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We assessed changes in sexual behavior among people with human immunodeficiency virus (HIV) over 20 years. Condom use with stable partners steadily declined from over 90% to 29% since the Swiss U = U statement, with similar trajectories between men who have sex with men (MSM) and heterosexuals. Occasional partnership remained higher among MSM compared to heterosexuals even during coronavirus disease 2019 (COVID-19) social distancing.

We followed adolescents and adults living with HIV aged older than 15 years who enrolled in a South African private-sector HIV programme to examine adherence and viral non-suppression (viral load 400 copies/mL) of participants with (20,743, 38%) and without (33,635, 62%) mental health diagnoses. Mental health diagnoses were associated with unfavourable adherence patterns. The risk of viral non-suppression was higher among patients with organic mental disorders [adjusted risk ratio (aRR) 1.55, 95% confidence interval (CI) 1.22-1.96], substance use disorders (aRR 1.53, 95% CI 1.19-1.97), serious mental disorders (aRR 1.30, 95% CI 1.09-1.54), and depression (aRR 1.19, 95% CI 1.10-1.28) when compared with patients without mental health diagnoses. The risk of viral non-suppression was also higher among males, adolescents (15-19 years), and young adults (20-24 years). Our study highlights the need for psychosocial interventions to improve HIV treatment outcomes-particularly of adolescents and young adults-and supports strengthening mental health services in HIV treatment programmes.Monitoreamos adolescentes y adultos mayores de 15 años que viven con VIH y que están registrados en un programa privado Surafricano para el tratamiento del VIH. Nuestro propósito fue examinar adherencia a los medicamentos y supresión viral (carga viral 400 copias/mL) en los participantes con (20,743, 38%) y sin (33,635, 62%) diagnósticos de salud mental. Los diagnósticos de salud mental estuvieron asociados con patrones de adherencia desfavorables. Comparados con pacientes sin diagnósticos de salud mental, el riesgo de no supresión viral fue más alto entre pacientes con desórdenes mentales orgánicos [riesgo relativo ajustado (aRR) 1.55, 95% intervalo de confidencia (CI) 1.22–1.96], desórdenes en el uso de sustancias (aRR 1.53, 95% CI 1.19–1.97), desórdenes mentales serios (aRR 1.30, 95% CI 1.09–1.54), y depresión (aRR 1.19, 95% CI 1.10–1.28). El riesgo de no supresión viral también fue más alto en hombres que en mujeres, en adolescentes (15–19 años), y en adultos jóvenes. Nuestro estudio resalta la necesidad de intervenciones psicosociales para mejorar los resultados del tratamiento contra el VIH –particularmente en adolescentes y adultos jóvenes—, y respalda el fortalecimiento de servicios de salud mental como parte de los programas para el tratamiento del VIH.

Objective:From January 1, 2018, until July 31, 2020, our hospital network experienced an outbreak of vancomycin-resistant enterococci (VRE). The goal of our study was to improve existing processes by applying machine-learning and graph-theoretical methods to a nosocomial outbreak investigation.Methods:We assembled medical records generated during the first 2 years of the outbreak period (January 2018 through December 2019). We identified risk factors for VRE colonization using standard statistical methods, and we extended these with a decision-tree machine-learning approach. We then elicited possible transmission pathways by detecting commonalities between VRE cases using a graph theoretical network analysis approach.Results:We compared 560 VRE patients to 86,684 controls. Logistic models revealed predictors of VRE colonization as age (aOR, 1.4 (per 10 years), with 95% confidence interval [CI], 1.3–1.5; P < .001), ICU admission during stay (aOR, 1.5; 95% CI, 1.2–1.9; P < .001), Charlson comorbidity score (aOR, 1.1; 95% CI, 1.1–1.2; P < .001), the number of different prescribed antibiotics (aOR, 1.6; 95% CI, 1.5–1.7; P < .001), and the number of rooms the patient stayed in during their hospitalization(s) (aOR, 1.1; 95% CI, 1.1–1.2; P < .001). The decision-tree machine-learning method confirmed these findings. Graph network analysis established 3 main pathways by which the VRE cases were connected: healthcare personnel, medical devices, and patient rooms.Conclusions:We identified risk factors for being a VRE carrier, along with 3 important links with VRE (healthcare personnel, medical devices, patient rooms). Data science is likely to provide a better understanding of outbreaks, but interpretations require data maturity, and potential confounding factors must be considered.

IntroductionMental disorders are highly prevalent among people living with HIV and are associated with adverse HIV treatment outcomes. We assessed HIV treatment outcomes in patients with and without mental health diagnoses by sex and age.MethodsUsing hospital, outpatient and pharmacy claims and laboratory data from 2011 to 2020, we followed HIV-positive adolescents and adults aged ≥15 years who enrolled in a South African private sector HIV treatment programme. We performed a longitudinal trajectory analysis to identify patients with similar adherence patterns and examined associations between mental health diagnoses and adherence patterns using multinomial logistic regression. We examined non-adherence and viral non-suppression (VNS, viral load >400 copies/mL) in patients with and without mental health diagnoses by sex and age using mixed-effects Poisson regression models.Results54,378 patients were followed for a median of 3.5 years (IQR 1.9-6.4), 20,743 (38%) of whom had received a mental health diagnosis. 90% of patients had HIV viral load ConclusionOur study highlights the need for psychosocial interventions to improve HIV treatment outcomes, particularly for adolescents and young adults, and supports strengthening mental health services in paediatric and general HIV treatment programs.

We hypothesize that patterns of sexual behavior play a role in the conformation of transmission networks, i.e., the way you behave might influence whom you have sex with. If that was the case, behavioral grouping might in turn correlate with, and potentially predict transmission networking, e.g., proximity in a viral phylogeny. We rigorously present an intuitive approach to address this hypothesis by quantifying mapped interactions between groups defined by similarities in sexual behavior along a virus phylogeny while discussing power and sample size considerations. Data from the Swiss HIV Cohort Study on condom use and hepatitis C virus (HCV) sequences served as proof-of-concept. In this case, a strict inclusion criteria contrasting with low HCV prevalence hindered our possibilities to identify significant relationships. This manuscript serves as guide for studies aimed at characterizing interactions between behavioral patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.

Background In 2016, the World Health Organization (WHO) introduced global targets for the elimination of hepatitis C virus (HCV) by 2030. We conducted a nationwide HCV micro-elimination program among men who have sex with men (MSM) living with human immunodeficiency virus (HIV) from the Swiss HIV Cohort Study (SHCS) to test whether the WHO goals are achievable in this population. Methods During phase A (10/2015–06/2016), we performed a population-based and systematic screening for HCV-RNA among MSM from the SHCS. During phase B (06/2016–02/2017) we offered treatment with HCV direct-acting antiviral (DAA) agents to MSM identified with a replicating HCV infection. During phase C (03/2017–11/2017), we offered rescreening to all MSM for HCV-RNA and initiated DAA treatment in MSM with replicating infections. Results We screened 3715/4640 (80%) MSM and identified 177 with replicating HCV infections (4.8%); 150 (85%) of whom started DAA treatment and 149 (99.3%) were cured. We rescreened 2930/3538 (83%) MSM with a prior negative HCV-RNA and identified 13 (0.4%) with a new HCV infection. At the end of the micro-elimination program, 176/190 MSM (93%) were cured, and the HCV incidence rate declined from .53 per 100 patient-years (95% CI, .35–.83) prior to the intervention to .12 (95% CI, .03–.49) by the end of 2019. Conclusions A systematic, population-based HCV micro-elimination program among MSM living with HIV was feasible and resulted in a strong decline in HCV incidence and prevalence. Our study can serve as a model for other countries aiming to achieve the WHO HCV elimination targets. Clinical Trials Registration NCT02785666.

Machine learning is increasingly introduced into medical fields, yet there is limited evidence for its benefit over more commonly used statistical methods in epidemiological studies. We introduce an unsupervised machine learning framework for longitudinal features and evaluate it using sexual behaviour data from the last 20 years from over 3'700 participants in the Swiss HIV Cohort Study (SHCS). We use hierarchical clustering to find subgroups of men who have sex with men in the SHCS with similar sexual behaviour up to May 2017, and apply regression to test whether these clusters enhance predictions of sexual behaviour or sexually transmitted diseases (STIs) after May 2017 beyond what can be predicted with conventional parameters. We find that behavioural clusters enhance model performance according to likelihood ratio test, Akaike information criterion and area under the receiver operator characteristic curve for all outcomes studied, and according to Bayesian information criterion for five out of ten outcomes, with particularly good performance for predicting future sexual behaviour and recurrent STIs. We thus assess a methodology that can be used as an alternative means for creating exposure categories from longitudinal data in epidemiological models, and can contribute to the understanding of time-varying risk factors.

Background The Swiss HCVree Trial (NCT 02785666) was conducted in 2015–2017 with the goal of implementing a population-based systematic hepatitis C virus (HCV) micro-elimination program among men who have sex with men (MSM) with human immunodeficiency virus (HIV) enrolled in the Swiss HIV Cohort Study (SHCS). The trial led to a 91% and 77% decline of HCV prevalence and incidence, respectively. The long-term effect of this HCV micro-elimination program is yet to be explored. Methods All MSM enrolled in the SHCS were screened for HCV RNA using stored plasma samples obtained in 2019, termed “Swiss HCVree Post” screen. The incidence of HCV infection over time was assessed using additional information on HCV testing routinely collected in the SHCS. Characteristics of participants with replicating HCV infection were analyzed. Results The point-prevalence of “Swiss HCVree Post” (N = 4641) was 0.6%, reflecting a decline of 48% compared to the end of the Swiss HCVree Trial where the prevalence was 1.2%. Further, the incidence of HCV among MSM in the SHCS declined from 0.31/100 person-years (py) (95% confidence interval [CI] [.17, .55]) in 2017 to 0.19/100 py (95% CI [.09, .39]) in 2019. Conclusions A systematic HCV RNA-based screening among MSM with HIV conducted 2 years after the Swiss HCVree Trial revealed a sustained effect and further decline of the prevalence and incidence of replicating HCV infection. This indicates that the Swiss HCVree Trial was successful in curbing the HCV epidemic among MSM with HIV in Switzerland. Clinical Trials Registration NCT02785666.

We hypothesize that patterns of sexual behaviour play a role in the conformation of transmission networks. If that was the case, behavioural grouping might in turn correlate with transmission networks and have the potential to predict proximity in viral phylogenies. To address this hypothesis, we present an intuitive approach for quantifying interactions between clusters of sexual behaviour along a virus phylogeny. Data from the Swiss HIV Cohort Study on condom use and incident Hepatitis C virus (HCV) sequences served as proof-of-concept. A strict inclusion criteria contrasting with relatively low HCV prevalence hindered our ability to identify significant relationships. This manuscript intends to serve as guide for studies aimed at characterizing interactions between behavioural patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.

Background Scale-up of direct-acting antiviral therapy is expected to abate hepatitis C virus (HCV) incidence among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). International transmission could influence this process. We classified HCV infections in HIV-positive MSM as either domestically or internationally acquired, and estimated how this classification changed over time. Methods HCV subtype 1a (the most frequent subtype among MSM) genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections, were sequenced. Sixty-six of these sequences were from MSM. We inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. We inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission. Results Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0–75%). It increased to 85% (range 67%–100%) between 2008 and 2016. Conclusions International and domestic transmission have played major roles in this epidemic. While international transmission persists, local transmission has established as the main source of infections., We used phylogenetics and phylodynamics to classify over time HCV infections in HIV-positive MSM as either domestically or internationally acquired. We found that while international transmission dominated initially and persists, local transmission has established as the main source of infections.

BackgroundOver the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions.Methods and FindingsWe set up an epidemiological model to assess the drivers of syphilis in MSM in Switzerland between 2006 and 2017. We stratified the model by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used ‘reported non-steady partners’ (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health.The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two-years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017).ConclusionsThe model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission.

HIV-1 genetic diversity can be used to infer time since infection (TSI) and infection recency. We adapted this approach for HCV and identified genomic regions with informative diversity. We included 72 HCV/HIV-1 coinfected participants of the Swiss HIV Cohort Study, for whom reliable estimates of infection date and viral sequences were available. Average pairwise diversity (APD) was calculated over each codon position for the entire open reading frame of HCV. Utilizing cross validation, we evaluated the correlation of APD with TSI, and its ability to infer TSI via a linear model. We additionally studied the ability of diversity to classify infections as recent (infected for &lt, 1 year) or chronic, using receiver-operator-characteristic area under the curve (ROC-AUC) in 50 patients whose infection could be unambiguously classified as either recent or chronic. Measuring HCV diversity over third or all codon positions gave similar performances, and notable improvement over first or second codon positions. APD calculated over the entire genome enabled classification of infection recency (ROC-AUC = 0.76). Additionally, APD correlated with TSI (R2 = 0.33) and could predict TSI (mean absolute error = 1.67 years). Restricting the region over which APD was calculated to E2-NS2 further improved accuracy (ROC-AUC = 0.85, R2 = 0.54, mean absolute error = 1.38 years). Genetic diversity in HCV correlates with TSI and is a proxy for infection recency and TSI, even several years post-infection.

BACKGROUND Separately addressing specific groups of people who share patterns of behavioural change might increase the impact of behavioural interventions to prevent transmission of sexually transmitted infections. We propose a method based on machine learning to assist the identification of such groups among men who have sex with men (MSM). METHODS By means of unsupervised learning, we inferred "behavioural clusters" based on the recognition of similarities and differences in longitudinal patterns of condomless anal intercourse with non-steady partners (nsCAI) in the Swiss HIV cohort study over the last 18 years. We then used supervised learning to investigate whether sociodemographic variables could predict cluster membership. RESULTS We identified four behavioural clusters. The largest behavioural cluster (Cluster 1) contained 53% of the study population and displayed the most stable behaviour. Cluster 3 (17% of the study population) displayed consistently increasing nsCAI. Sociodemographic variables were predictive for both of these clusters. The other two clusters displayed more drastic changes: nsCAI frequency in Cluster 2 (20% of the study population) was initially similar to that in Cluster 3, but accelerated in 2010. Cluster 4 (10% of the study population) had significantly lower estimates of nsCAI than all other clusters until 2017, when it increased drastically, reaching 85% by the end of the study period. CONCLUSIONS We identified highly dissimilar behavioural patterns across behavioural clusters, including drastic, atypical changes. These patterns suggest that the overall increase in the frequency of nsCAI is largely attributable to two clusters, accounting for a third of the population.

Hepatitis C virus reinfection rates among men who have sex with men are high. Factors associated with infection point to varied sexual and drug-related risks that could be targeted for interventions to prevent infection/reinfection. Modeling indicates that tackling increasing incidence and high reinfection rates requires high levels of hepatitis C virus treatment combined with behavioral interventions. Enhanced testing strategies and prompt retreating of reinfection may be required to promptly diagnosed reinfections. Behavioral interventions studies addressing reinfection are required. Other interventions include traditional harm reduction interventions, adapted behavioral interventions, and interventions to prevent harms related to ChemSex and other risk factors.

Increasing access to direct-acting antiviral (DAA)-treatment for hepatitis C virus (HCV) infection and decelerating the rise in high-risk behaviour over the next decade, could curb the HCV epidemic among HIV-positive men-who-have-sex-with-men (MSM). We investigated if similar outcomes would be achieved by short-term intensive interventions like the Swiss-HCVree-trial. We used a HCV-transmission model emulating two 12-months intensive-interventions combining risk-counselling with 1) universal DAA-treatment (pangenotypic intervention) and 2) DAA-treatment for HCV-genotypes 1 and 4 (replicating the Swiss-HCVree-trial). To capture potential changes outside intensive-interventions, we varied time from HCV-infection to treatment in clinical-routine and overall high-risk behaviour among HIV-positive MSM. Simulated prevalence dropped from 5.5% in 2016 to ≤2.0% over the intervention period (June/2016-May/2017) with the pangenotypic-intervention, and to ≤3.6% with the Swiss-HCVree-trial. Assuming time to treatment in clinical-routine reflected reimbursement restrictions (METAVIR ≥F2, 16.9 years) and stable high-risk behaviour in the overall MSM population, prevalence in 2025 reached 13.1% without intensive intervention, 11.1% with the pangenotypic intervention and 11.8% with the Swiss-HCVree-trial. If time to treatment in clinical-routine was 2 years, prevalence in 2025 declined to 4.8% without intensive-intervention, to 2.8% with the pangenotypic intervention, and to 3.5% with the Swiss-HCVree-trial. In this scenario, the pangenotypic intervention and the Swiss-HCVree-trial reduced cumulative (2016-2025) treatment episodes by 36% and 24% respectively. Therefore, intensive interventions could reduce future HCV-treatment costs and boost the benefits of long-term efforts to prevent high-risk behaviour and to reduce treatment delay. But if after intensive interventions treatment is deferred until F2, short-term benefits of intensive interventions would dissipate in the long-term. This article is protected by copyright. All rights reserved.

BackgroundExtended-spectrum betalactamase (ESBL-) producingK. pneumoniaeis one of the most common causes of infections with antimicrobial resistant bacteria worldwide. The spread of colonization of humans with this pathogen is on the rise. The future prevalence of colonization with ESBL-producingK. pneumoniae, and the potential of public health interventions to lower it, remain uncertain.MethodsBased on detailed data on antimicrobial consumption and susceptibility systematically recorded for over 13 years in a Swiss region, we developed a mathematical model toi)reconstruct the observed course of colonization with ESBL-producingK. pneumoniae;andii)to assess the potential impact of public health interventions on future trends in colonization.ResultsSimulated prevalence of colonization with ESBL-producingK. pneumoniaestabilized in the near future when rates of antimicrobial consumption and in-hospital transmission remained stable in the main analyses (simulated prevalence in 2025 was 5.3% (5.0%-9.1%) in hospitals and 2.7% (2.1%-4.6%) in the communityversus5.6% (5.1%-9.5%) and 2.8% (2.2%-5.0%) in 2019). The largest changes in future prevalence were observed in simulations that assumed changes in overall antimicrobial consumption. When overall antimicrobial consumption was set to decrease by 50%, prevalence in 2025 declined by 89% in hospitals and by 84% in the community. A 50% decline in transmission rate within hospitals led to a reduction in prevalence of 43% in hospitals and of 13% in the community by 2025. Prevalence changed much less (≤9%) across scenarios with reduced carbapenem consumption. Assuming higher rates for the contribution from external sources of colonization, led to decreasing estimations of future prevalence in hospitals. While high uncertainty remains on the magnitude of these contribution, the best model fit suggested that as much as 46% (95% CI: 12%-96 %) of observed colonizations could be attributable to sources other than human-to-human transmission within the geographical setting (i.e., non-local transmission).ConclusionsThis study suggests that overall antimicrobial consumption will be, by far, the most powerful driver of future prevalence and that a large fraction of colonizations could be attributed to non-local transmission.

Beta-lactam- and in particular carbapenem-resistant Enterobacteriaceae represent a major public health threat. Despite strong variation of resistance across geographical settings, there is limited understanding of the underlying drivers. To assess these drivers, we developed a transmission model of cephalosporin- and carbapenem-resistant Klebsiella pneumoniae. The model is parameterized using antibiotic consumption and demographic data from eleven European countries and fitted to the resistance rates for Klebsiella pneumoniae for these settings. The impact of potential drivers of resistance is then assessed in counterfactual analyses. Based on reported consumption data, the model could simultaneously fit the prevalence of extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumoniae (ESBL and CRK) across eleven European countries over eleven years. The fit could explain the large between-country variability of resistance in terms of consumption patterns and fitted differences in hospital transmission rates. Based on this fit, a counterfactual analysis found that reducing nosocomial transmission and antibiotic consumption in the hospital had the strongest impact on ESBL and CRK prevalence. Antibiotic consumption in the community also affected ESBL prevalence but its relative impact was weaker than inpatient consumption. Finally, we used the model to estimate a moderate fitness cost of CRK and ESBL at the population level. This work highlights the disproportionate role of antibiotic consumption in the hospital and of nosocomial transmission for resistance in gram-negative bacteria at a European level. This indicates that infection control and antibiotic stewardship measures should play a major role in limiting resistance even at the national or regional level., Author summary As beta-lactam resistant gram-negative bacteria represent one of the most critical threats in the ongoing antibiotic resistance crisis, it is crucial to identify the underlying drivers and develop appropriate measures to curb their spread. By combining a transmission model with epidemiological data at a European level, we can explain the strong differences of extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumonia across European countries and their often-rapid temporal increase. We find that among potentially modifiable drivers, inpatient antibiotic consumption and nosocomial transmission rates have the strongest impact on resistance. This implies that measures aimed to improve the infection control and the antibiotic stewardship in hospitals are crucial for preventing antibiotic resistance in gram-negatives even beyond individual hospitals as they may affect resistance prevalence at the level of entire countries.

BackgroundSelf-reported neurocognitive impairment (SRNI) in people living with human immunodeficiency virus type 1 (HIV-1) infection is frequent. We use longitudinal information on SRNI in the Swiss HIV Cohort Study (SHCS) to identify and characterize groups of patients with persisting SRNI over time.MethodsWe included all SHCS patients who were assessed for SRNI during at least 5 visits spanning at least 2.5 years in 2013–2017. We first compared patients with SRNI to those without SRNI over the whole study period. Second, we used a hierarchical cluster algorithm to identify groups of patients with similar changes of SRNI over time. In both analyses, we studied clinical and demographic factors potentially influencing SRNI.ResultsIn total, 79 683 questionnaires of 11 029 patients contained information about SRNI, and 8545 of 11 029 (77.5%) patients had longitudinal information. The overall percentage of patients with SRNI decreased from 19.6% in 2013 to 10.7% in 2017. Compared to patients in the cluster with low-level SRNI over time, patients in the cluster with high-level persisting SRNI more often had a prior opportunistic infection of the central nervous system (CNS) (odds ratio [OR], 3.7; P < .001), imperfect adherence to antiretroviral therapy (ART) (OR, 2.8; P < .001), and depression (OR, 1.9; P < .001).ConclusionsAlthough overall SRNI is decreasing in the SHCS, there is a group of patients with persisting SRNI over time. Past opportunistic infections of the CNS, imperfect adherence to ART, and depression were associated most with persisting SRNI. Patients with these characteristics should be preferentially tested for neurocognitive impairment.Although overall self-reported neurocognitive impairment (SRNI) is decreasing in the Swiss HIV Cohort Study, there is a group of patients with persisting SRNI over time, characterized by more past opportunistic infections of the central nervous system, imperfect adherence to antiretroviral therapy, and depression.

Summary Background The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030. Methods We developed a simulation model for HIV and applied it to each sub-Saharan African country. We used the WHO country intelligence database to estimate the number of adult patients receiving antiretroviral therapy from 2005 to 2014. We fitted the number of adult patients receiving antiretroviral therapy to observed estimates, and predicted first-line and second-line needs between 2015 and 2030. We present results for sub-Saharan Africa, and eight selected countries. We present 18 scenarios, combining the availability of viral load monitoring, speed of antiretroviral scale-up, and rates of retention and switching to second-line. HIV transmission was not included. Findings Depending on the scenario, 8·7–25·6 million people are expected to receive antiretroviral therapy in 2020, of whom 0·5–3·0 million will be receiving second-line antiretroviral therapy. The proportion of patients on treatment receiving second-line therapy was highest (15·6%) in the scenario with perfect retention and immediate switching, no further scale-up, and universal routine viral load monitoring. In 2030, the estimated range of patients receiving antiretroviral therapy will remain constant, but the number of patients receiving second-line antiretroviral therapy will increase to 0·8–4·6 million (6·6–19·6%). The need for second-line antiretroviral therapy was two to three times higher if routine viral load monitoring was implemented throughout the region, compared with a scenario of no further viral load monitoring scale-up. For each monitoring strategy, the future proportion of patients receiving second-line antiretroviral therapy differed only minimally between countries. Interpretation Donors and countries in sub-Saharan Africa should prepare for a substantial increase in the need for second-line drugs during the next few years as access to viral load monitoring improves. An urgent need exists to decrease the costs of second-line drugs. Funding World Health Organization, Swiss National Science Foundation, National Institutes of Health.

BACKGROUND Tuberculosis (TB) is the leading cause of death in South Africa. The burden of disease varies by age, with peaks in TB notification rates in the HIV-negative population at ages 0-5, 20-24, and 45-49 years. There is little variation between age groups in the rates in the HIV-positive population. The drivers of this age pattern remain unknown. METHODS We developed an age-structured simulation model of Mycobacterium tuberculosis (Mtb) transmission in Cape Town, South Africa. We considered five states of TB progression: susceptible, infected (latent TB), active TB, treated TB, and treatment default. Latently infected individuals could be re-infected; a previous Mtb infection slowed progression to active disease. We further considered three states of HIV progression: HIV negative, HIV positive, on antiretroviral therapy. To parameterize the model, we analysed treatment outcomes from the Cape Town electronic TB register, social mixing patterns from a Cape Town community and used literature estimates for other parameters. To investigate the main drivers behind the age patterns, we conducted sensitivity analyses on all parameters related to the age structure. RESULTS The model replicated the age patterns in HIV-negative TB notification rates of Cape Town in 2009. Simulated TB notification rate in HIV-negative patients was 1000/100,000 person-years (pyrs) in children aged

Background Human immunodeficiency virus (HIV)–positive gay and bisexual men (GBM) in Australia are well engaged in care. The World Health Organization’s (WHO) hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030 may be reachable ahead of time in this population. Methods We predicted the effect of treatment and behavioral changes on HCV incidence among HIV-positive GBM up to 2025 using a HCV transmission model parameterized with Australian data. We assessed the impact of changes in behavior that facilitate HCV transmission in the context of different rates of direct-acting antiviral (DAA) use. Results HCV incidence in our model increased from 0.7 per 100 person-years in 2000 to 2.5 per 100 person-years in 2016 and had the same trajectory as previously reported clinical data. If the proportion of eligible (HCV RNA positive) patients using DAAs stays at 65% per year between 2016 and 2025, with high-risk sexual behavior and injecting drug use remaining at current levels, HCV incidence would drop to 0.4 per 100 person-years (85% decline from 2016). In the same treatment scenario but with substantial increases in risk behavior, HCV incidence would drop to 0.6 per 100 person-years (76% decline). If the proportion of eligible patients using DAAs dropped from 65% per year in 2016 to 20% per year in 2025 and risk behavior did not change, HCV incidence would drop to 0.7 per 100 person-years (70% reduction). Conclusions Reaching the WHO HCV elimination target by 2025 among HIV-positive GBM in Australia is achievable.

In the Swiss HIV Cohort Study, the number of people who inject drugs with replicating hepatitis C virus (HCV) infection decreased substantially after the introduction of direct-acting antivirals (DAAs). Among men who have sex with men, the increase in DAA uptake and efficacy was counterbalanced by frequent incident HCV infections.

Background Antiretroviral therapy (ART) reduces HIV transmission, but treated patients may again become infectious. We used a mathematical model to determine whether ART as prevention is more effective if viral load (VL) is routinely monitored and patients lost to follow-up (LTFU) traced. Methods We simulated ART cohorts to parameterize a deterministic transmission model calibrated to Malawi. We investigated the following strategies for improving treatment and retention: monitoring VL every 12 or 24 months, tracing patients LTFU, or a generic strategy leading to uninterrupted treatment. We tested 3 scenarios, where ART scale-up continues at current (Universal ART), reduced (Failed scale-up), or accelerated speed (Test&Treat). Results In the Universal ART scenario, between 2017 and 2020 (2050), monitoring VL every 24 months prevented 0.5% (0.9%), monitoring every 12 months prevented 0.8% (1.4%), tracing prevented 0.3% (0.5%), and uninterrupted treatment prevented 5.5% (9.9%) of HIV infections. Failed scale-up resulted in 25% more infections than the Universal ART scenarios, whereas Test&Treat resulted in 7%–8% less. Conclusions Test&Treat reduces transmission of HIV, despite individual cases of treatment failure and ART interruption. Whereas viral load monitoring and tracing have only a minor impact on transmission, interventions that aim to minimize treatment interruptions can further increase the preventive effect of ART.

Initiation criteria and pediatric antiretroviral treatment regimens have changed over the past few years in South Africa. We reported worse early virological outcomes associated with the use of abacavir (ABC)-based regimens at 1 large site: here, we expand this analysis to multiple sites in the IeDEA-Southern Africa collaboration.Data for 9543 antiretroviral treatment-naïve children16 years at treatment initiation started on either stavudine/lamivudine (d4T/3TC) or ABC/3TC with efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) treated at 6 clinics in Johannesburg and Cape Town, South Africa, were analyzed with χ tests and logistic regression to evaluate viral suppression at 6 and 12 months.Prevalence of viral suppression at 6 months in 2174 children started on a d4T-based LPV/r regimen was greater (70%) than among 438 children started on an ABC-based LPV/r regimen (54%, P0.0001). Among 3189 children started on a d4T-based EFV regimen, a higher proportion (86%) achieved suppression at 6 months compared with 391 children started on ABC-containing EFV regimens (78%, P0.0001). Relative benefit of d4T versus ABC on 6-month suppression remained in multivariate analysis after adjustment for pretreatment characteristics, cohort and year of program [LPV/r: odds ratio = 0.57 (confidence interval: 0.46-0.72); EFV: odds ratio = 0.46 (confidence interval: 0.32-0.65)].This expanded analysis is consistent with our previous report of worse virological outcomes after ABC was introduced as part of first-line antiretroviral treatment in South Africa. Whether due to the drug itself or coincident with other changes over time, continued monitoring and analyses must clarify causes and prevent suboptimal long-term outcomes.

Objectives: HIV ‘treatment as prevention’ (TasP) describes early treatment of HIVinfected patients intended to reduce viral load and transmission. Crucial assumptions for estimating TasP’s effectiveness are the underlying estimates of transmission risk. We aimed to determine transmission risk during primary infection, and describe the relation of HIV transmission risk to viral load. Design: A systematic review and meta-analysis. Methods: We searched PubMed and Embase databases for studies that established a relationship between viral load and transmission risk, or primary infection and transmission risk, in serodiscordant couples. We analysed assumptions about the relationship between viral load and transmission risk, and between duration of primary infection and transmission risk. Results: We found 36 eligible articles, based on six different study populations. Studies consistently found that higher viral loads lead to higher HIV transmission rates, but assumptions about the shape of this increase varied from exponential increase to saturation. The assumed duration of primary infection ranged from 1.5 to 12 months; for each additional month, the log10 transmission rate ratio between primary and asymptomatic infection decreased by 0.40. Conclusion: Assumptions and estimates of the relationship between viral load and transmission risk, and the relationship between primary infection and transmission risk, vary substantially and predictions of TasP’s effectiveness should take this uncertainty into account. 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2014, 28:1021–1029

Summary Background WHO's 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-effectiveness of alternative patient monitoring strategies. Methods We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at different frequencies and with different criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantified impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-effectiveness analysis. Findings All models show that clinical monitoring delivers significant benefit compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6–12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility. Interpretation The priority for HIV programmes should be to expand antiretroviral therapy coverage, firstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more affordable in future. Funding Bill & Melinda Gates Foundation, WHO.

Background In 2018 we experienced a nosocomial outbreak due to vancomycin-resistant enterococci (VRE) in our hospital network. Our goals were to characterize risk factors for VRE acquisition, elicit potential hot spots of transmission, and delineate an optimized approach to tracing contacts. Methods We assembled diverse datasets of variable quality and covering different aspects of care from electronic medical records generated during the outbreak period (1/2018–9/2018). Patients who tested VRE-positive during this period were compared with controls with up to 3 negative screenings. First, we identified risk factors for VRE colonization by means of uni- and multivariate analyses. Next, we elicited transmission pathways by detecting commonalities between VRE cases, and determined whether patients with characteristics and connections similar to VRE cases were missed by our current contact tracing strategy. Results We compared 221 VRE patients to 33,624 controls. Independent predictors of VRE colonization were ICU admission (OR 4.9, with 95% confidence interval [3.7–6.5], P < 0.001)], number of records in the database (a proxy for severity-of-illness, OR 1.1 [1.1–1.1], P < 0.001), length of hospital stay (OR 2.7 [2.0–3.5], P < 0.001), age (OR 1.3 [1.2–1.4], P < 0.001), and weeks of antibiotics (OR 1.2 [1.1–1.3], P < 0.001). By using complex network analysis, we were able to establish three main pathways by which the 221 VRE cases are connected: healthcare personnel, medical devices, and patient rooms. This multi-dimensional network extends beyond our current contact tracing strategy, which captures inpatients based on geographical proximity (cf. figure). Conclusion In this outbreak investigation based on a large electronic healthcare data collection, we found three main risk factors for being a VRE carrier (ICU admission, length of hospital stay, antibiotic exposure), along with three important links between VRE cases (healthcare personnel, medical devices, patient rooms). Data science is likely to provide a better understanding of outbreaks, but interpretations should take data maturity, the scope of included sources, and potential confounding factors into account. Disclosures All authors: No reported disclosures.

BACKGROUND AND AIMS Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression. METHODS We developed an individual-based model of liver disease progression in HIV/HCV coinfected men who have sex with men. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale. RESULTS The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. CONCLUSIONS Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with replicating HCV infection.

One-third of women enrolled in Malawi's program to prevent human immunodeficiency virus mother-to-child-transmission (Option B+) adhered inadequately to antiretroviral therapy during pregnancy and breastfeeding. Long-term virological outcomes must be closely monitored, and effective interventions to improve adherence should be deployed., Background. Adherence to antiretroviral therapy (ART) is crucial to preventing mother-to-child transmission of human immunodeficiency virus (HIV) and ensuring the long-term effectiveness of ART, yet data are sparse from African routine care programs on maternal adherence to triple ART. Methods. We analyzed data from women who started ART at 13 large health facilities in Malawi between September 2011 and October 2013. We defined adherence as the percentage of days “covered” by pharmacy claims. Adherence of ≥90% was deemed adequate. We calculated inverse probability of censoring weights to adjust adherence estimates for informative censoring. We used descriptive statistics, survival analysis, and pooled logistic regression to compare adherence between pregnant and breastfeeding women eligible for ART under Option B+, and nonpregnant and nonbreastfeeding women who started ART with low CD4 cell counts or World Health Organization clinical stage 3/4 disease. Results. Adherence was adequate for 73% of the women during pregnancy, for 66% in the first 3 months post partum, and for about 75% during months 4–21 post partum. About 70% of women who started ART during pregnancy and breastfeeding adhered adequately during the first 2 years of ART, but only about 30% of them had maintained adequate adherence at every visit. Risk factors for inadequate adherence included starting ART with an Option B+ indication, at a younger age, or at a district hospital or health center. Conclusions. One-third of women retained in the Option B+ program adhered inadequately during pregnancy and breastfeeding, especially soon after delivery. Effective interventions to improve adherence among women in this program should be implemented.

OBJECTIVES: To determine magnitude and reasons of loss to program and poor antiretroviral prophylaxis coverage in prevention of mother-to-child transmission (PMTCT) programs in sub-Saharan Africa. DESIGN: Systematic review and meta-analysis. METHODS: We searched PubMed and Embase databases for PMTCT studies in sub-Saharan Africa published between January 2002 and March 2012. Outcomes were the percentage of pregnant women tested for HIV initiating antiretroviral prophylaxis having a CD4 cell count measured and initiating antiretroviral combination therapy (cART) if eligible. In children outcomes were early infant diagnosis for HIV and cART initiation. We combined data using random-effects meta-analysis and identified predictors of uptake of interventions. RESULTS: Forty-four studies from 15 countries including 75172 HIV-infected pregnant women were analyzed. HIV-testing uptake at antenatal care services was 94% [95% confidence intervals (CIs) 92-95%] for opt-out and 58% (95% CI 40-75%) for opt-in testing. Coverage with any antiretroviral prophylaxis was 70% (95% CI 64-76%) and 62% (95% CI 50-73%) of pregnant women eligible for cART received treatment. Sixty-four percent (95% CI 48-81%) of HIV exposed infants had early diagnosis performed and 55% (95% CI 36-74%) were tested between 12 and 18 months. Uptake of PMTCT interventions was improved if cART was provided at the antenatal clinic and if the male partner was involved. CONCLUSION: In sub-Saharan Africa uptake of PMTCT interventions and early infant diagnosis is unsatisfactory. An integrated family-centered approach seems to improve retention.

BackgroundThe cost-effectiveness of routine viral load (VL) monitoring of HIV-infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource-limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring.MethodsWe used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs.ResultsIntroducing 2nd-line ART had an ICER of US$1651-1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1st- and 2nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure.ConclusionCompared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs.

Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The 𝖱 package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application.