Abstract
Introduction
The continuum of care (CoC) model has been used to describe the main pillars of HIV care. This study aims to systematically review methods and elucidate gaps in the CoC ...analyses, especially in terms of the timing of the progression through steps, recognized nowadays as a critical parameter for an effective response to the epidemic.
Methods
A PubMed and EMBASE databases search up to December 2019 resulted in 1918 articles, of which 209 were included in this review; 84 studies presented in major HIV conferences were also included. Studies that did not provide explicit definitions, modelling studies and those reporting only on metrics for subpopulations or factors affecting a CoC stage were excluded. Included articles reported results on 1 to 6 CoC stages.
Results
Percentage treated and virally suppressed was reported in 78%, percentage diagnosed and retained in care in 58%, percentage linked to care in 54% and PLHIV in 36% of the articles. Information for all stages was provided in 23 studies. Only 6 articles use novel CoC estimates:
One presents a dynamic CoC based on multistate analysis techniques, two base their time-to-next-stage estimates on a risk estimation method based on the cumulative incidence function, weighted for confounding and censoring and three studies estimated the HIV infection time based on mathematical modelling.
Conclusion
A limited number of studies provide elaborated time analyses of the CoC. Although time analyses lack the straightforward interpretation of the cross-sectional CoC, they provide valuable insights for the timely response to the HIV epidemic. A future goal would be to develop a model that retains the simplicity of the cross-sectional CoC but also incorporates timing between stages.
Missing data are common in longitudinal studies. Likelihood‐based methods ignoring the missingness mechanism are unbiased provided missingness is at random (MAR); under not‐at‐random missingness ...(MNAR), joint modeling is commonly used, often as part of sensitivity analyses. In our motivating example of modeling CD4 count trajectories during untreated HIV infection, CD4 counts are mainly censored due to treatment initiation, with the nature of this mechanism remaining debatable. Here, we evaluate the bias in the disease progression marker's change over time (slope) of a specific class of joint models, termed shared‐random‐effects‐models (SREMs), under MAR drop‐out and propose an alternative SREM model. Our proposed model relates drop‐out to both the observed marker's data and the corresponding random effects, in contrast to most SREMs, which assume that the marker and the drop‐out processes are independent given the random effects. We analytically calculate the asymptotic bias in two SREMs under specific MAR drop‐out mechanisms, showing that the bias in marker's slope increases as the drop‐out probability increases. The performance of the proposed model, and other commonly used SREMs, is evaluated under specific MAR and MNAR scenarios through simulation studies. Under MAR, the proposed model yields nearly unbiased slope estimates, whereas the other SREMs yield seriously biased estimates. Under MNAR, the proposed model estimates are approximately unbiased, whereas those from the other SREMs are moderately to heavily biased, depending on the parameterization used. The examined models are also fitted to real data and results are compared/discussed in the light of our analytical and simulation‐based findings.
The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate ...with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.
Background:
More than 300 cities including the city of Amsterdam in the Netherlands have joined the UNAIDS Fast-Track Cities initiative, committing to accelerate their HIV response and end the AIDS ...epidemic in cities by 2030. To support this commitment, we aimed to estimate the number and proportion of Amsterdam HIV infections that originated within the city, from Amsterdam residents. We also aimed to estimate the proportion of recent HIV infections during the 5-year period 2014–2018 in Amsterdam that remained undiagnosed.
Methods:
We located diagnosed HIV infections in Amsterdam using postcode data (PC4) at time of registration in the ATHENA observational HIV cohort, and used HIV sequence data to reconstruct phylogeographically distinct, partially observed Amsterdam transmission chains. Individual-level infection times were estimated from biomarker data, and used to date the phylogenetically observed transmission chains as well as to estimate undiagnosed proportions among recent infections. A Bayesian Negative Binomial branching process model was used to estimate the number, size, and growth of the unobserved Amsterdam transmission chains from the partially observed phylogenetic data.
Results:
Between 1 January 2014 and 1 May 2019, there were 846 HIV diagnoses in Amsterdam residents, of whom 516 (61%) were estimated to have been infected in 2014–2018. The rate of new Amsterdam diagnoses since 2014 (104 per 100,000) remained higher than the national rates excluding Amsterdam (24 per 100,000), and in this sense Amsterdam remained a HIV hotspot in the Netherlands. An estimated 14% 12–16% of infections in Amsterdan MSM in 2014–2018 remained undiagnosed by 1 May 2019, and 41% 35–48% in Amsterdam heterosexuals, with variation by region of birth. An estimated 67% 60–74% of Amsterdam MSM infections in 2014–2018 had an Amsterdam resident as source, and 56% 41–70% in Amsterdam heterosexuals, with heterogeneity by region of birth. Of the locally acquired infections, an estimated 43% 37–49% were in foreign-born MSM, 41% 35–47% in Dutch-born MSM, 10% 6–18% in foreign-born heterosexuals, and 5% 2–9% in Dutch-born heterosexuals. We estimate the majority of Amsterdam MSM infections in 2014–2018 originated in transmission chains that pre-existed by 2014.
Conclusions:
This combined phylogenetic, epidemiologic, and modelling analysis in the UNAIDS Fast-Track City Amsterdam indicates that there remains considerable potential to prevent HIV infections among Amsterdam residents through city-level interventions. The burden of locally acquired infection remains concentrated in MSM, and both Dutch-born and foreign-born MSM would likely benefit most from intensified city-level interventions.
Funding:
This study received funding as part of the H-TEAM initiative from Aidsfonds (project number P29701). The H-TEAM initiative is being supported by Aidsfonds (grant number: 2013169, P29701, P60803), Stichting Amsterdam Dinner Foundation, Bristol-Myers Squibb International Corp. (study number: AI424-541), Gilead Sciences Europe Ltd (grant number: PA-HIV-PREP-16-0024), Gilead Sciences (protocol numbers: CO-NL-276-4222, CO-US-276-1712, CO-NL-985-6195), and M.A.C AIDS Fund.
Migrant populations are overrepresented among persons diagnosed with HIV in the European Union and the European Economic Area. Understanding the timing of HIV acquisition (premigration or ...postmigration) is crucial for developing public health interventions and for producing reliable estimates of HIV incidence and the number of people living with undiagnosed HIV infection. We summarize a recently proposed method for determining the timing of HIV acquisition and apply it to both real and simulated data.
The considered method combines estimates from a mixed model, applied to data from a large seroconverters' cohort, with biomarker measurements and individual characteristics to derive probabilities of premigration HIV acquisition within a Bayesian framework. The method is applied to a subset of data from the European Surveillance System (TESSy) and simulated data.
Simulation study results showed good performance with the probabilities of correctly classifying a premigration case or a postmigration case being 87.4% and 80.4%, respectively. Applying the method to TESSy data, we estimated the proportions of migrants who acquired HIV in the destination country were 31.9%, 37.1%, 45.3%, and 45.2% for those originating from Africa, Europe, Asia, and other regions, respectively.
Although the considered method was initially developed for cases with multiple biomarkers' measurements, its performance, when applied to data where only one CD4 count per individual is available, remains satisfactory. Application of the method to TESSy data, estimated that a substantial proportion of HIV acquisition among migrants occurs in destination countries, having important implications for public health policy and programs.
Clinical disadvantages of initiating ART at low CD4 counts have been clearly demonstrated but whether any excess risk remains even after reaching relatively high/safe CD4 levels remains unclear. We ...explore whether individuals starting ART with <500 CD4 cells/μL who increased their CD4 count above this level, have, from this point onwards, similar risk of clinical progression to serious AIDS/non-AIDS events or death with individuals starting ART with ≥500 CD4 cells/μL.
Data were derived from a multicenter cohort (AMACS). Adults, starting PI, NNRTI or INSTI based ART, in or after 2000 were eligible, provided they started ART with ≥500 ("High CD4") or started with CD4 <500 cells/μL but surpassed this threshold while on ART ("Low CD4"). Baseline was the date of ART initiation ("High CD4") or of first reaching 500 CD4 cells/μL ("Low CD4"). Survival analysis, allowing for competing risks, was used to explore the risk of progression to study's endpoints.
The study included 694 persons in the "High CD4" and 3,306 in the "Low CD4" group. Median (IQR) follow-up was 66 (36, 106) months. In total, 257 events (40 AIDS related, 217 SNAEs) were observed. Rates of progression did not differ significantly between the two groups but the subgroup of those initiating ART with <200 CD4 cells/μL had significantly higher risk of progression after baseline, compared to those in the "High CD4" group.
Individuals starting ART with <200 cells/μL remain on increased risk even after reaching 500 CD4 cells/μL. These patients should be closely followed.
Knowledge of HIV-1 molecular transmission clusters (MTCs) is important, especially in large-scale datasets, for designing prevention programmes and public health intervention strategies. We used a ...large-scale HIV-1 sequence dataset from nine European HIV cohorts and one Canadian, to identify MTCs and investigate factors associated with the probability of belonging to MTCs.
To identify MTCs, we applied maximum likelihood inferences on partial pol sequences from 8955 HIV-positive individuals linked to demographic and clinical data. MTCs were defined using two different criteria: clusters with bootstrap support >75% (phylogenetic confidence criterion) and clusters consisting of sequences from a specific region at a proportion of >75% (geographic criterion) compared to the total number of sequences within the network. Multivariable logistic regression analysis was used to assess factors associated with MTC clustering.
Although 3700 (41%) sequences belonged to MTCs, proportions differed substantially by country and subtype, ranging from 7% among UK subtype C sequences to 63% among German subtype B sequences. The probability of belonging to an MTC was independently less likely for women than men (OR = 0.66; P < 0.001), older individuals (OR = 0.79 per 10-year increase in age; P < 0.001) and people of non-white ethnicity (OR = 0.44; P < 0.001 and OR = 0.70; P = 0.002 for black and 'other' versus white, respectively). It was also more likely among men who have sex with men (MSM) than other risk groups (OR = 0.62; P < 0.001 and OR = 0.69; P = 0.002 for people who inject drugs, and sex between men and women, respectively), subtype B (ORs 0.36-0.70 for A, C, CRF01 and CRF02 versus B; all P < 0.05), having a well-estimated date of seroconversion (OR = 1.44; P < 0.001), a later calendar year of sampling (ORs 2.01-2.61 for all post-2002 periods versus pre-2002; all P < 0.01), and being naïve to antiretroviral therapy at sampling (OR = 1.19; P = 0.010).
A high proportion (>40%) of individuals belonged to MTCs. Notably, the HIV epidemic dispersal appears to be driven by subtype B viruses spread within MSM networks. Expansion of regional epidemics seems mainly associated with recent MTCs, rather than the growth of older, established ones. This information is important for designing prevention and public health intervention strategies.
Mortality rates for people living with HIV (PLHIV) on antiretroviral therapy (ART) in high-income countries continue to decline. We compared mortality rates among PLHIV on ART in Europe for 2016-2020 ...with Spectrum's estimates.
The AIDS Impact Module in Spectrum is a compartmental HIV epidemic model coupled with a demographic population projection model. We used national Spectrum projections developed for the 2022 HIV estimates round to calculate mortality rates among PLHIV on ART, adjusting to the age/country distribution of PLHIV starting ART from 1996 to 2020 in the Antiretroviral Therapy Cohort Collaboration (ART-CC)'s European cohorts.
In the ART-CC, 11,504 of 162,835 PLHIV died. Between 1996-1999 and 2016-2020, AIDS-related mortality in the ART-CC decreased from 8.8 (95% CI: 7.6 to 10.1) to 1.0 (0.9-1.2) and from 5.9 (4.4-8.1) to 1.1 (0.9-1.4) deaths per 1000 person-years among men and women, respectively. Non-AIDS-related mortality decreased from 9.1 (7.9-10.5) to 6.1 (5.8-6.5) and from 7.0 (5.2-9.3) to 4.8 (4.3-5.2) deaths per 1000 person-years among men and women, respectively. Adjusted all-cause mortality rates in Spectrum among men were near ART-CC estimates for 2016-2020 (Spectrum: 7.02-7.47 deaths per 1000 person-years) but approximately 20% lower in women (Spectrum: 4.66-4.70). Adjusted excess mortality rates in Spectrum were 2.5-fold higher in women and 3.1-3.4-fold higher in men in comparison to the ART-CC's AIDS-specific mortality rates.
Spectrum's all-cause mortality estimates among PLHIV are consistent with age/country-controlled mortality observed in ART-CC, with some underestimation of mortality among women. Comparing results suggest that 60%-70% of excess deaths among PLHIV on ART in Spectrum are from non-AIDS causes.
Background: Diode-assisted endodontics is nowadays utilized for pulp space disinfection, but little is known on the bonding potential of this lased root dentin when the tooth is restored with an ...intracanal polymer post. Objectives: to investigate the influence of diode laser irradiation settings, in laser-assisted endodontics, on the intraradicular bonding of composite materials. Methods: Sixteen two-rooted, maxillary first premolars were collected, prepared up to F4 (Protaper Universal. Dentsply-Maillefer, Ballaigues, Switzerland), and randomly assigned in two groups: group A (chopped mode or short pulse), diode irradiated according to protocol, pulse 25 ms, power 2.5 W, and group B (microchopped mode or ultrashort pulse), pulse 25 μs, peak power 12 W (both groups GentleRay. KaVo Dental, Biberach an der Riss, Germany). Buccal canals were irradiated, palatal ones served as controls. Canals were then obturated, post space was created in all canals, and quartz-fiber posts (ICE light Danville. Danville Materials, San Ramon, CA, USA) were cemented by self-etch self-curing cement (Max Cem Elite. Kerr, West Collins Orange, CA, USA) (Max Cem Elite. Kerr, Brea, CA, USA). A week later, teeth were sectioned horizontally in 1 mm increments. Push-out test was conducted in a Zwick testing machine (Zwick Roell, Ulm, Germany) at 1 mm/min speed, and the force required to dislodge the post from each specimen (F-max) was recorded. Weibull regression models were applied for statistical analyses. Results: Differences in F-max by group (control vs. chopped mode vs. microchopped mode) and height (meaning the apical-to-coronal position of each specimen along the root) were statistically significant (p < 0.05 in all cases). Conclusions: Short pulses (or chopped mode) had a profound positive effect on the quality of intraradicular bonding, while Ultrashort pulses (or microchopped mode) affected it negatively. In addition, apically positioned bonding proved weaker compared with more coronally located specimens.
Background/Objectives: The right-sided aortic arch (RAA) is an uncommon variation of the aortic arch (AA), characterized by the aorta crossing over the right main bronchus. In the RAA, the descending ...aorta can be found on either the right or left side of the spine. The current study comprises a comprehensive retrospective computed tomography angiography (CTA) investigation into the prevalence of the RAA within the Greek population. Additionally, we will conduct a systematic review and meta-analysis to elucidate both common and rare morphological variants of the RAA. This research is significant as it sheds light on the prevalence and characteristics of the RAA in a specific population, providing valuable insights for clinical practice. Methods: Two hundred CTAs were meticulously investigated for the presence of a RAA. In addition, the PubMed, Google Scholar, and Scopus online databases were thoroughly searched for studies referring to the AA morphology. The R programming language and RStudio were used for the pooled prevalence meta-analysis, while several subgroup analyses were conducted. Results: Original study: A unique case of 200 CTAs (0.5%) was identified with an uncommon morphology. The following branches emanated from the RAA under the sequence: the right subclavian artery (RSA), the right common carotid artery (RCCA), the left common carotid artery (LCCA), and the left vertebral artery (LVA) in common origin with the aberrant left subclavian artery (ALSA). The ALSA originated from a diverticulum (of Kommerell) and followed a retroesophageal course. Systematic Review and Meta-Analysis: Sixty-two studies (72,187 total cases) met the inclusion criteria. The pooled prevalence of the RAA with a mirror-image morphology was estimated at 0.07%, and the RAA with an ALSA was estimated at <0.01%. Conclusions: AA anomalies, specifically the RAA, raise clinical interest due to their coexistence with developmental heart anomalies and possible interventional complications. Congenital heart anomalies, such as the Tetralogy of Fallot and patent foramen ovale, coexisted with RAA mirror-image morphology.
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