Publications by authors named "Helen Kovari"

52 Publications

Alcohol consumption and neurocognitive deficits in people with well-treated HIV in Switzerland.

PLoS One 2021 2;16(3):e0246579. Epub 2021 Mar 2.

Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland.

Background: Hazardous alcohol consumption and HIV infection increase the risk of neurocognitive impairment (NCI). We examined the association between alcohol consumption and specific neurocognitive domain function in people with HIV (PWH) taking modern antiretroviral therapy.

Methods: The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is a prospective, longitudinal, multicentre and multilingual (French, German and Italian) study of patients aged ≥45 years old enrolled in the Swiss HIV Cohort Study (SHCS). Baseline data from 981 study participants were examined. Five neurocognitive domains were evaluated: motor skills, speed of information processing, attention/working memory, executive function and verbal episodic memory. NCI was examined as binary (presence/absence) and continuous (mean z-score) outcomes against Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) scores using logistic and linear regression models, respectively.

Results: Most participants (96.2%) had undetectable viral loads and 64% were aged >50 years old. Hazardous alcohol consumption was observed in 49.4% of participants and binge drinking in 4.2%. While alcohol consumption frequency and quantity were not associated with NCI, the practice of binge drinking was significantly associated with impaired motor skills and overall neurocognitive function in both binary (odds ratio, OR ≥2.0, P <0.05) and continuous (mean z-score difference -0.2 to -0.4, P ≤0.01) outcomes. A significant U-shaped distribution of AUDIT-C score was also observed for motor skills and overall neurocognitive function.

Conclusions: In this cohort of PWH with well-controlled HIV infection, NCI was associated with the practice of binge drinking rather than alcohol consumption frequency or quantity. Longitudinal analysis of alcohol consumption and NCI in this population is currently underway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246579PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924787PMC
March 2021

The association between depressive symptoms and neurocognitive impairment in people with well-treated HIV in Switzerland.

Int J STD AIDS 2021 Feb 25:956462420987434. Epub 2021 Feb 25.

Infectious Diseases Service, 30635Lausanne University Hospital, Lausanne, Switzerland.

Background: Depression may contribute to neurocognitive impairment (NCI) in people with HIV (PWH). Attributing NCI to depression rather than to HIV is complicated as depression may be both a causal factor and an effect of NCI. This study aimed to determine the association between depressive symptoms and NCI among PWH with well-controlled infection.

Methods: The Neurocognitive Assessment in the Metabolic and Ageing Cohort study is an ongoing, prospective, longitudinal study of PWH aged ≥45 years old nested within the Swiss HIV Cohort Study. Neurocognitive Assessment in the Metabolic and Ageing Cohort study participants underwent neurocognitive assessment and grading of depressive symptoms using the Centre for Epidemiological Studies Depression Scale. Neurocognitive impairment categories were defined using Frascati criteria. Participants with NCI related to neurological or psychiatric confounders other than depression were excluded. The cross-sectional association between the Centre for Epidemiological Studies Depression score and neurocognitive impairment was examined taking Centre for Epidemiological Studies Depression score as a continuous variable and then as a binary variable using two score thresholds, 16 and 27.

Results: Excluding 79 participants with confounding factors, 902 participants were studied: 81% were men; 96% had plasma viral loads <50 copies/ml; 35% had neurocognitive impairment; 28% had Centre for Epidemiological Studies Depression scores ≥16. Higher Centre for Epidemiological Studies Depression scores were associated with female sex ( = 0.0003), non-Caucasian origin ( = 0.011) and current/past intravenous drug use ( = 0.002). Whilst neurocognitive impairment was associated with higher Centre for Epidemiological Studies Depression scores, the Centre for Epidemiological Studies Depression score was a poor predictor of having neurocognitive impairment (area under the ROC curve 0.604). Applying a Centre for Epidemiological Studies Depression score threshold of 16 predicted the presence of neurocognitive impairment with a sensitivity of 38.3% (specificity 77.2%), increasing the threshold to 27 lowered sensitivity to 15.4% (specificity 93.6%).

Conclusion: In this large cohort of PWH in Switzerland, we did not observe a Centre for Epidemiological Studies Depression score threshold that was sensitive in predicting neurocognitive impairment. As neurocognitive impairment was however associated with higher Centre for Epidemiological Studies Depression scores, the data support the screening for and treatment of depression among PWH diagnosed with neurocognitive impairment.
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http://dx.doi.org/10.1177/0956462420987434DOI Listing
February 2021

Longitudinal Progression of Subclinical Coronary Atherosclerosis in Swiss HIV-Positive Compared With HIV-Negative Persons Undergoing Coronary Calcium Score Scan and CT Angiography.

Open Forum Infect Dis 2020 Oct 16;7(10):ofaa438. Epub 2020 Sep 16.

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

Background: People with HIV (HIV+) may have increased cardiovascular event rates compared with HIV-negative (HIV-) persons. Cross-sectional data from the United States and Switzerland, based on coronary artery calcium scan (CAC) and coronary computed tomography angiography (CCTA), suggest, respectively, increased and similar prevalence of subclinical atherosclerosis in HIV+ vs HIV- persons.

Methods: We repeated CAC/CCTA in 340 HIV+ and 90 HIV- study participants >2 years after baseline CAC/CCTA. We assessed the association of HIV infection, Framingham risk score (FRS), and HIV-related factors with the progression of subclinical atherosclerosis.

Results: HIV+ were younger than HIV- participants (median age, 52 vs 56 years;  < .01) but had similar median 10-year FRS (8.9% vs 9.0%;  = .82); 94% had suppressed HIV viral load. In univariable and multivariable analyses, FRS was associated with the incidence rate ratio (IRR) of new subclinical atherosclerosis at the follow-up CAC/CCTA, but HIV infection was not: any plaque (adjusted IRR for HIV+ vs HIV- participants, 1.21; 95% CI, 0.62-2.35), calcified plaque (adjusted IRR for HIV+ vs HIV- participants, 1.06; 95% CI, 0.56-2), noncalcified/mixed plaque (adjusted IRR for HIV+ vs HIV- participants, 1.24; 95% CI, 0.69-2.21), and high-risk plaque (adjusted IRR for HIV+ vs HIV- participants, 1.46; 95% CI, 0.66-3.20). Progression of CAC score between baseline and follow-up CAC/CCTA was similar in HIV+ (median annualized change [interquartile range {IQR}], 0.41 [0-10.19]) and HIV- participants (median annualized change [IQR], 2.38 [0-16.29];  = .11), as was progression of coronary segment severity score (HIV+: median annualized change [IQR], 0 [0-0.47]; HIV-: median annualized change [IQR], 0 [0-0.52];  = .10) and coronary segment involvement score (HIV+: median annualized change [IQR], 0 [0-0.45]; HIV-: median annualized change [IQR], 0 [0-0.41];  = .25).

Conclusions: In this longitudinal CAC/CCTA study from Switzerland, Framingham risk score was associated with progression of subclinical atherosclerosis, but HIV infection was not.
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http://dx.doi.org/10.1093/ofid/ofaa438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585327PMC
October 2020

Changes in Renal Function After Switching From TDF to TAF in HIV-Infected Individuals: A Prospective Cohort Study.

J Infect Dis 2020 07;222(4):637-645

Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular filtration rate (eGFR) remains unclear.

Methods: In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models.

Results: Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (-1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval [CI], .5-2.5) if the baseline eGFR was 60-89 mL/min, and 4.1 mL/min (95% CI, 1.6-6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3-9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR.

Conclusions: Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.
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http://dx.doi.org/10.1093/infdis/jiaa125DOI Listing
July 2020

Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort.

BMC Infect Dis 2019 Oct 10;19(1):834. Epub 2019 Oct 10.

Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Tenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function.

Methods: We included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF.

Results: We included 5'012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2'796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07-1.50), age > 50 years (1.43, 1.23-1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77-2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09-0.13), those treated in non-tertiary care centers (0.56, 0.46-0.70), as well as those with CD4 cell counts below 500/μL (0.77, 0.66-0.90) and with chronic hepatitis C infection (0.66, 0.54-0.80) were most likely to stay on TDF.

Conclusions: Over 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.
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http://dx.doi.org/10.1186/s12879-019-4454-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785894PMC
October 2019

Predictors of Ischemic and Hemorrhagic Strokes Among People Living With HIV: The D:A:D International Prospective Multicohort Study.

EClinicalMedicine 2019 Aug 11;13:91-100. Epub 2019 Aug 11.

Institute for Global Health, UCL, London, United Kingdom.

Background: Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV).

Methods: HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype.

Findings: 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60-1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29-5.50] and 2.24 [1.77-2.84] respectively) and older age (1.28 [1.17-1.39] and 1.19 [1.12-1.25]). Male gender (1.62 [1.14-2.31] and 0.60 [0.35-0.91]), previous cardiovascular events (4.03 [2.91-5.57] and 1.44 [0.66-3.16]) and smoking (1.90 [1.41-2.56] and 1.08 [0.68-1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72-2.40] and 0.46 [0.30-0.70]) and estimated glomerular filtration rate < 60 mL/min/1.72 m (4.80 [2.47-9.36] and 1.04 [0.67-1.60]) were stronger predictors of hemorrhagic than ischemic strokes. A CD4 count < 200 cells/μL was associated with an increased risk of hemorrhagic stroke only.

Interpretation: Risk factors for stroke may differ by subtype in PLWHIV, emphasizing the importance of further research to increase the precision of stroke risk estimation.
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http://dx.doi.org/10.1016/j.eclinm.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737207PMC
August 2019

Subclinical Atherosclerosis Imaging in People Living with HIV.

J Clin Med 2019 Jul 29;8(8). Epub 2019 Jul 29.

University Department of Medicine and Infectious Diseases Service, Kantonsspital Baselland, University of Basel, 4101 Bruderholz, Switzerland.

In many, but not all studies, people living with HIV (PLWH) have an increased risk of coronary artery disease (CAD) events compared to the general population. This has generated considerable interest in the early, non-invasive detection of asymptomatic (subclinical) atherosclerosis in PLWH. Ultrasound studies assessing carotid artery intima-media thickness (CIMT) have tended to show a somewhat greater thickness in HIV+ compared to HIV-, likely due to an increased prevalence of cardiovascular (CV) risk factors in PLWH. Coronary artery calcification (CAC) determination by non-contrast computed tomography (CT) seems promising to predict CV events but is limited to the detection of calcified plaque. Coronary CT angiography (CCTA) detects calcified and non-calcified plaque and predicts CAD better than either CAC or CIMT. A normal CCTA predicts survival free of CV events over a very long time-span. Research imaging techniques, including black-blood magnetic resonance imaging of the vessel wall and 18F-fluorodeoxyglucose positron emission tomography for the assessment of arterial inflammation have provided insights into the prevalence of HIV-vasculopathy and associated risk factors, but their clinical applicability remains limited. Therefore, CCTA currently appears as the most promising cardiac imaging modality in PLWH for the evaluation of suspected CAD, particularly in patients <50 years, in whom most atherosclerotic coronary lesions are non-calcified.
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http://dx.doi.org/10.3390/jcm8081125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723163PMC
July 2019

Cross-Sectional and Cumulative Longitudinal Central Nervous System Penetration Effectiveness Scores Are Not Associated With Neurocognitive Impairment in a Well Treated Aging Human Immunodeficiency Virus-Positive Population in Switzerland.

Open Forum Infect Dis 2019 Jul 8;6(7):ofz277. Epub 2019 Jul 8.

Infectious Diseases Service, Lausanne University Hospital, Switzerland.

Background: Neurocognitive impairment (NCI) in people with human immunodeficiency virus (PWH) remains a concern despite potent antiretroviral therapy (ART). Higher central nervous system (CNS) penetration effectiveness (CPE) scores have been associated with better CNS human immunodeficiency virus (HIV) replication control, but the association between CPE and NCI remains controversial.

Methods: The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is a subgroup of the Swiss HIV Cohort Study (SHCS) that invited patients aged ≥45 years enrolled in the SHCS and followed-up at NAMACO-affiliated centers in Switzerland to participate between May 2013 and November 2016. In total, 981 patients were enrolled, all of whom underwent standardized neurocognitive assessment. Neurocognitive impairment, if present, was characterized using Frascati criteria. The CPE scores of NAMACO study participants with undetectable plasma HIV-ribonucleic acid at enrollment (909 patients) were analyzed. Cross-sectional CPE scores (at neurocognitive assessment) were examined as potential predictors of NCI in multivariate logistic regression models. The analysis was then repeated taking CPE as a cumulative score (summarizing CPE scores from ART initiation to the time of neurocognitive assessment).

Results: Most patients were male (80%) and Caucasian (92%). Neurocognitive impairment was present in 40%: 27% with HIV-associated NCI (mostly asymptomatic neurocognitive impairment), and 13% with NCI related to other factors. None of the CPE scores, neither cross-sectional nor cumulative, was statistically significantly associated with NCI.

Conclusions: In this large cohort of aviremic PWH, we observed no association between NCI, whether HIV-associated or related to other factors, and CPE score, whether cross-sectional or cumulative.
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http://dx.doi.org/10.1093/ofid/ofz277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612860PMC
July 2019

Antiretroviral Drugs Associated With Subclinical Coronary Artery Disease in the Swiss Human Immunodeficiency Virus Cohort Study.

Clin Infect Dis 2020 02;70(5):884-889

Department of Medicine and Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital Baselland, University of Basel, Bruderholz, Switzerland.

Background: Coronary artery disease (CAD) events have been associated with certain antiretroviral therapy (ART) agents. In contrast, the influence of ART on subclinical atherosclerosis is not clear. The study objective was to assess the association between individual ART agents and the prevalence and extent of subclinical CAD.

Methods: Coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) were performed in ≥45-year-old Swiss Human Immunodeficiency Virus Cohort Study participants. The following subclinical CAD endpoints were analyzed separately: CAC score >0, any plaque, calcified plaque, noncalcified/mixed plaque, segment involvement score (SIS), and segment severity score (SSS). Logistic regression models calculated by inverse probability of treatment weights (IPTW) were used to explore associations between subclinical CAD and cumulative exposure to the 10 most frequently used drugs.

Results: There were 403 patients who underwent CCTA. A CAC score >0 was recorded in 188 (47%), any plaque in 214 (53%), calcified plaque in 151 (38%), and noncalcified/mixed plaque in 150 (37%) participants. A CAC score >0 was negatively associated with efavirenz (IPTW adjusted odds ratio per 5 years 0.73, 95% confidence interval [CI] 0.56-0.96), tenofovir disoproxil fumarate (0.68, 95% CI 0.49-0.95), and lopinavir (0.64, 95% CI 0.43-0.96). Any plaque was negatively associated with tenofovir disoproxil fumarate (0.71, 95% CI 0.51-0.99). Calcified plaque was negatively associated with efavirenz (0.7, 95% CI 0.57-0.97). Noncalcified/mixed plaque was positively associated with abacavir (1.46, 95% CI 1.08-1.98) and negatively associated with emtricitabine (0.67, 95% CI 0.46-0.99). For SSS and SIS, we found no association with any drug.

Conclusions: An increased risk of noncalcified/mixed plaque was only found in patients exposed to abacavir. Emtricitabine was negatively associated with noncalcified/mixed plaque, while tenofovir disoproxil fumarate and efavirenz were negatively associated with any plaque and calcified plaque, respectively.
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http://dx.doi.org/10.1093/cid/ciz283DOI Listing
February 2020

Lipodystrophy Increases the Risk of CKD Development in HIV-Positive Patients in Switzerland: The LIPOKID Study.

Kidney Int Rep 2018 Sep 8;3(5):1089-1099. Epub 2018 May 8.

Division of Infectious Diseases, HIV Unit, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

Introduction: Antiretroviral therapy has improved the life expectancy of patients living with HIV. However, lipodystrophy syndrome (LD) remains prevalent, affecting mostly patients treated with first-generation antiretroviral drugs. This syndrome is characterized by changes in body fat distribution with or without associated metabolic changes. Here, we studied whether clinically evaluated LD is independently associated with chronic kidney disease (CKD) development (sustained estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m) in HIV-positive patients.

Methods: We conducted a prospective cohort study (the LIPOKID Study) among all the patients from the Swiss HIV Cohort Study (SHCS) with an eGFR >60 ml/min per 1.73 m upon their entry into the cohort with more than 3 months of follow-up from January 2002 to August 2016. Cox regression models were used to estimate the association between LD and CKD development.

Results: Among the 5384 patients included, 1341 (24.9%) developed LD during the follow-up. The mean follow-up time was 72.3 months (SD ±48.4). In total, 252 patients (4.7%) reached the primary endpoint after a median time of 51.3 months (±SD 39.9 months) from inclusion. A diagnosis of LD significantly increased the risk of an eGFR on univariate analysis (hazard ratio [HR] = 2.72; 95% confidence interval [95% CI] = 2.07-3.58;  < 0.001) and remained significantly higher after adjustment for known HIV and non-HIV risk factors for CKD (HR = 2.37; 95% CI = 1.67-3.36;  < 0.001). The effect of LD on CKD was not mediated through the use of nephrotoxic antiretroviral drugs.

Conclusion: Lipodystrophy syndrome is independently associated with CKD after adjustment for previously reported risk factors.
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http://dx.doi.org/10.1016/j.ekir.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127405PMC
September 2018

HIV and Aging - Perhaps Not as Dramatic as We Feared?

Gerontology 2018 15;64(5):446-456. Epub 2018 Jun 15.

University Department of Medicine and Infectious Diseases Service, Kantonsspital Baselland, University of Basel, Bruderholz, Switzerland.

Ever since the introduction of highly active antiretroviral therapy (ART) in 1995, HIV infection has been linked to "metabolic" complications (insulin resistance, dyslipidemia, osteoporosis, and others). Studies suggested increased rates of myocardial infarction, renal insufficiency, neurocognitive dysfunction, and fractures in HIV-postitive patients. Even long-term suppression of HIV seemed to be accompanied by an excess of deleterious inflammation that could promote these complications. The aims of this viewpoint paper are to summarize recent data and to examine the possibility that the problem of aging-related morbidity in HIV might not be as dramatic as previously believed.
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http://dx.doi.org/10.1159/000489172DOI Listing
December 2018

Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.

Euro Surveill 2018 05;23(21)

The members of the EuroSIDA Study Group are acknowledged at the end of the article.

Background: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection.

Aim: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends.

Methods: In three cross-sectional analyses in 2004-05, 2009-10 and 2014-15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression.

Results: Overall, the percentage of people on ART increased from 2004-05 (67.8%) to 2014-15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004-05, 87.7% in 2014-15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014-15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014-15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13-0.21) in Eastern Europe.

Conclusions: Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.
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http://dx.doi.org/10.2807/1560-7917.ES.2018.23.21.1700382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152212PMC
May 2018

Incidental Findings on Coronary Computed Tomography Angiography in Human Immunodeficiency Virus (HIV)-Positive and HIV-Negative Persons.

Open Forum Infect Dis 2018 May 20;5(5):ofy084. Epub 2018 Apr 20.

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

Background: Incidental findings on coronary computed tomography angiography (CCTA) have a great impact on the benefits and costs of testing for cardiovascular disease. The number of incidental findings might be increased in human immunodeficiency virus (HIV)-positive individuals compared with the general population. Data are limited regarding the association between incidental findings and HIV infection.

Methods: We assessed the prevalence and factors associated with incidental findings among HIV-positive and HIV-negative participants ≥45 years undergoing CCTA. Logistic regression was performed to evaluate the factors associated with incidental findings in the HIV-positive and HIV-negative groups. For the analysis of the HIV effect, a propensity score-matched dataset of HIV-positive/HIV-negative participants was used.

Results: We included 553 participants, 341 with and 212 without HIV infection. Incidental findings were observed in 291 of 553 (53%) patients. In 42 of 553 (7.6%) participants, an incidental finding resulted in additional workup. A malignancy was diagnosed in 2 persons. In the HIV-positive group, age (1.31 per 5 years, 1.10-1.56) and smoking (2.29, 1.43-3.70) were associated with incidental findings; in the HIV-negative group, age (1.26, 1.01-1.59) and a CAC score >0 (2.08, 1.09-4.02) were associated with incidental findings. Human immunodeficiency virus seropositivity did not affect the risk of incidental findings.

Conclusions: Incidental findings were highly prevalent among HIV-positive and HIV-negative persons. Human immunodeficiency virus infection was not associated with an increased risk of incidental findings.
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http://dx.doi.org/10.1093/ofid/ofy084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952950PMC
May 2018

Dietary Patterns and Physical Activity Correlate With Total Cholesterol Independently of Lipid-Lowering Drugs and Antiretroviral Therapy in Aging People Living With Human Immunodeficiency Virus.

Open Forum Infect Dis 2018 Apr 23;5(4):ofy067. Epub 2018 Mar 23.

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

Background: Hypercholesterolemia is a well established risk factor for coronary heart disease and is highly prevalent among human immunodeficiency virus (HIV)-positive persons. Antiretroviral therapy (ART) can both directly modify total cholesterol and have drug-drug interactions with statins. This makes investigating modifiable behavioral predictors of total cholesterol a pertinent task.

Methods: To explore the association between diet and physical activity with cross-sectionally measured total cholesterol, we administered a validated Food-Frequency-Questionnaire to participants of the Swiss HIV Cohort Study ≥45 years old. Linear mixed-effects models were applied to explore the associations between dietary patterns and physical activity with total cholesterol, after adjustment for clinical and demographic covariates.

Results: In total, 395 patients were included. Forty percent (158 of 395) had elevated total cholesterol (>5.2 mmol/L), and 41% (164 of 395) were not regularly physically active. In multivariable analysis, 2 factors were positively associated with total cholesterol; female sex (β = 0.562; 95% confidence interval [CI], 0.229-0.896) and the combined consumption of meat, refined/milled grains, carbonated beverages, and coffee (β = 0.243; 95% CI, 0.047-0.439). On the other hand, regular physical activity (β = -0.381; 95% CI, -0.626 to -0.136), lipid-lowering drugs (β = -0.443; 95% CI -0.691 to -0.196), ART containing tenofovir (β = -0.336; 95% CI -0.554 to -0.118), and black ethnicity (β = -0.967; 95% CI -1.524 to -0.410) exhibited a negative association.

Conclusions: We found independent associations between certain dietary patterns and physical activity with total cholesterol. Increasing physical activity might achieve cardiovascular and other health benefits in HIV-positive individuals. The clinical relevance of the identified dietary patterns requires further investigation in prospective cohort studies and randomized controlled trials.
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http://dx.doi.org/10.1093/ofid/ofy067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905359PMC
April 2018

Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons.

Eur Heart J 2018 06;39(23):2147-2154

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Rämistr. 100, University of Zurich, 8091 Zurich, Switzerland.

Aims: HIV-positive persons have increased cardiovascular event rates but data on the prevalence of subclinical atherosclerosis compared with HIV-negative persons are not uniform. We assessed subclinical atherosclerosis utilizing coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) in 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA.

Methods And Results: We assessed the association of HIV infection, cardiovascular risk profile, and HIV-related factors with subclinical atherosclerosis in univariable and multivariable analyses. HIV-positive participants (median duration of HIV infection, 15 years) were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score >0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; 95% confidence interval (CI) 0.40-0.82; P < 0.01], lower coronary segment severity score (aOR 0.72; 95% CI 0.53-0.99; P = 0.04), and lower segment involvement score (aOR 0.71, 95% CI 0.52-0.97; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; 95% CI 1.09-3.56; P = 0.02).

Conclusion: HIV-positive persons in Switzerland had a similar degree of non-calcified/mixed plaque and high-risk plaque, and may have less calcified coronary plaque, and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores.
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http://dx.doi.org/10.1093/eurheartj/ehy163DOI Listing
June 2018

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study.

J Int AIDS Soc 2018 03;21(3)

Institute for Global Health, UCL, London, United Kingdom.

Introduction: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV-positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study.

Methods: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders.

Results: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti-hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow-up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti-hypertensives (1.17 [1.10, 1.25]).

Conclusion: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV-positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions.
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http://dx.doi.org/10.1002/jia2.25083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839235PMC
March 2018

Effect of Immediate Initiation of Antiretroviral Treatment in HIV-Positive Individuals Aged 50 Years or Older.

J Acquir Immune Defic Syndr 2017 11;76(3):311-318

1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; 2Sorbonne Universités, INSERM, UPMC Univ Paris 06, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France; 3Institute of Global Health, University College London, London, United Kingdom; 4Centro Nacional de Epidemiologia, Instituto de Salud Carlos III, Madrid, Spain; 5CIBERESP, Instituto de Salud Carlos III, Madrid, Spain; 6AP-HP, Hôpital Antoine Béclère, Service de Médecine Interne, Clamart, France; 7Stichting HIV Monitoring, Amsterdam, the Netherlands; 8Academic Medical Centre, Department of Global Health and Division of Infectious Diseases, University of Amsterdam, Amsterdam, the Netherlands; 9Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands; 10Hospital San Pedro-CIBIR, Logroño, Spain; 11Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, University of Basel, Basel, Switzerland; 12Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; 13Infectious Disease Department, Hospital Parc Tauli, Sabadell, Spain; 14Hospital Clinic-IDIBAPS, Barcelona, Spain; 15Division of Infectious Diseases, Patras University Hospital, Patras, Greece; 16Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 17Université de Bordeaux, ISPED, Centre INSERM U1219-Epidemiologie-Biostatistique, Bordeaux, France; 18Centre INSERM U1219- Centre Inserm Epidémiologie et Biostatistique, Université de Bordeaux, Bordeaux, France; 19Department of Internal Medicine, Bordeaux University Hospital, Bordeaux, France; 20Université Paris Sud, UMR 1018, le Kremlin Bicêtre, Paris, France; 21Inserm, UMR 1018, le Kremlin Bicêtre, Paris, France; 22AP-HP, Hôpital de Bicêtre, Service de Santé Publique, le Kremlin Bicêtre, Paris, France; 23Southern Alberta Clinic, Calgary, AB, Canada; 24Department of Medicine, University of Calgary, Calgary, AB, Canada; 25Instituto Nacional de Infectologia Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brasil; 26Programa de Computação Científica, Fundacao Oswaldo Cruz, Rio de Janeiro, Brasil; 27Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 28Department of Internal Medicine, Yale University School of Medicine, New Haven; 29VA Connecticut Healthcare System, West Haven, CT; 30Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston; and 31Harvard-MIT Division of Health Sciences and Technology, Boston, MA.

Background: Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants.

Methods: We included HIV-positive antiretroviral therapy-naive, AIDS-free individuals aged 50-70 years after 2004 in the HIV-CAUSAL Collaboration. We used the parametric g-formula to estimate the 5-year risk of all-cause and non-AIDS mortality under (1) immediate initiation at baseline and initiation at CD4 count, (2) <500 cells/mm, and (3) <350 cells/mm. Results were presented separately for the general HIV population and for a US Veterans cohort with high mortality.

Results: The study included 9596 individuals (28% US Veterans) with median (interquantile range) age of 55 (52-60) years and CD4 count of 336 (182-513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: -0.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm.

Conclusions: Immediate initiation seems to reduce all-cause and non-AIDS mortality in patients aged 50-70 years.
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http://dx.doi.org/10.1097/QAI.0000000000001498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704899PMC
November 2017

Trends in HCV treatment uptake, efficacy and impact on liver fibrosis in the Swiss HIV Cohort Study.

Liver Int 2018 03 23;38(3):424-431. Epub 2017 Aug 23.

Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.

Background & Aims: Hepatitis C virus (HCV) therapies with interferon-free second-generation direct-acting antivirals (DAAs) are highly effective and well tolerated. They have the potential to increase treatment eligibility and efficacy in HIV-infected patients. We assessed the impact of DAAs on treatment uptake and efficacy, as well as its impact on the burden of liver disease in the Swiss HIV Cohort Study (SHCS).

Methods: We describe clinical and virological characteristics of patients treated with second-generation DAAs. We compared treatment incidence, sustained virological response (SVR)12 and liver fibrosis stages between three time periods: period 1, 01/2009-08/2011 (prior to the availability of DAAs); period 2, 09/2011-03/2014 (first generation DAAs); period 3, 04/2014-12/2015 (second generation DAAs).

Results: At the beginning of the third period, 876 SHCS participants had a chronic HCV infection of whom 180 (20%) started treatment with a second-generation DAA. Three-quarters of them had advanced liver fibrosis (Metavir ≥ F3) of whom 80% were cirrhotics. SVR12 was achieved in 173/180 (96%) patients, three patients died and four experienced a virological failure. Over the three time periods, treatment uptake (4.5/100 py, 5.7/100 py, 22.4/100 py) and efficacy (54%, 70%, 96% SVR12) continuously increased. The proportion of cirrhotic patients with replicating HCV infection in the SHCS declined from 25% at the beginning to 12% at the end of the last period.

Conclusions: After the introduction of second-generation DAAs, we observed an increase in treatment uptake and efficacy which resulted in a significant reduction in the number of cirrhotic patients with a replicating HCV infection in the SHCS.
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http://dx.doi.org/10.1111/liv.13528DOI Listing
March 2018

Another statin option in HIV.

Lancet HIV 2017 07 13;4(7):e278-e279. Epub 2017 Apr 13.

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

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http://dx.doi.org/10.1016/S2352-3018(17)30072-3DOI Listing
July 2017

Hepatitis C Infection and the Risk of Non-Liver-Related Morbidity and Mortality in HIV-Infected Persons in the Swiss HIV Cohort Study.

Clin Infect Dis 2017 02;64(4):490-497

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

Background: Hepatitis C virus (HCV) infection has been associated with increased non-liver-related morbidity and mortality. However, studies have yielded inconsistent results.

Methods: The incidence of clinical events in human immunodeficiency virus (HIV)–infected HCV-seropositive and incidence density–matched HCV-seronegative participants of the Swiss HIV Cohort Study from August 1994 to December 2014 was studied. We compared (1) HCV-seropositive with HCV-seronegative participants and (2) HCV-viremic with successfully treated nonviremic patients. Poisson regression was used to assess differences between these groups.

Results: We included 2503 HCV-seropositive participants (540 with spontaneous HCV clearance, 1294 untreated HCV RNA positive, 345 treated with sustained virologic response [SVR], 43 during treatment, and 281 treated without SVR), and 2503 HCV-seronegative controls. After a mean follow-up of 8.2 years, we observed (HCV seropositive and HCV seronegative, respectively) 107 and 18 liver events, 41 and 14 kidney events, 230 and 121 osteoporosis/fractures, 82 and 94 diabetes mellitus, 114 and 129 cardiovascular events, 119 and 147 non-AIDS malignancies, 162 and 126 Centers for Disease Control and Prevention HIV category B/C events, 106 and 10 liver-related deaths, and 227 and 218 non-liver-related deaths. Compared with HCV-negative controls, HCV-seropositive participants had an increased risk of liver events (incidence rate ratio [IRR], 6.29 [95% confidence interval {CI}, 3.52–11.22]), liver-related death (IRR, 8.24 [95% CI, 3.61–18.83]), kidney events (IRR, 2.43 [95% CI, 1.11–5.33]), and osteoporosis/fracture (IRR, 1.43 [95% CI, 1.03–2.01]). Among HCV-seropositive individuals, treated participants without SVR vs those with SVR had a higher risk of liver events (IRR, 6.79 [95% CI, 2.33–19.81]), liver-related death (IRR, 3.29 [95% CI, 1.35–8.05]), and diabetes mellitus (IRR, 4.62 [95% CI, 1.53–13.96]). Similar but not statistically significant differences were found between untreated HCV RNA–positive patients and those with SVR.

Conclusions: While HCV exposure was associated with an increased risk of kidney disease and osteoporosis/fracture, this risk did not seem to be dependent of persistent HCV RNA. Successful HCV treatment was associated with a lower incidence of liver disease, liver-related death, and diabetes mellitus, whereas the other conditions studied were less affected.
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http://dx.doi.org/10.1093/cid/ciw809DOI Listing
February 2017

Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals.

Medicine (Baltimore) 2017 Jan;96(2):e5849

aDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich bInstitute of Medical Virology, University of Zurich, Zurich cBasel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel dInfectious Diseases Department, Genève University Hospital, Genève eInfectious Diseases Department, Lausanne University Hospital, Lausanne fDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel gDivision of Infectious Diseases and Hospital Epidemiology, Kantonal Hospital St. Gallen, St. Gallen hDivision of Infectious Diseases, Regional Hospital Lugano, Lugano iDepartment of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

After several years of steady decline, syphilis is reemerging globally as a public health hazard, especially among people living with human immunodeficiency virus (HIV). Syphilis resurgence is observed mainly in men who have sex with men (MSM), yet other transmission groups are affected too. In this manuscript, we study the factors associated with syphilis incidence in the Swiss HIV cohort study in the era of highly effective antiretrovirals. Using parametric interval censored models with fixed and time-varying covariates, we studied the immunological, behavioral, and treatment-related elements associated with syphilis incidence in 3 transmission groups: MSM, heterosexuals, and intravenous drug users. Syphilis incidence has been increasing annually since 2005, with up to 74 incident cases per 1000 person-years in 2013, with MSM being the population with the highest burden (92% of cases). While antiretroviral treatment (ART) in general did not affect syphilis incidence, nevirapine (NVP) was associated with a lower hazard of syphilis incidence (multivariable hazard ratio 0.5, 95% confidence interval 0.2-1.0). We observed that condomless sex and younger age were associated with higher syphilis incidence. Moreover, time-updated CD4, nadir CD4, and CD8 cell counts were not associated with syphilis incidence. Finally, testing frequency higher than the recommended once a year routine testing was associated with a 2-fold higher risk of acquiring syphilis. Condomless sex is the main driver of syphilis resurgence in the Swiss HIV Cohort study; ART and immune reconstitution provide no protection against syphilis. This entails targeted interventions and frequent screening of high-risk populations. There is no known effect of NVP on syphilis; therefore, further clinical, epidemiological, and microbiological investigation is necessary to validate our observation.
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http://dx.doi.org/10.1097/MD.0000000000005849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266180PMC
January 2017

Liver fibrosis in treatment-naïve HIV-infected and HIV/HBV co-infected patients: Zambia and Switzerland compared.

Int J Infect Dis 2016 Oct 3;51:97-102. Epub 2016 Sep 3.

Department of Infectious Diseases, Bern University Hospital and University of Bern, CH-3010 Bern, Switzerland.

Objective: To examine the association between hepatitis B virus (HBV) infection and liver fibrosis in HIV-infected patients in Zambia and Switzerland.

Methods: HIV-infected adults starting antiretroviral therapy in two clinics in Zambia and Switzerland were included. Liver fibrosis was evaluated using the aspartate aminotransferase-to-platelet-ratio index (APRI), with a ratio >1.5 defining significant fibrosis and a ratio >2.0 indicating cirrhosis. The association between hepatitis B surface antigen (HBsAg) positivity, HBV replication, and liver fibrosis was examined using logistic regression.

Results: In Zambia, 96 (13.0%) of 739 patients were HBsAg-positive compared to 93 (4.5%) of 2058 in Switzerland. HBsAg-positive patients were more likely to have significant liver fibrosis than HBsAg-negative ones: the adjusted odds ratio (aOR) was 3.25 (95% confidence interval (CI) 1.44-7.33) in Zambia and 2.50 (95% CI 1.19-5.25) in Switzerland. Patients with a high HBV viral load (≥20000 IU/ml) were more likely to have significant liver fibrosis compared to HBsAg-negative patients or patients with an undetectable viral load: aOR 3.85 (95% CI 1.29-11.44) in Zambia and 4.20 (95% CI 1.64-10.76) in Switzerland. In both settings, male sex was a strong risk factor for significant liver fibrosis.

Conclusions: Despite the differences in HBV natural history between Sub-Saharan Africa and Europe, the degree of liver fibrosis and the association with important risk factors were similar.
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http://dx.doi.org/10.1016/j.ijid.2016.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363287PMC
October 2016

Contribution of Genetic Background and Clinical Risk Factors to Low-Trauma Fractures in Human Immunodeficiency Virus (HIV)-Positive Persons: The Swiss HIV Cohort Study.

Open Forum Infect Dis 2016 Apr 18;3(2):ofw101. Epub 2016 May 18.

Infectious Diseases Service, Kantonsspital Baselland , University of Basel , Bruderholz , Switzerland.

Background.  The impact of human genetic background on low-trauma fracture (LTF) risk has not been evaluated in the context of human immunodeficiency virus (HIV) and clinical LTF risk factors. Methods.  In the general population, 6 common single-nucleotide polymorphisms (SNPs) associate with LTF through genome-wide association study. Using genome-wide SNP arrays and imputation, we genotyped these SNPs in HIV-positive, white Swiss HIV Cohort Study participants. We included 103 individuals with a first, physician-validated LTF and 206 controls matched on gender, whose duration of observation and whose antiretroviral therapy start dates were similar using incidence density sampling. Analyses of nongenetic LTF risk factors were based on 158 cases and 788 controls. Results.  A genetic risk score built from the 6 LTF-associated SNPs did not associate with LTF risk, in both models including and not including parental hip fracture history. The contribution of clinical LTF risk factors was limited in our dataset. Conclusions.  Genetic LTF markers with a modest effect size in the general population do not improve fracture prediction in persons with HIV, in whom clinical LTF risk factors are prevalent in both cases and controls.
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http://dx.doi.org/10.1093/ofid/ofw101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943531PMC
April 2016

Dually Active HIV/HBV Antiretrovirals as Protection Against Incident Hepatitis B Infections: Potential for Prophylaxis.

J Infect Dis 2016 Aug 18;214(4):599-606. Epub 2016 May 18.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich Institute of Medical Virology, University of Zurich.

Background: Hepatitis B virus (HBV) has a detrimental effect on human immunodeficiency virus (HIV) natural course, and HBV vaccination is less effective in the HIV infected. We examine the protective effect of dually active antiretroviral therapy (DAART) for HIV/HBV (tenofovir, lamivudine, and emtricitabine) in a large cohort encompassing heterosexuals, men who have sex with men, and intravenous drug users who are HIV infected yet susceptible to HBV, with comprehensive follow-up data about risky behavior and immunological profiles.

Methods: We defined an incident HBV infection as the presence of any of HBV serological markers (hepatitis B surface antigen, anti-hepatitis B core antibodies, or HBV DNA) after a negative baseline test result for anti-hepatitis B core antibodies. Patients with positive anti-hepatitis B surface antigen serology were excluded. Cox proportional hazards models were used, with an incident case of HBV infection as the outcome variable.

Results: We analyzed 1716 eligible patients from the Swiss HIV Cohort Study with 177 incident HBV cases. DAART was negatively associated with incident HBV infection (hazard ratio [HR], 0.4; 95% confidence interval [CI], .2-.6). This protective association was robust to adjustment (HR, 0.3; 95% CI, .2-.5) for condomless sex, square-root-transformed CD4 cell count, drug use, and patient demographics. Condomless sex (HR, 1.9; 95% CI, 1.4-2.6), being a man who has sex with men (2.7; 1.7-4.2), and being an intravenous drug user (3.8; 2.4-6.1) were all associated with a higher hazard of contracting HBV.

Conclusions: Our study suggests that DAART, independently of CD4 cell count and risky behavior, has a potentially strong public health impact, including pre-exposure prophylaxis of HBV coinfection in the HIV infected.
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http://dx.doi.org/10.1093/infdis/jiw195DOI Listing
August 2016

Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation.

Eur J Clin Pharmacol 2016 Jul 29;72(7):859-67. Epub 2016 Mar 29.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.

Purpose: Some macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions.

Methods: We conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records.

Results: Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7 %) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1 % had no ECG monitoring. Of all MQAB users, 547 (15.9 %) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions.

Conclusion: In the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.
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http://dx.doi.org/10.1007/s00228-016-2043-zDOI Listing
July 2016

Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study.

Open Forum Infect Dis 2016 Jan 21;3(1):ofw009. Epub 2016 Jan 21.

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

Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results.  Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89-6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11-1.49; >2 years RR = 1.26, 95% CI, 1.13-1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26-1.81; >2 years RR = 1.17, 95% CI, 1.03-1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40-1.72; >2 years RR = 1.18, 95% CI, 1.05-1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29-1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03-1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04-1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04-1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions.  Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.
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http://dx.doi.org/10.1093/ofid/ofw009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767274PMC
January 2016

Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons.

AIDS 2016 07;30(11):1731-43

aDepartment of Infectious Diseases, CHIP, Section 8632, Finsenscentret, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark bDepartment of Infectious Diseases, CHU Saint-Pierre, Brussels, Belgium cDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland dDivision of Infectious Diseases and Department of Global Health, Academic Medical Center, University of Amsterdam, and the HIV Monitoring Foundation, Amsterdam The Netherlands eThe Kirby Institute, UNSW, Sydney, Australia fICAP-Columbia University and Harlem Hospital, New York, USA gDipartimento di Scienze della Salute, Clinica di Malattie Infectitive e Tropicali, Azienda Ospedaliera-Polo Universitario San Paolo, Milan, Italy hResearch Department of Infection and Population Health, UCL, London, UK iDepartment of Public Health, Nice University Hospital, Nice, France jUniversité Bordeaux Segalen, INSERM U 897 kEpidemiologie-Biostatistique, CHU de Bordeaux, France.

Objectives: Although several antiretroviral drugs, including the d-drugs stavudine (d4T) and didanosine (ddI), may cause biomarker-defined hepatotoxicity, their association with clinically defined end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) remains unknown.

Design: Prospective cohort study.

Methods: Data collection on adverse events of anti-HIV drugs study (D:A:D) participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or α-fetoprotein along with imaging), death, 6 months after last visit or 1 February 2014. Associations between ESLD/HCC and cumulative use of individual antiretrovirals were investigated using Poisson regression adjusting for potential confounders.

Results: During a median follow-up of 8.4 years, 319 ESLD/HCC cases occurred [incidence 1.01/1000 person-years (95% confidence interval 0.90-1.12)] with a 1-year mortality rate of 62.6%. After adjustment, cumulative (per 5 years) exposure to d4T [relative rate 1.46 (95% confidence interval 1.20-1.77)], ddI [1.32 (1.07-1.63)], tenofovir [TDF, 1.46 (1.11-1.93)] and (fos)amprenavir [APV; 1.47 (1.01-2.15)] was associated with increased ESLD/HCC rates. Longer exposure to emtricitabine [0.51 (0.32-0.83)] and nevirapine [0.76 (0.58-0.98)] were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation.

Conclusion: Cumulative use of d4T, ddI, TDF and APV were independently associated with increased ESLD/HCC rates, and intensified monitoring of liver function should hence be considered among all individuals exposed for longer time periods. The use of d-drugs should furthermore be avoided, where there are alternatives available, and focus should be put on those with longer-term d-drugs exposure who remain at increased ESLD/HCC risk. The unexpected, and viral hepatitis-independent, TDF association calls for further investigations.
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http://dx.doi.org/10.1097/QAD.0000000000001018DOI Listing
July 2016

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

PLoS One 2015 28;10(7):e0133879. Epub 2015 Jul 28.

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

Background: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR).

Methods: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT).

Results: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype.

Conclusion: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133879PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517877PMC
May 2016

High hepatic and extrahepatic mortality and low treatment uptake in HCV-coinfected persons in the Swiss HIV cohort study between 2001 and 2013.

J Hepatol 2015 Sep 1;63(3):573-80. Epub 2015 May 1.

University Clinic of Infectious Diseases, University Hospital Berne and University of Berne, Berne, Switzerland.

Background & Aims: The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy.

Methods: We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk.

Results: Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive.

Conclusions: Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.
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http://dx.doi.org/10.1016/j.jhep.2015.04.019DOI Listing
September 2015

[CME. Larva migrans].

Praxis (Bern 1994) 2014 Dec;103(25):1491-8

Klinik für Infektionskrankheiten und Spitalhygiene, Universitätsspital Zürich, Universität Zürich.

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http://dx.doi.org/10.1024/1661-8157/a001859DOI Listing
December 2014