The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort ...Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicity.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Objectives
Understanding the drivers of HIV‐1 transmission is of importance for curbing the ongoing epidemic. Phylogenetic methods based on single viral sequences allow us to assess whether two ...individuals are part of the same viral outbreak, but cannot on their own assess who potentially transmitted the virus. We developed and assessed a molecular epidemiology method with the main aim to screen cohort studies for and to characterize individuals who are ‘potential HIV‐1 transmitters’, in order to understand the drivers of HIV‐1 transmission.
Methods
We developed and validated a molecular epidemiology approach using longitudinally sampled viral Sanger sequences to characterize potential HIV‐1 transmitters in the Swiss HIV Cohort Study.
Results
Our method was able to identify 279 potential HIV‐1 transmitters and allowed us to determine the main epidemiological and virological drivers of transmission. We found that the directionality of transmission was consistent with infection times for 72.9% of 85 potential HIV‐1 transmissions with accurate infection date estimates. Being a potential HIV‐1 transmitter was associated with risk factors including viral load adjusted odds ratiomultivariable (95% confidence interval): 1.86 (1.49–2.32), syphilis coinfection 1.52 (1.06–2.19), and recreational drug use 1.45 (1.06–1.98). By contrast for the potential HIV‐1 recipients, this association was weaker or even absent 1.18 (0.82–1.72), 0.89 (0.52–1.55) and 1.53 (0.98–2.39), respectively, indicating that inferred directionality of transmission is useful at the population level.
Conclusions
Our results indicate that longitudinally sampled Sanger sequences do not provide sufficient information to identify transmitters with high certainty at the individual level, but that they allow the drivers of transmission at the population level to be characterized.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
An abstract of the study of Bernasconi et al. about the BET bromodomain inhibitor (BET-i) BAY 1238097: Mechanism of action and pre-clinical activity in diffuse large B-cell lymphoma (DLBCL) is ...presented. Among other things BAY 1238097 is a novel BET-i, active in lymphoma models (ENA2015). Here, we characterize its mechanism of action and report further in vitro and in vivo activity data in DLBCL. BAY 1238097 affected the growth of both GCB and ABC DLBCL xenografts: treated tumors resulted 6-8 fold smaller in volume respect to controls. At GEP, BAY 1238097 decreased target genes of Myc, Notch and E2F, members of the NFKB/MYDB8 and mTORIAKT signaling. The up- regulated transcripts were mainly represented by histones. The GEP signatures highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-i, mTOR-i and demethylatirig agents. BAY 1238097 has anti lymphoma in vivo activity, and is able to interfere with pathways relevant for lymphoma cells and is synergistic with EZH2-i and mTOR-i.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
An abstract of a study by Arribas et al on PQR309, idelalisib, duvelisib and ibrutinib that lead to similar gene expression changes in activated B-cell like (ABC) diffuse large B-cell lymphoma ...(DLBCL) is presented. Gene expression profiling was obtained with the lllumina-HumanHT-12 Expression-BeadChips and analyzed with limma t-test. A GSEA was performed using the limma-derived gene expression profiling signatures obtained for each drug. The study demonstrated the targeted fundamental pathways of all models sustaining lymphoma cell proliferation and survival. Their early effects on the lymphoma cell transcriptome were very similar, but with varied degree of changes among drugs, possibly reflecting their main targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective
Data from observational cohorts may be influenced by population structure and loss to follow‐up (LTFU). Quality of care may be associated with participation in cohort networks. We aimed to ...study the participation, characteristics and retention rates of immigrants in the Swiss HIV Cohort Study (SHCS).
Methods
We compared enrolment over time (1996–1999, 2000–2003 and 2004–2008) and LTFU between individuals from different geographical regions. In 2008, we performed a cross‐sectional survey to investigate the proportion of individuals not participating in the SHCS but who were in care at SHCS institutions. Predictors for LTFU were analysed using Cox proportional hazard models, and those for nonparticipation using logistic regression.
Results
A total of 7840 individuals entered the SHCS during the observation period. The proportion of immigrants increased over time, especially the proportion of women from sub‐Saharan Africa, which increased from 21 to 48% during the observation period. Overall LTFU was 3.76 95% confidence interval (CI) 3.58–3.95/100, with the highest hazard ratio in men from sub‐Saharan Africa (2.82/100 patient‐years; 95% CI 2.30–3.46/100), compared with men from northwestern countries. Other predictors for LTFU were age <30 years, lower education, injecting drug use, and higher baseline CD4 cell counts. Participants taking antiretroviral therapy had reduced LTFU. The survey showed that 84% of HIV‐infected patients in care at SHCS institutions were enrolled in the cohort. Nonparticipation was more likely among men from non‐European regions (odds ratio 2.73; 95% CI 2.29–3.24), women from sub‐Saharan Africa (odds ratio 3.01; 95% CI 2.40–3.77) and women from Latin America/Caribbean (odds ratio 2.10; 95% CI 1.30–3.39).
Conclusions
Numbers of HIV‐infected immigrants are increasing but they are underrepresented in the SHCS, and immigrants are more likely to be lost to follow‐up.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS).
Methods
...Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self‐reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART.
Results
A total of 6529 participants (including 31% women) were followed during 31 215 person‐years; 5.1% participants died; 10.5% were lost to follow‐up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all‐cause mortality subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07–2.83, compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49–3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users.
Conclusions
Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV‐positive persons. We assessed the effect on smoking cessation of training HIV care physicians in ...counselling.
Methods
The Swiss HIV Cohort Study (SHCS) is a multicentre prospective observational database. Our single‐centre intervention at the Zurich centre included a half day of standardized training for physicians in counselling and in the pharmacotherapy of smokers, and a physicians' checklist for semi‐annual documentation of their counselling. Smoking status was then compared between participants at the Zurich centre and other institutions. We used marginal logistic regression models with exchangeable correlation structure and robust standard errors to estimate the odds of smoking cessation and relapse.
Results
Between April 2000 and December 2010, 11 056 SHCS participants had 121 238 semi‐annual visits and 64 118 person‐years of follow‐up. The prevalence of smoking decreased from 60 to 43%. During the intervention at the Zurich centre from November 2007 to December 2009, 1689 participants in this centre had 6068 cohort visits. These participants were more likely to stop smoking odds ratio (OR) 1.23; 95% confidence interval (CI) 1.07–1.42; P = 0.004 and had fewer relapses (OR 0.75; 95% CI 0.61–0.92; P = 0.007) than participants at other SHCS institutions. The effect of the intervention was stronger than the calendar time effect (OR 1.19 vs. 1.04 per year, respectively). Middle‐aged participants, injecting drug users, and participants with psychiatric problems or with higher alcohol consumption were less likely to stop smoking, whereas persons with a prior cardiovascular event were more likely to stop smoking.
Conclusions
An institution‐wide training programme for HIV care physicians in smoking cessation counselling led to increased smoking cessation and fewer relapses.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Following clearance of incident hepatitis C virus (HCV) infections, HCV antibody levels may decline, resulting in seroreversion. It is unclear to what extent HCV antibody level ...trajectories differ between patients with treatment‐induced sustained virological response (SVR), those with spontaneous clearance and those with untreated replicating HCV infection. We investigated HCV antibody level dynamics in HIV‐infected MSM with different clinical outcomes.
Methods
We investigated anti‐HCV antibody level dynamics following an incident HCV infection in 67 HIV‐infected men who have sex with men (MSM) with different clinical outcomes: SVR (n = 33), spontaneous clearance (n = 12), and untreated replicating infection (n = 22). Antibody levels were measured at the time of HCV diagnosis, and at yearly intervals for 3 years thereafter.
Results
At baseline, median HCV antibody levels were similar in the three groups: 13.4, 13.8 and 13.5 sample to cut‐off (S/CO) for SVR, spontaneous clearance and untreated infection, respectively. Over 3 years of follow‐up, SVR was associated with a more pronounced decrease in anti‐HCV levels compared with spontaneous clearance and untreated infection median decline 71% interquartile range (IQR: 43–87%), 38% (IQR: 29–60%) and 12% (IQR: 9–22%), respectively; P < 0.001. Seroreversions occurred in five of 33 (15%) patients with SVR and in one of 12 (8%) with spontaneous clearance. A shorter delay between time of infection and treatment start correlated with higher rates of decline in antibody levels. Seven patients experienced a reinfection.
Conclusions
Treatment‐induced HCV clearance was associated with a more pronounced decline in anti‐HCV antibody levels and with higher rates of seroreversion compared with spontaneous clearance or untreated replicating HCV infection among HIV‐infected MSM with incident HCV infections. Rapid clearance of HCV RNA following early HCV treatment might impair the development of persistent antibody titres.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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