Nevirapine has an exceptional record for long-term tolerability with few side effects in human immunodeficiency virus (HIV) combined antiretroviral therapy (cART). Owing to relatively frequent ...hypersensitivity reactions (HSR) (15-25%) in the first 3 months after treatment initiation (especially in patients with a high CD4 count (>250/µl in women, >400/µl in men)), it is being used less and less. However, the rate of adverse events is lower when patients are already under suppressive cART. We present the results of a single centre strategy to offer the switch to a nevirapine-containing regimen and evaluate the potential role nevirapine could play in current antiretroviral treatment.
All adult HIV-positive patients starting nevirapine at our centre since 2010 were evaluated in this retrospective analysis. We examined the proportion of patients on cART containing nevirapine, as well as the number of starts and stops every 6 months. Nevirapine discontinuation rates were analysed by sex, age, hepatitis C virus (HCV) status, time on nevirapine, ethnicity, CD4 nadir as well as CD4 count, HIV-RNA and ART backbone at nevirapine start.
Since 2014, more than a third of our treated HIV patients have been on nevirapine-containing therapy, with a stable percentage in the following years; 277 patients starting nevirapine for the first time were analysed. Thirty-three percent (92/277) of these first nevirapine therapies were discontinued, with 16 cases (17%) resuming nevirapine later during follow-up. Of the patients who continued nevirapine for more than 90 days (n = 221), 80% maintained nevirapine until their last follow-up. The nevirapine stop rate after the first 90 days was 15-fold lower (5.4 per 100 patient years, 95% confidence interval CI 4.0-7.2) than in the first 90 days. Overall, nevirapine was used for a median of 2.9 years (interquartile range IQR 0.5-5.6). In HCV co-infected patients, the treatment stop rate was 4-fold higher than in HIV mono-infected patients, but this difference was mainly due to treatment interruptions caused by drug-drug interactions with intermittent HCV therapy. Six out of seven Asian patients experienced HSR (hepatotoxicity / skin rash). In a population with 74% 3TC/ABC backbone, 81% fully suppressed, median CD4 nadir 240/µl (IQR 120-360) and median CD4 count at nevirapine start 590/µl (IQR 400-840), both high CD4 nadir and high CD4 count at nevirapine start were associated with lower rather than higher discontinuation rates. In fully suppressed patients with high CD4 count at nevirapine start, high CD4 nadir was not a risk factor for HSR. Major reasons for the discontinuation of nevirapine were HSR (liver, skin rash) in 38 cases (41% of all discontinuations) followed by other adverse drug reactions (n = 17) and non-adherence (n = 14). In patients who stopped nevirapine after more than 90 days, the major cause was non-adherence or other adverse drug reaction (both n = 12).
In this study, two thirds of the patients continued nevirapine with favourable long-term tolerability and efficacy. Thus, this low-cost "old drug" may still represent a valid treatment switch option for maintenance therapy in selected patients with a fully suppressed viral load. However, further evaluation is needed.  .
Data on antimicrobial resistance mechanisms are scanty for Cedecea spp., with very variable antibiotic resistance patterns documented. Here we report the first in vivo resistance evolution of a C. ...davisae clinical isolate in a patient with a complex hand trauma and provide insight in the resistance mechanism, leading to therapeutic implications for this pathogen.
Cedecea davisae was isolated from a patient with hand trauma during a first surgical debridement. Six days after primary surgical treatment and under antimicrobial treatment with amoxicillin-clavulanic acid and later cefepime, follow up cultures yielded C. davisae which demonstrated a resistance development. The susceptible parental isolate and its resistant derivative were characterized by whole genome sequencing, ampC, ompC and ompF by RT- PCR. The resistant derivative demonstrated an A224G SNP in ampD, the transcriptional regulator of ampC, leading to a His75Arg change in the corresponding AmpD protein. AmpC transcription of the resistant derivative was 362-times higher than the susceptible isolate. Transcription levels of ompF and ompC were 8.5-fold and 1.3-fold lower, respectively, in the resistant derivative. Downregulation of OmpF putatively resulted from a mutation in the presumed promoter region upstream of the dusB-Fis operon, a proposed regulator for ompF.
This case demonstrates the in vivo resistance development of C. davisae within 7 days similar to that of the members of the Enterobacter cloacae complex. Our findings add valuable information for future therapeutic management of these opportunistic pathogens as they warrant the same empirical treatment as AmpC producers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Changes in mental and sexual health among men having sex with men (MSM) due to the SARS-CoV-2 pandemic remain unclear.
METHODS: Design: Longitudinal analysis of an ongoing, multicentre, ...pre-exposure prophylaxis (PrEP) cohort (NCT03893188) in Switzerland. Participants: HIV-negative MSM aged ≥18 who completed at least one questionnaire before and one after the start of the SARS-CoV-2 pandemic. Outcomes: Primary: mental health, defined as anxiety and depression scores assessed by the Patient Health Questionnaire-4. Secondary: sexual behaviour, well-being, PrEP use and disruption of care. Outcomes were assessed over seven periods corresponding to different SARS-CoV-2 prevention measures in Switzerland. We performed pairwise comparisons between periods (Wilcoxon signed rank test).
RESULTS: Data from 1,043 participants were included. Whilst anxiety scores remained stable over time, depression scores worsened in the second wave and the second lockdown period compared to pre-pandemic scores. This was confirmed by pairwise comparisons (pre-SARS-CoV-2/second wave and pre-SARS-CoV-2/second lockdown: p <0.001). Downward trends in sexual activity,sexualized substance use, and a switch from daily to "event-driven" PrEP were found. Disruption of care affected 42.6% (790/1856) of daily PrEP users’ follow-up visits.
CONCLUSION: In this longitudinal analysis of a PrEP cohort enrolling MSM, depression scores worsened in the second wave and the second lockdown compared to the pre-pandemic period.
has clinical antiviral activity against respiratory viruses and modulates immune functions. In this study, we compared higher doses of new
formulations with conventional formulations at lower, ...preventive doses for therapy of respiratory tract infections (RTIs).
In this randomized, blinded, controlled trial, healthy adults (
= 409) were randomized between November 2018 and January 2019 to one of four
formulations, which were taken in case of an RTI for up to 10 days. New formulations A (lozenges) and B (spray) delivered an increased dose of 16,800 mg/d
extract during days 1-3 and 2,240-3,360 mg/d afterward; as controls, conventional formulations C (tablets) and D (drops) delivered a lower daily dose of 2,400 mg, usually taken for prevention. The primary endpoint was time to clinical remission of first RTI episodes based on the Kaplan-Meier analysis of patient-reported, investigator-confirmed, respiratory symptoms assessed for up to 10 days. In a sensitivity analysis, the mean time to remission beyond day 10 was calculated by extrapolating the treatment effects observed on days 7 to 10.
A total of 246 participants (median age 32 years, 78% female participants) were treated for at least one RTI. Recovery by day 10 (complete absence of symptoms) was achieved in 56 and 44% of patients with the new and conventional formulations, respectively, showing a median time to recovery of 10 and 11 days, respectively (
= 0.10 in intention-to-treat analysis,
= 0.07 in per-protocol analysis). In the extrapolated sensitivity analysis, new formulations resulted in a significantly shorter mean time to remission (9.6 vs. 11.0 days,
< 0.001). Among those with an identified respiratory virus, viral clearance until day 10 based on real-time PCR from nasopharyngeal swabs was more frequent with new formulations (70 vs. 53%,
= 0.046). Tolerability and safety (adverse events: 12 vs. 6%,
= 0.19) were good and similar between formulations. There was one severe adverse event with a potential hypersensitivity reaction in a recipient of the novel spray formulation.
In adults with acute RTI, new
formulations with higher doses resulted in faster viral clearance than conventional formulations in prophylactic dosages. The trend for faster clinical recovery was not significant by day 10 but became so upon extrapolation. A dose increase during acute respiratory symptoms might improve the clinical benefits of orally administered
formulations.
The study was registered in the Swiss National Clinical Trials Portal (SNCTP000003069) and on ClinicalTrials.gov (NTC03812900; URL https://clinicaltrials.gov/ct2/show/NCT03812900?cond=echinacea&draw=3&rank=14).
Older persons (≥65 years) are at risk for invasive group B streptococcal (GBS) infections. The most frequent clinical syndromes in 174 infection episodes were osteoarticular (40%) and skin and ...soft-tissue infections (30%). In 36% of episodes, a companion microorganism was isolated, and in 45%, blood culture results were positive. Antibiotics were streamlined after species identification in 29% of monomicrobial infections. These findings have clinical and therapeutic implications for GBS infections in the elderly.
•Osteoarticular infections and skin and soft-tissue infections (SSTI) are frequent clinical manifestations of invasive GBS disease in patients ≥65 years old.•In 47% of SSTI episodes, GBS grew in blood cultures.•In only 29% of monomicrobial GBS infection episodes, the antibiotic therapy streamlined to penicillin or amoxicillin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Complementary and alternative medicine (CAM) providers' roles in parents' decision-making about vaccinations for their children have only recently begun receiving research attention, despite studies ...showing CAM to be used by 25–50% of the population in Western countries. This article examines how CAM practitioners discuss vaccinations with parents in Switzerland, with a focus on childhood vaccinations and human papillomavirus (HPV) vaccinations. We describe how the CAM providers we interviewed (N = 17) and observed during vaccination consultations (N = 18 observations with 5 providers) employed individualized approaches to vaccination. Triangulation of qualitative evidence from interviews and observations allowed us to analyze their discourses and descriptions of experiences (i.e. what they said) and their practices in situ (i.e. what they did). Evidence gathered shows that practitioners framed vaccination decisions as choices at individual and family levels rather than focusing on public health benefits and consequences. They articulated their perspectives in terms of personal clinical experiences and parents' wishes, concerns, and contexts. Such findings challenge recurring narratives depicting CAM providers as categorically anti-vaccination and suggest that approaches to address vaccine hesitancy in clinical practice could benefit from communication and relational approaches similar to those demonstrated by participants in this study. Such approaches include taking time to understand parents’ wishes, involving them in vaccination decisions, and taking their concerns seriously.
•Complementary medical providers' individualized vaccine counseling in Switzerland.•Complementary and alternative medical providers not categorically anti-vaccine.•Ethnographic observations and descriptions of vaccine consultations.•Qualitative interviews about vaccination with complementary medical providers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This article reports on our qualitative inquiry into the meanings biomedically trained doctors in Switzerland attach to treating vaccine hesitant (VH) and underimmunized patients. With support from ...social science literature on ‘good’ and ‘bad’ patients and doctors, we explore how both doctors and patients cross the boundaries of these conceptual categories in situations involving vaccine hesitancy and underimmunization. The doctors we interviewed (N = 20) and observed (N = 16 observations, subsample of 6 doctors from the interview sample) described how they screened, measured, and diagnosed patients' levels of vaccine hesitancy. Our results emphasize the meanings doctors associated with counseling hesitant patients, especially while managing their own professional responsibilities, legitimacy, and reputations among colleagues and patients. Doctors' discourses constructed the figure of ‘problem patients,’ characterized through their (potential) non-adherence to vaccination recommendations, desire for lengthy consultations and individualized counseling, and dogmatic ideologies running contra to biomedicine. Discussions around the dilemmas faced by doctors in vaccination consultations brings to the fore several key, yet underdiscussed, paradoxes concerning VH, patient-doctor relationships, and the constructs of ‘good’/‘bad’ doctors and patients. These paradoxes revolve around expectations in Western societies for ‘good’ patients to be autonomous health-information seekers and active participants in clinical encounters, which research shows to be the case for many VH and underimmunizing individuals. However, in the eyes of many vaccination advocates and proponents of biomedical approaches, VH patients become ‘bad’ patients thru their risk of non-adherence, which has implications for the population at large. In these consultations, doctors find themselves conflicted around the expectations to promote vaccination while, at the same time, being active listeners and good communicators with those who question their biomedical training and legitimacy. Understanding these paradoxes highlights the need to better support HCPs in addressing VH in clinical practice.
•Vaccine hesitancy stimulates discussion of paradoxes of good/bad doctors/patients.•Biomedical doctors sometimes perceive vaccine hesitant patients as problematic.•Biomedical doctors' vaccination approaches have implications for their reputations.•Qualitative interviews and ethnographic observations with biomedical doctors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Influenza was recently reported as a risk factor for invasive aspergillosis (IA). We aimed to describe prognostic factors for influenza-associated IA (IAA) and poor outcome and mortality in ...critically ill patients in Switzerland. All adults with confirmed influenza admitted to the ICU at two Swiss tertiary care centres during the 2017/2018 influenza season were retrospectively evaluated. IAA was defined by clinical, mycological and radiological criteria: a positive galactomannan in bronchoalveolar lavage or histopathological or cultural evidence in respiratory specimens of
Aspergillus
spp., any radiological infiltrate and a compatible clinical presentation. Poor outcome was defined as a composite of in-hospital mortality, ICU length of stay (LOS), invasive ventilation for > 7 days or extracorporeal membrane oxygenation. Of 81 patients with influenza in the ICU, 9 (11%) were diagnosed with IAA. All patients with IAA had poor outcome compared to 26 (36%) patients without IAA (
p
< 0.001). Median ICU-LOS and mortality were 17 vs. 3 days (
p
< 0.01) and 3/9 (33%) vs. 13/72 (18%;
p
= 0.37) in patients with vs. without IAA, respectively. Patients with IAA had significantly longer durations of antibiotic therapy, vasoactive support and mechanical ventilation.
Aspergillus
was the most common respiratory co-pathogen (9/40, 22%) followed by classical bacterial co-pathogens. IAA was not associated with classical risk factors. Aspergillus is a common superinfection in critically ill influenza patients associated with poor outcome and longer duration of organ supportive therapies. Given the absence of classical risk factors for aspergillosis, greater awareness is necessary, particularly in those requiring organ supportive therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
HIV-1 RNA genetic diversity predicts time since infection which is important for clinical care and research. It's unclear, however, whether proviral DNA genetic diversity sampled under suppressive ...antiretroviral therapy can be used for this purpose. We tested whether proviral genetic diversity from NGS sequences predicts time since infection and recency in 221 people with HIV-1 with known infection time. Proviral diversity was significantly associated with time since infection (p<5*10-07, R2 up to 25%) and predictive of treatment initiation during recent infection (AUC-ROC up to 0.85). This shows the utility of proviral genetic diversity as a proxy for time since infection.
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to ...assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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