Publications by authors named "Manuel Battegay"

376 Publications

Evolution of COVID-19 mortality over time: results from the Swiss hospital surveillance system (CH-SUR).

Swiss Med Wkly 2021 Nov 24;151:w30105. Epub 2021 Nov 24.

Division of Infectious Diseases and Hospital Hygiene, Thurgau Hospital Group Münsterlingen and Frauenfeld, Switzerland.

Background: When the periods of time during and after the first wave of the ongoing SARS-CoV-2/COVID-19 pandemic in Europe are compared, the associated COVID-19 mortality seems to have decreased substantially. Various factors could explain this trend, including changes in demographic characteristics of infected persons and the improvement of case management. To date, no study has been performed to investigate the evolution of COVID-19 in-hospital mortality in Switzerland, while also accounting for risk factors.

Methods: We investigated the trends in COVID-19-related mortality (in-hospital and in-intermediate/intensive-care) over time in Switzerland, from February 2020 to June 2021, comparing in particular the first and the second wave. We used data from the COVID-19 Hospital-based Surveillance (CH-SUR) database. We performed survival analyses adjusting for well-known risk factors of COVID-19 mortality (age, sex and comorbidities) and accounting for competing risk.

Results: Our analysis included 16,984 patients recorded in CH-SUR, with 2201 reported deaths due to COVID-19 (13.0%). We found that overall in-hospital mortality was lower during the second wave of COVID-19 than in the first wave (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.63- 0.78; p <0.001), a decrease apparently not explained by changes in demographic characteristics of patients. In contrast, mortality in intermediate and intensive care significantly increased in the second wave compared with the first wave (HR 1.25, 95% CI 1.05-1.49; p = 0.029), with significant changes in the course of hospitalisation between the first and the second wave.

Conclusion: We found that, in Switzerland, COVID-19 mortality decreased among hospitalised persons, whereas it increased among patients admitted to intermediate or intensive care, when comparing the second wave to the first wave. We put our findings in perspective with changes over time in case management, treatment strategy, hospital burden and non-pharmaceutical interventions. Further analyses of the potential effect of virus variants and of vaccination on mortality would be crucial to have a complete overview of COVID-19 mortality trends throughout the different phases of the pandemic.
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http://dx.doi.org/10.4414/smw.2021.w30105DOI Listing
November 2021

Decreasing incidence and determinants of Bacterial Pneumonia in people with HIV: The Swiss HIV Cohort Study.

J Infect Dis 2021 Nov 18. Epub 2021 Nov 18.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Bacterial pneumonia is one of the leading reasons for hospitalization among people with HIV (PWH), yet there is limited evidence regarding its drivers in the era of potent antiretroviral therapy.

Methods: We assessed risk-factors for bacterial pneumonia in PWH enrolled in the Swiss HIV Cohort Study using univariable and multivariable marginal models. We further assessed the relationship between risk-factors and changes in bacterial pneumonia incidence using mediation analysis.

Results: We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years(py). bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 py in 2008 to 6.8 cases/1000 py in 2018. Older age, lower education-level, intravenous drug use, smoking, lower CD4-cell-count, higher HIV-viral load, and prior pneumonia events were significantly associated with higher bacterial pneumonia incidence. Notably, even CD4-cell-counts 350-499 were significantly associated with an increased risk compared to CD4≥500 (adjusted HR,1.39; 95% CI,1.01-1.89). Finally, we found that the decreasing incidence over the last decade can be explained by decreasing proportion of patients with CD4<500, viral-RNA>200, and smoking>one cigarette/day.

Conclusion: Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.
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http://dx.doi.org/10.1093/infdis/jiab573DOI Listing
November 2021

Anticholinergic medication use in elderly people living with HIV and self-reported neurocognitive impairment: a prospective cohort study.

J Antimicrob Chemother 2021 Nov 3. Epub 2021 Nov 3.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Anticholinergic (ACH) medications have been associated with neurocognitive impairment, particularly in the elderly. This study determined prospectively the prevalence of prescribed ACH medications and their association with self-reported neurocognitive impairment (SRNI) in elderly people living with HIV (PLWH) of the Swiss HIV Cohort Study (SHCS).

Methods: A literature review was performed to identify ACH medications, which were scored 0 to 3 (higher score indicating more ACH burden). Prescriptions were reviewed in July 2019 for all SHCS participants ≥65 years old to assess the prevalence of ACH medications. Association between ACH burden and neurocognitive impairment was evaluated using the SHCS SRNI questions addressing memory loss, attention difficulties and slowing in reasoning.

Results: One thousand and nineteen PLWH (82% male) with a median age of 70 (IQR = 67-74) years were included. Most participants were on ART (99%). The average number of non-HIV drugs was 5.1 ± 3.6, representing a polypharmacy prevalence of 50%. Two hundred participants (20%) were on ≥1 ACH medication, with an average ACH score of 1.7 ± 1.3. SRNI, adjusted for age, sex, CD4, nadir CD4, viral load, efavirenz use and polypharmacy, was associated with depression (OR = 4.60; 95% CI = 2.62-8.09) and a trend was observed with being on ≥1 ACH medication (OR = 1.69; 95% CI = 0.97-2.95). In a subgroup analysis of participants without depression (n = 911), SRNI was associated with the use of ≥1 ACH medication (OR = 2.51; 95% CI = 1.31-4.80).

Conclusions: ACH medication use is common in elderly PLWH and contributes to SRNI. The effect of ACH medications on neurocognitive impairment warrants further evaluation using neurocognitive tests.
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http://dx.doi.org/10.1093/jac/dkab386DOI Listing
November 2021

Assessing the drivers of syphilis among men who have sex with men in Switzerland reveals a key impact of screening frequency: A modelling study.

PLoS Comput Biol 2021 Oct 26;17(10):e1009529. Epub 2021 Oct 26.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

Over the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions. In order to identify the drivers of syphilis transmission in MSM in Switzerland between 2006 and 2017 as well as the effect of potential interventions, we set up an epidemiological model stratified by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used 'reported non-steady partners' (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health. The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs. 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017). The model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission.
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http://dx.doi.org/10.1371/journal.pcbi.1009529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570495PMC
October 2021

Long-term outcome after SARS-CoV-2 infection in healthcare workers: a single centre cohort study.

Swiss Med Wkly 2021 10 22;151:w30094. Epub 2021 Oct 22.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.

Background: Long-term symptoms after acute COVID-19 are highly debated. Nevertheless, data on long-term symptoms of COVID-19 in healthcare workers are scarce.

Methods: We assessed frequency and risk factors of persisting symptoms in a retrospective cohort of healthcare workers infected with SARS-CoV-2.

Results: Persistent symptoms at 3 and 12 months were reported by 26.5% and 13.5% of participants, respectively. Most commonly reported symptoms were fatigue, impaired sense of taste or smell and general weakness. A history of depression or state of exhaustion, pre-existing lung disease and older age were associated with persisting symptoms.

Conclusion: Our study shows that a relevant proportion of healthcare workers with mild COVID-19 report persisting symptoms over 3 and 12 months. Although in the majority of cases symptoms are mild, this study highlights the need for further research into causes and therapy.
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http://dx.doi.org/10.4414/smw.2021.w30094DOI Listing
October 2021

Offering ART refill through community health workers versus clinic-based follow-up after home-based same-day ART initiation in rural Lesotho: The VIBRA cluster-randomized clinical trial.

PLoS Med 2021 Oct 21;18(10):e1003839. Epub 2021 Oct 21.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Community-based antiretroviral therapy (ART) dispensing by lay workers is an important differentiated service delivery model in sub-Sahara Africa. However, patients new in care are generally excluded from such models. Home-based same-day ART initiation is becoming widespread practice, but linkage to the clinic is challenging. The pragmatic VIBRA (Village-Based Refill of ART) trial compared ART refill by existing lay village health workers (VHWs) versus clinic-based refill after home-based same-day ART initiation.

Methods And Findings: The VIBRA trial is a cluster-randomized open-label clinical superiority trial conducted in 249 rural villages in the catchment areas of 20 health facilities in 2 districts (Butha-Buthe and Mokhotlong) in Lesotho. In villages (clusters) randomized to the intervention arm, individuals found to be HIV-positive during a door-to-door HIV testing campaign were offered same-day ART initiation with the option of refill by VHWs. The trained VHWs dispensed drugs and scheduled clinic visits for viral load measurement at 6 and 12 months. In villages randomized to the control arm, participants were offered same-day ART initiation with clinic-based ART refill. The primary outcome was 12-month viral suppression. Secondary endpoints included linkage and 12-month engagement in care. Analyses were intention-to-treat. The trial was registered on ClinicalTrials.gov (NCT03630549). From 16 August 2018 until 28 May 2019, 118 individuals from 108 households in 57 clusters in the intervention arm, and 139 individuals from 130 households in 60 clusters in the control arm, were enrolled (150 [58%] female; median age 36 years [interquartile range 30-48]; 200 [78%] newly diagnosed). In the intervention arm, 48/118 (41%) opted for VHW refill. At 12 months, 46/118 (39%) participants in the intervention arm and 64/139 (46%) in the control arm achieved viral suppression (adjusted risk difference -0.07 [95% CI -0.20 to 0.06]; p = 0.256). Arms were similar in linkage (adjusted risk difference 0.03 [-0.10 to 0.16]; p = 0.630), but engagement in care was non-significantly lower in the intervention arm (adjusted risk difference -0.12 [-0.23 to 0.003]; p = 0.058). Seven and 0 deaths occurred in the intervention and control arm, respectively. Of the intervention participants who did not opt for drug refill from the VHW at enrollment, 41/70 (59%) mentioned trust or conflict issues as the primary reason. Study limitations include a rather small sample size, 9% missing viral load measurements in the primary endpoint window, the low uptake of the VHW refill option in the intervention arm, and substantial migration among the study population.

Conclusions: The offer of village-based ART refill after same-day initiation led to similar outcomes as clinic-based refill. The intervention did not amplify the effect of home-based same-day ART initiation alone. The findings raise concerns about acceptance and safety of ART delivered by lay health workers after initiation in the community.

Trial Registration: Registered with Clinicaltrials.gov (NCT03630549).
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http://dx.doi.org/10.1371/journal.pmed.1003839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568187PMC
October 2021

Comparing Immunoassays for SARS-CoV-2 Antibody Detection in Patients with and without Laboratory-Confirmed SARS-CoV-2 Infection.

J Clin Microbiol 2021 11 15;59(12):e0138121. Epub 2021 Sep 15.

Clinical Virology, University Hospital Basel, Basel, Switzerland.

Commercially available SARS-CoV-2-directed antibody assays may assist in diagnosing past exposure to SARS-CoV-2 antigens. We cross-compared the following eight immunoassays detecting antibodies against SARS-CoV-2 nucleocapsid (N) or spike (S) antigens in three cohorts consisting of 859 samples from 622 patients: (#1) EDI novel coronavirus COVID-19 (Epitope), (#2) RecomWell SARS-CoV-2 (Mikrogen), (#3) COVID-19 ELISA (VirCell), (#4) Elecsys anti-SARS-CoV-2 N (Roche), (#5) Liaison SARS-CoV-2 S1/S2 (DiaSorin), (#6) anti-SARS-CoV-2 ELISA (EuroImmun), (#7) Elecsys anti-SARS-CoV-2 S (Roche), and (#8) Liaison SARS-CoV-2 TrimericS (DiaSorin). In cross-sectional cohort 1 (68 sera from 38 patients with documented SARS-CoV-2 infection), agreement between assays #1 to #6 ranged from 75% to 93%, whereby discordance mostly resulted from N-based assays #1 to #4. In cross-sectional cohort 2 (510 sera from 510 patients; 56 documented, 454 unknown SARS-CoV-2 infection), assays #4 to #6 were analyzed further together with assays #7 and #8, revealing 94% concordance (44 [9%] positives and 485 [85%] negatives). Discordance was highest within 2 weeks after SARS-CoV-2/COVID-19 diagnosis and confirmed in the longitudinal cohort 3 (281 sera from 74 COVID-19 patients), using assays #4, #6, #7, and #8. Subanalysis of 20 (27%) initially seronegative cohort 3 patients revealed assay-dependent 50% and 90% seroconversion rates after 8 to 11 days and 14 to 18 days, respectively. Increasing SARS-CoV-2 antibodies were significantly associated with declining levels of viral loads, lactate dehydrogenase, interleukin-6, and C-reactive protein and preceded clearance of SARS-CoV-2 detection in the upper respiratory tract by approximately 1 week. SARS-CoV-2-specific antibody assays show substantial agreement, but interpretation of qualitative and semiquantitative results depends on the time elapsed postdiagnosis and the choice of viral antigen. Mounting of systemic SARS-CoV-2-specific antibodies may predict recovery from viral injury and clearance of mucosal replication.
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http://dx.doi.org/10.1128/JCM.01381-21DOI Listing
November 2021

Physiologically Based Pharmacokinetic Modelling to Investigate the Impact of the Cytokine Storm on CYP3A Drug Pharmacokinetics in COVID-19 Patients.

Clin Pharmacol Ther 2021 Sep 8. Epub 2021 Sep 8.

Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Patients with coronavirus disease 2019 (COVID-19) may experience a cytokine storm with elevated interleukin-6 (IL-6) levels in response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). IL-6 suppresses hepatic enzymes, including CYP3A; however, the effect on drug exposure and drug-drug interaction magnitudes of the cytokine storm and resulting elevated IL-6 levels have not been characterized in patients with COVID-19. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate the effect of inflammation on the pharmacokinetics of CYP3A metabolized drugs. A PBPK model was developed for lopinavir boosted with ritonavir (LPV/r), using clinically observed data from people living with HIV (PLWH). The inhibition of CYPs by IL-6 was implemented by a semimechanistic suppression model and verified against clinical data from patients with COVID-19, treated with LPV/r. Subsequently, the verified model was used to simulate the effect of various clinically observed IL-6 levels on the exposure of LPV/r and midazolam, a CYP3A model drug. Clinically observed LPV/r concentrations in PLWH and patients with COVID-19 were predicted within the 95% confidence interval of the simulation results, demonstrating its predictive capability. Simulations indicated a twofold higher LPV exposure in patients with COVID-19 compared with PLWH, whereas ritonavir exposure was predicted to be comparable. Varying IL-6 levels under COVID-19 had only a marginal effect on LPV/r pharmacokinetics according to our model. Simulations showed that a cytokine storm increased the exposure of the CYP3A paradigm substrate midazolam by 40%. Our simulations suggest that CYP3A metabolism is altered in patients with COVID-19 having increased cytokine release. Caution is required when prescribing narrow therapeutic index drugs particularly in the presence of strong CYP3A inhibitors.
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http://dx.doi.org/10.1002/cpt.2402DOI Listing
September 2021

Lactic acidosis and hyperlactatemia associated with lamivudine accumulation and sepsis in a kidney transplant recipient-a case report and review of the literature.

AIDS Res Ther 2021 09 4;18(1):56. Epub 2021 Sep 4.

Department of Clinical Pharmacology and Toxicology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.

Background: We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation.

Case Presentation: The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine.

Conclusions: NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.
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http://dx.doi.org/10.1186/s12981-021-00382-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418711PMC
September 2021

Ninety-day outcome of patients with severe COVID-19 treated with tocilizumab - a single centre cohort study.

Swiss Med Wkly 2021 08 10;151:w20550. Epub 2021 Aug 10.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, Switzerland / Department of Clinical Research, University Hospital Basel, Switzerland / Infection Biology Laboratory, Department of Biomedicine, University of Basel, Switzerland.

Objectives: Patients with severe COVID-19 may be at risk of longer term sequelae. Long-term clinical, immunological, pulmonary and radiological outcomes of patients treated with anti-inflammatory drugs are lacking.

Methods: In this single-centre prospective cohort study, we assessed 90-day clinical, immunological, pulmonary and radiological outcomes of hospitalised patients with severe COVID-19 treated with tocilizumab from March 2020 to May 2020. Criteria for tocilizumab administration were oxygen saturation <93%, respiratory rate >30/min, C-reactive protein levels >75 mg/l, extensive area of ground-glass opacities or progression on computed tomography (CT). Descriptive analyses were performed using StataIC 16.

Results: Between March 2020 and May 2020, 50 (27%) of 186 hospitalised patients had severe COVID-19 and were treated with tocilizumab. Of these, 52% were hospitalised on the intensive care unit (ICU) and 12% died. Eleven (22%) patients developed at least one microbiologically confirmed super-infection, of which 91% occurred on ICU. Median duration of hospitalisation was 15 days (interquartile range [IQR] 10–24) with 24 days (IQR 14–32) in ICU patients and 10 days (IQR 7–15) in non-ICU patients. At day 90, 41 of 44 survivors (93%) were outpatients. No long-term adverse events or late-onset infections were identified after acute hospital care. High SARS-CoV-2 antibody titres were found in all but one patient, who was pretreated with rituximab. Pulmonary function tests showed no obstructive patterns, but restrictive patterns in two (5.7%) and impaired diffusion capacities for carbon monoxide in 11 (31%) of 35 patients, which predominated in prior ICU patients. Twenty-one of 35 (60%) CT-scans at day 90 showed residual abnormalities, with similar distributions between prior ICU and non-ICU patients.

Conclusions: In this cohort of severe COVID-19 patients, no tocilizumab-related long-term adverse events or late-onset infections were identified. Although chest CT abnormalities were highly prevalent at day 90, the majority of patients showed normal lung function.

Trial Registration: ClinicalTrials.gov NCT04351503.
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http://dx.doi.org/10.4414/smw.2021.20550DOI Listing
August 2021

Recognition and management of clinically significant drug-drug interactions between antiretrovirals and co-medications in a cohort of people living with HIV in rural Tanzania: a prospective questionnaire-based study.

J Antimicrob Chemother 2021 09;76(10):2681-2689

University of Basel, Basel, Switzerland.

Background: The extent to which drug-drug interactions (DDIs) between antiretrovirals (ARVs) and co-medications are recognized and managed has not been thoroughly evaluated in limited-resource settings.

Objectives: This prospective questionnaire-based study aimed to determine the prevalence and risk factors for unrecognized/incorrectly managed DDIs in people living with HIV followed-up at the Chronic Diseases Clinic of Ifakara (CDCI) and enrolled in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO).

Methods: We prospectively included ARV-treated adults receiving ≥1 co-medication coming for a follow-up visit at the CDCI between March and July 2017. Using a structured questionnaire, physicians were requested to identify potentially clinically significant DDIs in the prescribed treatment, to provide recommendations for their management and to indicate any hurdles to implement the recommendations. Prescriptions were subsequently screened for DDIs using the Liverpool DDIs database. Identified clinically significant DDIs and their recommended management according to the DDIs database were compared with the information provided in the questionnaires.

Results: Among 334 participants, the median age was 47 years (IQR = 40-56 years), 69% were female and 82% had ≥1 non-communicable disease (NCD). Overall, 129 participants had ≥1 clinically relevant DDI, which was not recognized and/or incorrectly managed in 56 participants (43%). Of those, 6 (11%) were due to limited monitoring options or medication affordability issues. In the multivariable logistic regression, the presence of ≥1 NCD was associated with an increased risk for unrecognized/incorrect DDI management (OR = 15.8; 95% CI = 1.8-139.6).

Conclusions: Recognition/appropriate management of DDIs is suboptimal, highlighting the need for educational programmes, pharmacovigilance activities and increased access to medications and monitoring options. This should become a focus of HIV programmes given the increasing burden of NCDs in sub-Saharan Africa.
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http://dx.doi.org/10.1093/jac/dkab254DOI Listing
September 2021

Temporal trends of COVID-19 related in-hospital mortality and demographics in Switzerland - a retrospective single centre cohort study.

Swiss Med Wkly 2021 07 19;151:w20572. Epub 2021 Jul 19.

Division of infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland.

Aims: The aim of this study was to analyse the demographics, risk factors and in-hospital mortality rates of patients admitted with coronavirus disease 2019 (COVID-19) to a tertiary care hospital in Switzerland.

Methods: In this single-centre retrospective cohort study at the University Hospital Basel, we included all patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection hospitalised from 27 February 2020 to 10 May 2021. Patients’ characteristics were extracted from the electronic medical record system. The primary outcome of this study was temporal trends of COVID-19-related in-hospital mortality. Secondary outcomes were COVID-19-related mortality in patients hospitalised on the intensive care unit (ICU), admission to ICU, renal replacement therapy and length of hospital stay, as well as a descriptive analysis of risk factors for in-hospital mortality.

Results: During the study period we included 943 hospitalisations of 930 patients. The median age was 65 years (interquartile range [IQR] 53–76) and 63% were men. The numbers of elderly patients, patients with multiple comorbidities and need for renal replacement therapy decreased from the first and second to the third wave. The median length of stay and need for ICU admission were similar in all waves. Throughout the study period 88 patients (9.3%) died during the hospital stay. Crude in-hospital mortality was similar over the course of the first two waves (9.5% and 10.2%, respectively), whereas it decreased in the third wave (5.4%). Overall mortality in patients without comorbidities was low at 1.6%, but it increased in patients with any comorbidity to 12.6%. Predictors of all-cause mortality over the whole period were age (adjusted odds ratio [aOR] per 10-year increase 1.81, 95% confidence interval [CI] 1.45–2.26; p <0.001), male sex (aOR 1.68, 95% CI 1.00–2.82; p = 0.048), immunocompromising condition (aOR 2.09, 95% CI 1.01–4.33; p = 0.048) and chronic kidney disease (aOR 2.25, 95% CI 1.35–3.76; p = 0.002).

Conclusion: In our study in-hospital mortality was 9.5%, 10.2% and 5.4% in the first, second and third waves, respectively. Age, immunocompromising condition, male sex and chronic kidney disease were factors associated with in-hospital mortality. Importantly, patients without any comorbidity had a very low in-hospital mortality regardless of age.
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http://dx.doi.org/10.4414/smw.2021.20572DOI Listing
July 2021

Identifying and Characterizing Trans women in the Swiss HIV Cohort Study as an Epidemiologically Distinct Risk Group.

Clin Infect Dis 2021 Jul 20. Epub 2021 Jul 20.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

Background: As trans women are disproportionately affected by the HIV epidemic, and are still understudied, we aimed to identify and characterize the trans women in the Swiss HIV Cohort Study (SHCS).

Methods: A combination of criteria from pre-existing cohort data was used to identify trans women. Information on socioeconomic factors, clinical data, risk behaviors, and mental health was collected. We also described their phylogenetic patterns within HIV transmission networks in relation to other risk groups.

Results: We identified 89 trans women out of a total 20925 cohort participants. Trans women were much more likely to be Asian (30.3%) and Hispanic (15.7%) compared to men-who-have-sex with-men/MSM (2.5% and 4.1%, P value<0.001) and cis heterosexual (HET) women (7.0% and 3.3%, P value<0.001). Trans women were more similar to cis HET women in some measures like education level (post-secondary education attainment: 22.6% and 20.7% [P value =0.574], vs. 46.5% for MSM [P value<0.001]), while being more similar to MSM for measures like prior syphilis diagnosis (36.0% and 44.0% [P value=0.170], vs. 6.7% for cis HET women [P value <0.001]). 11.2% of trans women have been priorly hospitalized for psychological reasons, compared to 4.2% of MSM (P value=0.004) and 5.1% of cis HET women (P value=0.025). An analysis of transmission clusters containing trans women suggested greater affinity within the transmission networks to MSM compared to cis HET women.

Conclusions: Trans women are epidemiologically distinct in the setting of the Swiss HIV epidemic, warranting better identification and study to better serve this underserved risk group.
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http://dx.doi.org/10.1093/cid/ciab628DOI Listing
July 2021

Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance.

Microorganisms 2021 May 19;9(5). Epub 2021 May 19.

Applied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.

A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by ) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting (Tajima's D = -2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic.
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http://dx.doi.org/10.3390/microorganisms9051094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160703PMC
May 2021

Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link.

Elife 2021 06 1;10. Epub 2021 Jun 1.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Considering the remaining threat of drug-resistantmutations (DRMs) to antiretroviral treatment (ART) efficacy, we investigated how the selective pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes drives certain DRMs' emergence and retention.

Methods: We systematically screened DRM:HLA class I allele combinations in 3997 ART-naïve Swiss HIV Cohort Study (SHCS) patients. For each pair, a logistic regression model preliminarily tested for an association with the DRM as the outcome. The three HLA:DRM pairs remaining after multiple testing adjustment were analyzed in three ways: cross-sectional logistic regression models to determine any HLA/infection time interaction, survival analyses to examine if HLA type correlated with developing specific DRMs, and via NetMHCpan to find epitope binding evidence of immune escape.

Results: Only one pair, RT-E138:HLA-B18, exhibited a significant interaction between infection duration and HLA. The survival analyses predicted two pairs with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075-1.273]; p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523-42.318]; p-value<0.001). The same two pairs were also predicted by netMHCpan to have epitopic binding.

Conclusions: We identified DRM:HLA pairs where HLA presence is associated with the presence or emergence of the DRM, indicating that the selective pressure for these mutations alternates direction depending on the presence of these HLA alleles.

Funding: Funded by the Swiss National Science Foundation within the framework of the SHCS, and the University of Zurich, University Research Priority Program: Evolution in Action: From Genomes Ecosystems, in Switzerland.
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http://dx.doi.org/10.7554/eLife.67388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169104PMC
June 2021

Prevalence and outcomes of pregnancies in women with HIV over a 20-year period.

AIDS 2021 10;35(12):2025-2033

Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK.

Objective: To evaluate time trends in pregnancies and pregnancy outcomes among women with HIV in Europe.

Design: European multicentre prospective cohort study.

Methods: EuroSIDA has collected annual cross-sectional audits of pregnancies between 1996 and 2015. Pregnancy data were extracted and described. Odds of pregnancy were modelled, adjusting for potential confounders using logistic regression with generalized estimating equations.

Results: Of 5535 women aged 16 to <50 years, 4217 (76.2%) had pregnancy information available, and 912 (21.6%) reported 1315 pregnancies. The proportions with at least one pregnancy were 28.1% (321/1143) in East, 24.5% (146/596) in North, 19.8% (140/706) in West/Central, 19.3% (110/569) in Central East and 16.2% (195/1203) in South Europe. Overall 319 pregnancies (24.3%) occurred in 1996-2002, 576 (43.8%) in 2003-2009 and 420 (31.9%) in 2010-2015. After adjustment, the odds of pregnancy were lower in 1996-2002, in South, Central East and East compared to West/Central Europe, in older women, those with low CD4+ cell count or with prior AIDS, and higher in those with a previous pregnancy or who were hepatitis C virus positive.Outcomes were reported for 999 pregnancies in 1996-2014, with 690 live births (69.1%), seven stillbirths (0.7%), 103 spontaneous (10.3%) and 199 medical abortions (19.9%).

Conclusions: Around 20% of women in EuroSIDA reported a pregnancy, with most pregnancies after 2002, when more effective antiretroviral therapy became available. Substantial differences were seen between European regions. Further surveillance of pregnancies and outcomes among women living with HIV is warranted to ensure equal access to care.
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http://dx.doi.org/10.1097/QAD.0000000000002954DOI Listing
October 2021

Immunophenotypic characterization of TCR γδ T cells and MAIT cells in HIV-infected individuals developing Hodgkin's lymphoma.

Infect Agent Cancer 2021 Apr 17;16(1):24. Epub 2021 Apr 17.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.

Background: Despite successful combined antiretroviral therapy (cART), the risk of non-AIDS defining cancers (NADCs) remains higher for HIV-infected individuals than the general population. The reason for this increase is highly disputed. Here, we hypothesized that T-cell receptor (TCR) γδ cells and/or mucosal-associated invariant T (MAIT) cells might be associated with the increased risk of NADCs. γδ T cells and MAIT cells both serve as a link between the adaptive and the innate immune system, and also to exert direct anti-viral and anti-tumor activity.

Methods: We performed a longitudinal phenotypic characterization of TCR γδ cells and MAIT cells in HIV-infected individuals developing Hodgkin's lymphoma (HL), the most common type of NADCs. Cryopreserved PBMCs of HIV-infected individuals developing HL, matched HIV-infected controls without (w/o) HL and healthy controls were used for immunophenotyping by polychromatic flow cytometry, including markers for activation, exhaustion and chemokine receptors.

Results: We identified significant differences in the CD4 T cell count between HIV-infected individuals developing HL and HIV-infected matched controls within 1 year before cancer diagnosis. We observed substantial differences in the cellular phenotype mainly between healthy controls and HIV infection irrespective of HL. A number of markers tended to be different in Vδ1 and MAIT cells in HIVHL patients vs. HIV w/o HL patients; notably, we observed significant differences for the expression of CCR5, CCR6 and CD16 between these two groups of HIV patients.

Conclusion: TCR Vδ1 and MAIT cells in HIV-infected individuals developing HL show subtle phenotypical differences as compared to the ones in HIV-infected controls, which may go along with functional impairment and thereby may be less efficient in detecting and eliminating malignant cells. Further, our results support the potential of longitudinal CD4 T cell count analysis for the identification of patients at higher risk to develop HL.
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http://dx.doi.org/10.1186/s13027-021-00365-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052713PMC
April 2021

Response to a sexual risk reduction intervention provided in combination with hepatitis C treatment by HIV/HCV co-infected men who have sex with men: a reflexive thematic analysis.

BMC Infect Dis 2021 Apr 6;21(1):319. Epub 2021 Apr 6.

Nursing Science, Department Public Health, Medical Faculty, University of Basel, Basel, Switzerland.

Background: Hepatitis C virus reinfections in HIV-positive men-who-have-sex-with-men (MSM) challenge the effectiveness of antiviral treatment. To fight this problem, an adapted sexual risk reduction intervention was implemented within a hepatitis C treatment trial. Following this, the current study had two aims and describes 1) how the program was received by participants; and 2) their responses to the program regarding sexual risk taking. Based on the participants' input, we hoped to judge the intervention's potential for scale-up.

Methods: Seventeen participants who received the sexual risk reduction intervention in addition to hepatitis C treatment were recruited for semi-structured interviews six to 12 months post-intervention. We evaluated the responses via reflexive thematic analysis and applied the concept of sense-making.

Results: Giving hepatitis C a place and living without it again illustrates how participants received the program and how their experiences were altered by the impact of sense-making. Based on their responses, we allocated participants to three groups: 1. Avoid risks: get rid of hepatitis C for life. For these men, hepatitis C remained a life-threatening disease: they actively modified their risk behavior and felt supported by the intervention in maintaining their behavioral changes. 2. Minimize risks: live as long as possible without hepatitis C. In contrast to group 1, these men saw hepatitis C as a manageable disease. The intervention facilitated reflection on risks and how to develop behavioral changes that suited them individually. 3. Accept risks; live with the risk of hepatitis C. These men perceived behavioral changes as much more difficult than "easy" medical treatment. They expected to either undergo repeated rounds of treatment or stay HCV re-infected.

Conclusion: These results illustrate the diversity of men's responses and their decisions regarding sexual risk behavior after participating in a combination of antiviral treatment and a sexual risk reduction intervention. Two major aspects were identified: 1) Teachable moments, particularly at the time of diagnosis/treatment, could offer an opportunity to develop openness for behavioral change; 2) adapting sexual risk reduction interventions to sense-making patterns could help to improve its effectiveness. Support for reducing infection risk and raising awareness of preventative measures are additional benefits.

Trial Registration: Clinical Trial Number: NCT02785666 , 30.05.2016.
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http://dx.doi.org/10.1186/s12879-021-06003-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022541PMC
April 2021

HIV-Infected Patients Developing Tuberculosis Disease Show Early Changes in the Immune Response to Novel Antigens.

Front Immunol 2021 12;12:620622. Epub 2021 Mar 12.

University of Basel Children's Hospital, Mycobacterial Research Laboratory, Basel, Switzerland.

In individuals living with HIV infection the development of tuberculosis (TB) is associated with rapid progression from asymptomatic TB infection to active TB disease. Sputum-based diagnostic tests for TB have low sensitivity in minimal and subclinical TB precluding early diagnosis. The immune response to novel expressed and latency associated antigens may help to measure the early stages of infection and disease progression and thereby improve early diagnosis of active TB disease. Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease ("cases") and matched patients with no TB disease ("controls") were stimulated with 10 novel antigens. Cytokine concentrations were measured in cases and controls at four time points prior to diagnosis of TB: T1-T4 with T4 being the closest time point to diagnosis. 50 samples from nine cases and nine controls were included. Median CD4 cell count at T4 was 289/ul for the TB-group and 456/ul for the control group. Viral loads were suppressed in both groups. At T4 Rv2431c-induced and Rv3614/15c-induced interferon gamma-induced protein (IP)-10 responses and Rv2031c-induced and Rv2346/Rv2347c-induced tumor necrosis factor (TNF)-α responses were significantly higher in cases compared to controls ( < 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-α was significantly higher in cases compared to controls ( < 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC > 0.92 for all four antigen-cytokine pairs. The -specific immune response in HIV-infected individuals that progress toward developing TB disease is different from those in HIV-infected individuals that do not progress to developing TB. These differences precede the clinical diagnosis of active TB up to 2 years, paving the way for the development of immune based diagnostics to predict TB disease at an early stage.
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http://dx.doi.org/10.3389/fimmu.2021.620622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994263PMC
June 2021

Patients with severe schistosomiasis mansoni in Ituri Province, Democratic Republic of the Congo.

Infect Dis Poverty 2021 Mar 25;10(1):39. Epub 2021 Mar 25.

Nanomedicine Translation Group, Intensive Care Unit, University Hospital Basel University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

Background: Severe hepatosplenic complications arise in patients with chronic Schistosoma mansoni infection after heavy exposure to disease agents in endemic areas. These complications are rarely reported and, hence, underestimated.

Case Presentation: We report on eight patients with severe morbidity associated with S. mansoni infection in Ituri Province, northeastern Democratic Republic of Congo (DRC). The patients were identified during a community-based survey in 2017; one patient was seen at the district hospital. After taking the patients' history, a clinical examination and an abdominal ultrasonographical examination were performed. S. mansoni infection was diagnosed in fecal (Kato-Katz technique) and urine (point-of-case circulating cathodic antigen test) samples. These eight patients with severe intestinal and hepatosplenic complications were identified from four villages with high S. mansoni infection prevalence and related morbidity. The patients' ages ranged from 19 to 57 years; four patients were women. Three patients reported hematemesis. Two patients were severely anemic. All patients reported non-specific abdominal symptoms, such as diarrhea (six patients), abdominal pain (seven patients), and blood in the stool (five patients), as well as weight loss (two patients). Abdominal ultrasonography revealed ascites in four patients. All patients had portal hypertension with hepatomegaly (seven patients) or splenomegaly (five patients). Of the six patients with a discernable liver parenchyma pattern, five displayed pattern F and three patient displayed pattern E. Liver parenchyma was not visible for two patients with severe ascites. An S. mansoni infection was confirmed in six patients, with infection intensity ranging from light to heavy. All S. mansoni positive patients were treated with praziquantel (40 mg/kg body weight) and referred to the district hospital for follow-up. One patient with severe ascites died two weeks after we saw her. Due to security and accessibility reasons, the villages could not be visited again and the patients were lost to follow-up.

Conclusions: Our observations of patients with severe schistosomiasis document the severe degree of endemicity of S. mansoni in the province and suggest an urgent need for adequate schistosomiasis control measures that target vulnerable population groups and address severe complications.
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http://dx.doi.org/10.1186/s40249-021-00815-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992822PMC
March 2021

SARS-CoV-2 outbreak in a tri-national urban area is dominated by a B.1 lineage variant linked to a mass gathering event.

PLoS Pathog 2021 03 19;17(3):e1009374. Epub 2021 Mar 19.

Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland.

The first case of SARS-CoV-2 in Basel, Switzerland was detected on February 26th 2020. We present a phylogenetic study to explore viral introduction and evolution during the exponential early phase of the local COVID-19 outbreak from February 26th until March 23rd. We sequenced SARS-CoV-2 naso-oropharyngeal swabs from 746 positive tests that were performed at the University Hospital Basel during the study period. We successfully generated 468 high quality genomes from unique patients and called variants with our COVID-19 Pipeline (COVGAP), and analysed viral genetic diversity using PANGOLIN taxonomic lineages. To identify introduction and dissemination events we incorporated global SARS-CoV-2 genomes and inferred a time-calibrated phylogeny. Epidemiological data from patient questionnaires was used to facilitate the interpretation of phylogenetic observations. The early outbreak in Basel was dominated by lineage B.1 (83·6%), detected first on March 2nd, although the first sample identified belonged to B.1.1. Within B.1, 68·2% of our samples fall within a clade defined by the SNP C15324T ('Basel cluster'), including 157 identical sequences at the root of the 'Basel cluster', some of which we can specifically trace to regional spreading events. We infer the origin of B.1-C15324T to mid-February in our tri-national region. The other genomes map broadly over the global phylogenetic tree, showing several introduction events from and/or dissemination to other regions of the world via travellers. Family transmissions can also be traced in our data. A single lineage variant dominated the outbreak in the Basel area while other lineages, such as the first (B.1.1), did not propagate. A mass gathering event was the predominant initial source of cases, with travel returners and family transmissions to a lesser extent. We highlight the importance of adding specific questions to epidemiological questionnaires, to obtain data on attendance of large gatherings and their locations, as well as travel history, to effectively identify routes of transmissions in up-coming outbreaks. This phylogenetic analysis in concert with epidemiological and contact tracing data, allows connection and interpretation of events, and can inform public health interventions. Trial Registration: ClinicalTrials.gov NCT04351503.
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http://dx.doi.org/10.1371/journal.ppat.1009374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011817PMC
March 2021

Systematic screening on admission for SARS-CoV-2 to detect asymptomatic infections.

Antimicrob Resist Infect Control 2021 02 27;10(1):44. Epub 2021 Feb 27.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

The proportion of asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains elusive and the potential benefit of systematic screening during the SARS-CoV-2-pandemic is controversial. We investigated the proportion of asymptomatic inpatients who were identified by systematic screening for SARS-CoV-2 upon hospital admission. Our analysis revealed that systematic screening of asymptomatic inpatients detects a low total number of SARS-CoV-2 infections (0.1%), questioning the cost-benefit ratio of this intervention. Even when the population-wide prevalence was low, the proportion of asymptomatic carriers remained stable, supporting the need for universal infection prevention and control strategies to avoid onward transmission by undetected SARS-CoV-2-carriers during the pandemic.
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http://dx.doi.org/10.1186/s13756-021-00912-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912536PMC
February 2021

Physiologically-Based Pharmacokinetic Modeling to Support the Clinical Management of Drug-Drug Interactions With Bictegravir.

Clin Pharmacol Ther 2021 11 29;110(5):1231-1239. Epub 2021 Mar 29.

Department of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir.
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http://dx.doi.org/10.1002/cpt.2221DOI Listing
November 2021

Association of Incomplete Adherence to Antiretroviral Therapy With Cardiovascular Events and Mortality in Virologically Suppressed Persons With HIV: The Swiss HIV Cohort Study.

Open Forum Infect Dis 2021 Feb 21;8(2):ofab032. Epub 2021 Jan 21.

University of Basel, Basel, Switzerland.

Background: Incomplete antiretroviral therapy (ART) adherence, even if sufficient to maintain viral suppression, is associated with enhanced inflammation in persons with HIV (PWH). However, its clinical implications remain unknown.

Methods: PWH enrolled in the Swiss HIV Cohort Study without a history of cardiovascular disease (CVD) who initiated ART between 2003 and 2018 and had viral suppression (<50 copies/mL) for ≥6 months were evaluated. The association between incomplete self-reported ART adherence (≥1 or ≥2 missed doses in the last month) and (1) any CVD event (myocardial infarction, revascularization, cerebral hemorrhage, stroke, and/or death due to CVD event) or (2) non-CVD-related death was evaluated using adjusted Cox proportional hazards models.

Results: A total of 6971 PWH (74% male) were included in the analysis (median age [interquartile range {IQR}], 39 [32-47] years). The median (IQR) follow-up was 8 (4-11) years, with 14 (8-23) adherence questionnaires collected per participant. In total, 205 (3%) participants experienced a CVD event, and 186 (3%) died a non-CVD-related death. In an adjusted competing risk model where missing data were imputed, missing ≥1 ART dose showed an increased, but not statistically significant, risk for CVD events (hazard ratio [HR], 1.23; 95% CI, 0.85-1.79;  = .28). Non-CVD-related mortality showed a statistically significantly increased risk with missing ≥1 ART dose (HR, 1.44; 95% CI, 1.00-2.07;  = .05) and missing ≥2 ART doses (HR, 2.21; 95% CI, 1.37-3.57;  = .001).

Conclusions: Incomplete ART adherence was significantly associated with an increased risk for non-CVD-related mortality in PWH with virologic suppression. This highlights the potential role of nonadherence to ART as a driver of non-AIDS clinical outcomes.
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http://dx.doi.org/10.1093/ofid/ofab032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880264PMC
February 2021

Mortality Rate in a Cohort of People Living With HIV in Rural Tanzania After Accounting for Unseen Deaths Among Those Lost to Follow-up.

Am J Epidemiol 2021 02;190(2):251-264

Mortality assessment in cohorts with high numbers of persons lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO)) of human immunodeficiency virus (HIV)-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005-2015 and traced a nonrandom sample of those LTFU. We estimated mortality using Kaplan-Meier methods 1) with routinely captured data (method A), 2) crudely incorporating tracing data (method B), 3) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU (method C), and 4) weighting using tracing data accounting for participant characteristics (method D). We investigated associated factors using proportional hazards models. Among 7,460 adults, 646 (9%) died, 883 (12%) transferred to other clinics, and 2,911 (39%) were LTFU. Of 2,010 (69%) traced participants, 325 (16%) were found: 131 (40%) had died and 130 (40%) had transferred. Five-year mortality estimates derived using the 4 methods were 13.1% (A), 16.2% (B), 36.8% (C), and 35.1% (D), respectively. Higher mortality was associated with male sex, referral as a hospital inpatient, living close to the index clinic, lower body mass index, more advanced World Health Organization HIV clinical stage, lower CD4 cell count, and less time since initiation of antiretroviral therapy. Adjusting for unseen deaths among participants LTFU approximately doubled the 5-year mortality estimates. Our approach is applicable to other cohort studies adopting targeted tracing.
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http://dx.doi.org/10.1093/aje/kwaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850129PMC
February 2021

Physiologically-Based Pharmacokinetic Modeling Combined with Swiss HIV Cohort Study Data Supports No Dose Adjustment of Bictegravir in Elderly Individuals Living With HIV.

Clin Pharmacol Ther 2021 04 27;109(4):1025-1029. Epub 2021 Feb 27.

Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Clinical studies in aging people living with HIV (PLWH) are sparse for the novel integrase inhibitor bictegravir, leading to some uncertainty about dosing recommendations for elderly PLWH. The objective of this study was to investigate the continuous impact of aging on bictegravir pharmacokinetics by combining clinically observed data with modeling to support a safe and efficient anti-HIV therapy with advanced age. A physiologically-based pharmacokinetic (PBPK) model was developed for bictegravir with clinically observed data from phase I studies. The predictive model performance was verified using bictegravir plasma concentrations sampled as part of the general therapeutic drug monitoring (TDM) program of the Swiss HIV Cohort Study in young (20-55 years) and elderly PLWH (55-85 years). The verified PBPK model subsequently predicted the continuous impact of aging on bictegravir pharmacokinetics across adulthood (20-99 years). Bictegravir exposure was unchanged in elderly compared with young PLWH when analyzing the TDM data of the Swiss HIV Cohort Study. PBPK simulations predicted clinically observed data from 60 young and 32 elderly PLWH mostly within the 95% confidence interval, demonstrating the predictive power of the used modeling approach. Simulations predicted drug exposure to increase up to 40% during adulthood, which was not statistically significantly different from the age-related pharmacokinetic changes of other HIV and non-HIV drugs. Sex had no impact on the age-related changes of bictegravir pharmacokinetics. Considering the safety margin of bictegravir, a dose adjustment for the novel integrase inhibitor is a priori not necessary in elderly PLWH in the absence of severe comorbidities.
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http://dx.doi.org/10.1002/cpt.2178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048864PMC
April 2021

The coArtHA trial-identifying the most effective treatment strategies to control arterial hypertension in sub-Saharan Africa: study protocol for a randomized controlled trial.

Trials 2021 Jan 21;22(1):77. Epub 2021 Jan 21.

Ifakara Health Institute, Ifakara branch, Ifakara, United Republic of Tanzania.

Background: Arterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa.

Methods: In this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged < 65 years and ≥ 65 years, respectively. Clinical manifestations of end-organ damage and cost-effectiveness at 6 months are secondary endpoints.

Discussion: This trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region.

Trial Registration: Clinicaltrials.gov NCT04129840 . Registered on 17 October 2019 ( https://www.clinicaltrials.gov/ ).
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http://dx.doi.org/10.1186/s13063-021-05023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818218PMC
January 2021

Community-acquired and hospital-acquired respiratory tract infection and bloodstream infection in patients hospitalized with COVID-19 pneumonia.

J Intensive Care 2021 Jan 18;9(1):10. Epub 2021 Jan 18.

Clinical Bacteriology and Mycology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.

Objectives: SARS-CoV-2 may cause acute lung injury, and secondary infections are thus relevant complications in patients with COVID-19 pneumonia. However, detailed information on community- and hospital-acquired infections among patients with COVID-19 pneumonia is scarce.

Methods: We identified 220 SARS-CoV-2-positive patients hospitalized at the University Hospital Basel, Switzerland (between 25 February and 31 May 2020). We excluded patients who declined the general consent (n = 12), patients without clinical evidence of pneumonia (n = 29), and patients hospitalized for < 24 h (n = 17). We evaluated the frequency of community- and hospital-acquired infections using respiratory and blood culture materials with antigen, culture-based, and molecular diagnostics. For ICU patients, all clinical and microbial findings were re-evaluated interdisciplinary (intensive care, infectious disease, and clinical microbiology), and agreement reached to classify patients with infections.

Results: In the final cohort of 162 hospitalized patients (median age 64.4 years (IQR, 50.4-74.2); 61.1% male), 41 (25.3%) patients were admitted to the intensive care unit, 34/41 (82.9%) required mechanical ventilation, and 17 (10.5%) of all hospitalized patients died. In total, 31 infections were diagnosed including five viral co-infections, 24 bacterial infections, and three fungal infections (ventilator-associated pneumonia, n = 5; tracheobronchitis, n = 13; pneumonia, n = 1; and bloodstream infection, n = 6). Median time to respiratory tract infection was 12.5 days (IQR, 8-18) and time to bloodstream infection 14 days (IQR, 6-30). Hospital-acquired bacterial and fungal infections were more frequent among ICU patients than other patients (36.6% vs. 1.7%). Antibiotic or antifungal treatment was administered in 71 (43.8%) patients.

Conclusions: Community-acquired viral and bacterial infections were rare among COVID-19 pneumonia patients. By contrast, hospital-acquired bacterial or fungal infections were frequently complicating the course among ICU patients.
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http://dx.doi.org/10.1186/s40560-021-00526-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812551PMC
January 2021
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