We assessed the risk for different exposures to SARS-CoV-2 during a COVID-19 outbreak among healthcare workers on a hospital ward in late 2020. We found working with isolated COVID-19 patients did ...not increase the risk of COVID-19 among workers, but working shifts with presymptomatic healthcare coworkers did.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Of 1,118 patients with COVID-19 at a university hospital in Switzerland during October 2020–June 2021, we found 83 (7.4%) had probable or definite healthcare-associated COVID-19. After in-hospital ...exposure, we estimated secondary attack rate at 23.3%. Transmission was associated with longer contact times and with lower cycle threshold values among index patients.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing ...the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all.
Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. ...Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (
Helicobacter pylori
,
Borrelia burgdorferi
sensu
lato
,
Toxoplasma gondii
, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for
Helicobacter pylori
(accelerated failure time (AFT) − 15.92, 95% CI − 29.96; − 1.88), cytomegalovirus (AFT − 22.81, 95% CI − 36.41; − 9.22) and
Borrelia burgdorferi
sensu
lato
(AFT − 25.25, 95% CI − 43.40; − 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection − 12.42 95% CI − 18.55; − 6.30). Our results suggest an effect of seropositivity for
Helicobacter pylori
, cytomegalovirus, and
Borrelia burgdorferi
sensu
lato
on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Starting combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection results in a smaller HIV-1 latent reservoir, reduced immune ...activation, and less viral diversity compared to starting cART during chronic infection. We report results of a 4-year study designed to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir (DTG) monotherapy.
Methods
EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. People with HIV (PWH) who started cART <180 days after a documented primary HIV-1 infection with suppressed viral load were randomized (2:1) to DTG monotherapy with 50 mg daily or continuation of cART. The primary endpoints were the proportion of PWH with viral failure at 48, 96, 144, and 192 weeks; noninferiority margin was 10%. After 96 weeks, randomization was lifted and patients were permitted to switch treatment groups as desired.
Results
Of 101 PWH randomized, 68 were assigned to DTG monotherapy and 33 to cART. At week 96 in the per-protocol population, 64/64 (100%) showed virological response in the DTG monotherapy group versus 30/30 (100%) in the cART group (difference, 0.00%; upper bound of 95% confidence interval 6.22%). This demonstrated noninferiority of DTG monotherapy at the prespecified level. At week 192, the study end, no virological failure occurred in either group during 13 308 and 4897 person weeks of follow-up for the DTG monotherapy (n = 80) and cART groups, respectively.
Conclusions
This trial suggests that early cART initiation during primary HIV infection allows sustained virological suppression after switching to DTG monotherapy.
EARLY-SIMPLIFIED is a 4-year open-label trial with randomized and observational phases showing noninferiority of dolutegravir monotherapy versus combination antiretroviral therapy in people with HIV-1 having initiated therapy during primary infection. At 192 weeks, no virological failure occurred in either group.
Graphical Abstract
Graphical Abstract
HIV-1 RNA genetic diversity predicts time since infection which is important for clinical care and research. It's unclear, however, whether proviral DNA genetic diversity sampled under suppressive ...antiretroviral therapy can be used for this purpose. We tested whether proviral genetic diversity from NGS sequences predicts time since infection and recency in 221 people with HIV-1 with known infection time. Proviral diversity was significantly associated with time since infection (p<5*10-07, R2 up to 25%) and predictive of treatment initiation during recent infection (AUC-ROC up to 0.85). This shows the utility of proviral genetic diversity as a proxy for time since infection.
Abstract
Human immunodeficiency virus type 1 (HIV-1) infection is treated with antiretroviral therapy (ART), usually consisting of 2–3 different drugs, referred to as combination ART (cART). Our ...recent randomized clinical trial comparing a switch to dolutegravir monotherapy with continuation of cART in early-treated individuals demonstrated sustained virological suppression over 48 weeks. Here, we characterize the longitudinal landscape of the HIV-1 reservoir in these participants, with particular attention to potential differences between treatment groups regarding evidence of evolution as a proxy for low-level replication. Near full-length HIV-1 proviral polymerase chain reaction and next-generation sequencing was applied to longitudinal peripheral blood mononuclear cell samples to assess proviral evolution and the potential emergence of drug resistance mutations (DRMs). Neither an increase in genetic distance nor diversity over time was detected in participants of both treatment groups. Single proviral analysis showed high proportions of defective proviruses and low DRM numbers. No evidence for evolution during dolutegravir monotherapy was found in these early-treated individuals.
We characterized the longitudinal proviral reservoir of individuals successfully treated with dolutegravir monotherapy and showed no evidence of evolution as a proxy for replication, no emerging drug resistance mutations, and no differences in single provirus landscape compared to individuals on standard treatment.
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to ...assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent ...TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear.
Methods
We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures.
Results
In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio HR 9.8, 5.8–16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease.
Conclusions
TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.
Incident active tuberculosis (TB) in people with human immunodeficiency virus type 1 (HIV-1) is declining in Switzerland, which is only in part explained by TB specific prevention. Controlling the HIV-1 infection and immune system restoration contribute to the TB decline.
Abstract
Background
HIV-1 replication capacity (RC) of transmitted/founder viruses may influence the further course of HIV-1 infection.
Methods
RCs of 355 whole-genome primary HIV-1 isolates derived ...from samples acquired during acute and recent primary HIV-1 infection (PHI) were determined using a novel high-throughput infection assay in primary cells. The RCs were used to elucidate potential factors that could be associated with RC during PHI.
Results
Increased RC was found to be associated with increased set point viral load (VL), and significant differences in RCs among 13 different HIV-1 subtypes were discerned. Notably, we observed an increase in RCs for primary HIV-1 isolates of HIV-1 subtype B over a 17-year period. Associations were not observed between RC and CD4 count at sample date of RC measurement, CD4 recovery after initiation of antiretroviral treatment, CD4 decline in untreated individuals, and acute retroviral syndrome severity scores.
Conclusions
These findings highlight that RCs of primary HIV-1 isolates acquired during the acute and recent phase of infection are more associated with viral factors, that is set point VL, than with host factors. Furthermore, we observed a temporal increase in RC for HIV-1 subtype B viruses over a period of 17 years.
Clinical Trials Registration
NCT00537966.
Using 355 primary HIV-1 isolates of acute and recently HIV-1–infected patients, we elucidated that replication capacity is associated with set point viral load, HIV-1 subtype, and viral diversity, as well as calendar year.
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