Drug resistant HIV is a major threat to the long-term efficacy of antiretroviral treatment. Around 10% of ART-naïve patients in Europe are infected with drug-resistant HIV type 1. Hence it is ...important to understand the dynamics of transmitted drug resistance evolution. Thanks to routinely performed drug resistance tests, HIV sequence data is increasingly available and can be used to reconstruct the phylogenetic relationship among viral lineages. In this study we employ a phylodynamic approach to quantify the fitness costs of major resistance mutations in the Swiss HIV cohort. The viral phylogeny reflects the transmission tree, which we model using stochastic birth-death-sampling processes with two types: hosts infected by a sensitive or resistant strain. This allows quantification of fitness cost as the ratio between transmission rates of hosts infected by drug resistant strains and transmission rates of hosts infected by drug sensitive strains. The resistance mutations 41L, 67N, 70R, 184V, 210W, 215D, 215S and 219Q (nRTI-related) and 103N, 108I, 138A, 181C, 190A (NNRTI-related) in the reverse trancriptase and the 90M mutation in the protease gene are included in this study. Among the considered resistance mutations, only the 90M mutation in the protease gene was found to have significantly higher fitness than the drug sensitive strains. The following mutations associated with resistance to reverse transcriptase inhibitors were found to be less fit than the sensitive strains: 67N, 70R, 184V, 219Q. The highest posterior density intervals of the transmission ratios for the remaining resistance mutations included in this study all included 1, suggesting that these mutations do not have a significant effect on viral transmissibility within the Swiss HIV cohort. These patterns are consistent with alternative measures of the fitness cost of resistance mutations. Overall, we have developed and validated a novel phylodynamic approach to estimate the transmission fitness cost of drug resistance mutations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hospital-acquired pneumonia (HAP) and its specific subset, non-ventilator hospital-acquired pneumonia (nvHAP) are significant contributors to patient morbidity and mortality. Automated surveillance ...systems for these healthcare-associated infections have emerged as a potentially beneficial replacement for manual surveillance. This systematic review aims to synthesise the existing literature on the characteristics and performance of automated nvHAP and HAP surveillance systems.
We conducted a systematic search of publications describing automated surveillance of nvHAP and HAP. Our inclusion criteria covered articles that described fully and semi-automated systems without limitations on patient demographics or healthcare settings. We detailed the algorithms in each study and reported the performance characteristics of automated systems that were validated against specific reference methods. Two published metrics were employed to assess the quality of the included studies.
Our review identified 12 eligible studies that collectively describe 24 distinct candidate definitions, 23 for fully automated systems and one for a semi-automated system. These systems were employed exclusively in high-income countries and the majority were published after 2018. The algorithms commonly included radiology, leukocyte counts, temperature, antibiotic administration, and microbiology results. Validated surveillance systems' performance varied, with sensitivities for fully automated systems ranging from 40 to 99%, specificities from 58 and 98%, and positive predictive values from 8 to 71%. Validation was often carried out on small, pre-selected patient populations.
Recent years have seen a steep increase in publications on automated surveillance systems for nvHAP and HAP, which increase efficiency and reduce manual workload. However, the performance of fully automated surveillance remains moderate when compared to manual surveillance. The considerable heterogeneity in candidate surveillance definitions and reference standards, as well as validation on small or pre-selected samples, limits the generalisability of the findings. Further research, involving larger and broader patient populations is required to better understand the performance and applicability of automated nvHAP surveillance.
Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for ...considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=51.4, 588.8 (for 184V) to 2.7/100-person-years;0.7, 10.9 (for 215D). RR increased significantly with fitness cost (increase by 1.61.3,2.0 per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, and the riskfactors for hepatitis C virus (HCV) among HIV-coinfected and HIV negative men who have ...sex with men (MSM).
Methods
A meta-analysis of 28 studies was carried out by pooling HCV incidence data of HIV-coinfected and HIV negative MSM. Differences in incidence outcome depending on the prospective or retrospective nature of the individual studies were investigated.
Results
The pooled incidence of HCV in MSM was 6.3 per 1000 person-years (95% CI 5.0–7.5). The overall estimated incidence was 19-fold higher in HIV positive compared to HIV negative MSM living in resource-rich countries. This result was confirmed when the analysis was restricted to high-quality studies. Factors associated with an increased risk for incident HCV included behavioural factors (sexual risk behaviour and recreational drug use) as well as biological characteristics (HIV coinfection and a recent history of syphilis).
Conclusion
In conclusion, incident HCV predominantly affects HIV positive MSM. The incidence rate varied largely between studies, factors such as study design might play an important role.
Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence ...of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles.
The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged).
In 9298 included individuals, median age was 51 years (IQR, 43-58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)-based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber-mostly with cardiovascular drugs-and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of co-medications was higher.
Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.
BACKGROUND:Little is known about prevalence of drug resistance among HIV-infected Ugandans, a setting with over 15 years of public-sector access to antiretroviral therapy (ART) and where virological ...monitoring was only recently introduced.
SETTING:This study was conducted in the adultsʼ out-patient clinic of the Infectious Diseases Institute, Kampala, Uganda.
METHODS:HIV genotyping was performed in ART naïve patients and in treatment experienced patients on ART for ≥ six months with virological failure (≥1000 copies/mL).
RESULTS:A total of 152 ART naïve and 2511 ART experienced patients were included. Transmitted drug resistance was detected in 9 (5.9%) patients. After a median time on ART of 4.7 years (interquartile range (IQR)2.5-8.7), 190 patients (7.6%) had virological failure with a median viral load of 4.4 log10 copies/mL (IQR:3.9-4.9). Additionally, 146 patients had a viral load between 51 and 999 copies/ml. Most patients with virological failure (142, 74.7%) were on first-line ART. For 163 (85.8%) ART experienced patients genotype results were available. Relevant drug resistance mutations were observed in 135 (82.8%), of which 103 (63.2%) had resistance to two drug classes, and 11 (6.7%) had resistance to all drug classes available in Uganda.
CONCLUSION:The prevalence of transmitted drug resistance was lower than recently reported by the WHO. With 92% of all patients virologically suppressed on ART, the prevalence of virological failure was low when a cut-off of 1000 copies/mL is applied, and is in-line with the third of the 90-90-90 UNAIDS targets. However, most failing patients had developed multi-class drug resistance.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
Since the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We ...explored the impact of asymptomatic status on adherence and clinical outcomes.
PLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure.
Of 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1-4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 95% confidence interval {CI}, .93-1.15). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 95% CI, .76-1.00) and less likely to develop resistance (14% vs 27%, P < .001) than symptomatic PLHIV.
Despite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.
Although combination antiretroviral therapy (cART) initiated in the acute phase of HIV-1 infection may prevent expansion of the latent reservoir, its benefits remain controversial. In the current ...study, HIV-1 RNA transcription patterns in peripheral blood mononuclear cells (PBMC) were monitored during acute cART to assess the effect of early treatment on cellular viral reservoirs.
Acutely HIV-1 infected patients (n = 24) were treated within 3-15 weeks after infection. Patients elected to cease treatment after ≥1 year of therapy. HIV-1 DNA (vDNA), HIV-1 RNA species expressed both in latently and productively infected cells, unspliced (UsRNA), multiply spliced (MsRNA-tatrev; MsRNA-nef), and PBMC-associated extracellular virion RNA (vRex), expressed specifically by productively infected cells, were quantified in PBMC by patient matched real-time PCR prior, during and post cART. In a matched control-group of patients on successful cART started during chronic infection (n = 15), UsRNA in PBMC and vDNA were measured cross-sectionally. In contrast to previous reports, PBMC-associated HIV-1 RNAs declined to predominantly undetectable levels on cART. After cART cessation, UsRNA, vRex, and MsRNA-tatrev rebounded to levels not significantly different to those at baseline (p>0.1). In contrast, MsRNA-nef remained significantly lower as compared to pretreatment (p = 0.015). UsRNA expressed at the highest levels of all viral RNAs, was detectable on cART in 42% of patients with cART initiated during acute infection as opposed to 87% of patients on cART initiated during chronic infection (Fisher's exact test; p = 0.008). Accordingly, UsRNA levels were 105-fold lower in the acute as compared to the chronic group.
Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on cART. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reconstructive vascular surgery has become increasingly common. Vascular graft infections (VGIs) are serious complications, leading to increased morbidity and mortality. Previously described risk ...factors for VGIs include groin incisions, wound infections, and comorbidities. We aimed to identify modifiable predictors for VGIs as targets for infection prevention strategies.
Participants of the prospective Vascular Graft Infection Cohort (VASGRA) with surgery between 2013 and 2017 were included. The observation time was calculated from surgery until a confirmed VGI or the last follow-up. Variables were assessed by infection status, using non-parametric tests. Univariable and multivariable Cox proportional hazard regression models, adjusted for demographic factors, were applied to assess risk factors for a VGI.
A total of 438 predominantly male (83.1%) patients with a median age of 71 years (interquartile range IQR 63 - 76) contributed to 554 person years of follow-up. Thereof, 39 (8.9%) developed a VGI, amounting to an incidence rate of 7.0/100 person years. We found incisional surgical site infections (adjusted hazard ratio aHR 10.09, 95% CI 2.88 - 35.34); hemorrhage (aHR 4.92, 1.28-18.94); renal insufficiency (aHR 4.85, 1.20 - 19.61); inadequate perioperative prophylaxis in patients with an established antibiotic treatment, compared to the additional application of perioperative prophylaxis (aHR 2.87, 95% CI 1.17 - 7.05); and procedure time increases of 1-hour intervals (aHR 1.22, 95% CI 1.08 - 1.39) to be risk factors for VGIs.
We identified procedure time; inadequate perioperative prophylaxis, especially among patients with an established antibiotic treatment; and several postsurgical infectious and non-infectious complications as modifiable, predictive factors for VGIs and, therefore, as keys to improved surveillance programs and prevention strategies.
NCT01821664.
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