaccination. Main outcome measures:Antibody titers determined by hemagglutination inhibition assay. Seroconversion to vaccination was defined by either an antibody titer of 1: 10 or less before and of at least 1: 40 after or at least 1: 10 before and at least four-fold increase in antibody titer 21 days after single vaccination. Results:One hundred and sixty patients (125 men/35 women) were analyzed. Before vaccination, 23 patients (14.4%) had a hemagglutination inhibition assay titer of at least 1: 40. A median of 22 ± 3 days after vaccination, 110 (69%) patients seroconverted. Seroconverters were younger (45.1 ± 10.0 vs. 48.8 ± 11.3 years; P = 0.04), had a higher CD4 cell count (532 ± 227 vs. 475 ± 281 cells/μl; P = 0.03) and were more likely to have received a previous H5N1 vaccination in 2009 (25 vs. 8%; P = 0.02) when compared to nonresponders. No other significant differences were found comparing the two groups (prevaccination hemagglutination inhibition assay titer of ≥1: 40, AIDS, HAART, HIV RNA PCR <50 copies/ml or CD4 nadir, CD4 and CD8 percentage, sex, BMI, chronic hepatitis B or C). Conclusion:Seroconversion after one dose of a split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine of HIV-infected patients was 69%. Studies to investigate whether a second dose of the vaccine will increase seroconversion rate are needed.

Strategies to enhance rational use of antibiotics in hospital : a guideline by the German society for infectious diseases

IntroductionIn the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute.Materials and methodsA structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development.ConclusionThe guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.

Infection control management of patients with suspected highly infectious diseases in emergency departments: data from a survey in 41 facilities in 14 European countries

BackgroundIn Emergency and Medical Admission Departments (EDs and MADs), prompt recognition and appropriate infection control management of patients with Highly Infectious Diseases (HIDs, e.g. Viral Hemorrhagic Fevers and SARS) are fundamental for avoiding nosocomial outbreaks.MethodsThe EuroNHID (European Network for Highly Infectious Diseases) project collected data from 41 EDs and MADs in 14 European countries, located in the same facility as a national/regional referral centre for HIDs, using specifically developed checklists, during on-site visits from February to November 2009.ResultsIsolation rooms were available in 34 facilities (82,9%): these rooms had anteroom in 19, dedicated entrance in 15, negative pressure in 17, and HEPA filtration of exhausting air in 12. Only 6 centres (14,6%) had isolation rooms with all characteristics. Personnel trained for the recognition of HIDs was available in 24 facilities; management protocols for HIDs were available in 35.ConclusionsPreparedness level for the safe and appropriate management of HIDs is partially adequate in the surveyed EDs and MADs.

Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir

OBJECTIVES The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohns disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Immune Response after a Single Dose of the 2010/11 Trivalent, Seasonal Influenza Vaccine in HIV-1–Infected Patients and Healthy Controls

Abstract Background: Immune response rates following influenza vaccination are often lower in HIV-infected individuals. Low vitamin D levels were correlated with weak immune response in cancer patients and are known to be lower in HIV-infected patients. Methods: Diagnostic study to determine immune response against the H1N1v component after a single, intramuscular dose of the 2010/11 seasonal, trivalent influenza vaccine (TIV) in adult HIV-infected and healthy controls scheduled for influenza vaccination (ClinicalTrials.gov Identifier: NCT01017172). Influenza A/H1N1 antibody titers (AB) were determined before and 21 days after vaccination by hemagglutination inhibition assay. Results: Immune response was not different between HIV-infected patients (n = 36) and healthy controls (n = 42) who were previously naïve to the H1N1v component of the TIV. Comparing HIV-infected patients (n = 55) and healthy controls (n = 63) who had received 1 or 2 doses of an AS03 adjuvanted H1N1 vaccine in the previous winter season (2009/10), seroconversion rate and the geometric mean AB titer after TIV of the HIV-infected patients were more than twice as high compared to healthy controls. This difference was mainly driven by the 2-dose schedule for HIV patients in 2009/10. Vitamin D levels were lower in HIV patients but did not correlate with immune response. Conclusion: HIV-infected patients who had received 1 or 2 doses of an adjuvanted H1N1 vaccine in the previous year (2009/10) had a significant higher seroconversion rate following TIV as compared to healthy controls, indicating a stronger memory cell response due to the 2-dose schedule.

Antiretrovirale Therapie der HIV-Infektion

on durch eine antiretrovirale Therapie verhindert die Krankheitsprogression, führt zur Rückbildung HIV-bedingter Symptome und zu einer klinisch relevanten Immunrekonstitution (2, 8, 15, 19). Die zentrale pathogenetische Hypothese, die besagt, dass die fortgesetzte Virusreplikation die Progression der HIV-Infektion bestimmt, hat sich bestätigt (13). Gerade die bessere Wirksamkeit der heute verfügbaren antiretroviralen Kombinationstherapien hat jedoch die Diskussion über den idealen Zeitpunkt des Beginns einer Therapie bei einer HIV-Infektion erneut angefacht. Die Zeitspanne einer einmal begonnenen Therapie hat sich wegen der guten Wirksamkeit und der immer unwahrscheinlicher erscheinenden Möglichkeit einer Eradikation des Virus deutlich verlängert. Für eine späte Therapieeinleitung könnte sprechen, dass die Therapie heute mit komplizierten und fehleranfälligen Einnahmevorschriften verbunden ist und Fehler bei der Einnahme zu einer Unwirksamkeit späterer Therapien führen könnten. Darüber hinaus kann die tägliche Medikamenteneinnahme zu einer deutlichen körperlichen und psychischen Belastung werden, insbesondere wenn sie bei asymptomatischen Patienten zu einem stärkeren Krankheitsgefühl und einer deutlichen Minderung der Lebensqualität führt. Die Langzeitnebenwirkungen der Therapie sind ebenfalls zu berücksichtigen. Außerdem ist eine klinische Besserung und Immunrekonstitution noch bei Therapiebeginn in einem weit fortgeschrittenen Stadium der HIV-Erkrankung beobachtet worden. Für einen frühen Therapiebeginn spricht, dass Aids eine schleichend beginnende Infektionskrankheit ist, und eine antiinfektiöse Therapie generell so früh wie möglich einzuleiten ist. Zudem könnten bei lange anhaltender Replikation des HIV ein „point of no return” des Immundefekts überschritten werden oder auch durch Spontanmutationen Viren mit höherer Pathogenität entstehen. Einigkeit besteht über das Ziel, die Progression einer asymptomatischen HIV-Infektion so lange wie möglich zu verhindern sowie darüber, eine Therapie zu beginnen, bevor irreversible Schäden des Immunsystems eingetreten sind. Mit abnehmender Gewichtung beruhen die hier gegebenen Empfehlungen auf der Beurteilung von randomisierten kontrollierten Studien mit klinischen Endpunkten (I), randomisierten kontrollierten Studien mit Labormarkern als Endpunkten (II) und der Auswertung von weiteren klinischen pathophysiologischen und pharmakologischen Daten durch ein Expertengremium (III) (Tabelle 1). Bei den verbleibenden Unsicherheiten, insbesondere über den besten Zeitpunkt des Therapiebeginns, ist auch ein breiter Konsens mit einem möglichen Irrtum behaftet. Diese Empfehlungen wurden von einem deutsch-österreichischen Expertengremium beraten und verabschiedet. M E D I Z I N

Impact of Stereotactic Biopsy in HIV Patients

OBJECTIVE During their disease a significant number of human immunodeficiency virus (HIV)-infected patients develop neurologic symptoms due to intracerebral pathologies. Entities commonly found are toxoplasmosis, lymphomas, or progressive multifocal leukoencephalopathy. In some patients, diagnosis is not feasible with imaging alone, requiring biopsy. The objective of this study was to evaluate the impact of stereotactic biopsy in HIV patients on adjustment of therapy. METHODS Between January 2004 and May 2015 at our clinic, 26 HIV-infected patients underwent stereotactic biopsy. Thin-layer magnetic resonance images were obtained and fused with computed tomography scans, taken with the stereotactic frame (Leksell) mounted. Biopsy material was evaluated pathologically and microbiologically. RESULTS Histologic analysis revealed B-cell lymphoma in 6 patients (23.1%) and progressive multifocal leukoencephalopathy in 2 patients (7.7%). Abscess and toxoplasmosis were found in 3 patients each (11.5% and 11.5%), and encephalitis occurred in 4 patients (15.4%). In 2 patients each (7.7%), vasculitis, metastasis, and glioblastoma were diagnosed. Further findings comprised non-Hodgkin lymphoma and Burkitt lymphoma in 1 patient each. After biopsy, treatment was significantly changed in 18 (69.2%) patients (P < 0.01). Antibiotic therapy was adjusted in 6 patients (23.1%), and chemotherapy in 3 patients (16.7%). Other changes included antibiotic/antiviral therapy to chemotherapy in 3 patients (16.7%), chemotherapy to radiation, cortisone to chemotherapy, and aciclovir to cortisone in 1 patient each. One patient with glioblastoma underwent resection, and another patient received radiation. One patient underwent palliative care. CONCLUSION Stereotactic biopsy in HIV-infected patients results in significant changes of therapy in more than two thirds of the patients.

Durability of protective antibody titres is not enhanced by a two-dose schedule of an ASO3-adjuvanted pandemic H1N1 influenza vaccine in adult HIV-1-infected patients

Abstract The immune response after influenza vaccination is impaired in HIV-infected individuals and can be enhanced by a second dose. The durability of the antibody protection and its clinical benefit is not known. We investigated clinical symptoms and antibody titres against H1N1 influenza A following no dose, 1 dose, or 2 doses of an ASO3-adjuvanted H1N1 vaccine in HIV-infected patients. Seroprotection was found in 7.9%, 52.2%, and 57.3% of patients who received no dose, 1 dose, and 2 doses of the vaccine, respectively (p-value for group comparison < 0.001), after a median of 8.2 ± 1.6 months. Clinical symptoms suggestive of an influenza-like illness were slightly more frequently reported in the unvaccinated group. Vaccinated HIV-infected patients were more likely to be seroprotected at follow-up, but there was no difference comparing those who had received 1 or 2 doses of the vaccine.