External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection

BACKGROUND & AIMS: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. METHODS: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. RESULTS: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10-17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03-3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. CONCLUSIONS: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. IMPACT AND IMPLICATIONS: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV

Role of common human TRIM5α variants in HIV-1 disease progression

BACKGROUND: The retroviral restriction factor tripartite motif protein (TRIM)5α, is characterized by marked amino acid diversity among primates, including specific clusters of residues under positive selection. The identification of multiple non-synonymous changes in humans suggests that TRIM5α variants might be relevant to retroviral pathogenesis. Previous studies have shown that such variants are unlikely to modify susceptibility to HIV-1 infection, or the course of early infection. However, the longterm effect of carrying Trim5α variants on disease progression in individuals infected with HIV-1 has not previously been investigated. METHODS: In a cohort of 979 untreated individuals infected with HIV-1 with median follow up 3.2 years and 9,828 CD4 T cell measurements, we analysed common amino acid variations: H43Y, V112F, R136Q, G249D, and H419Y. The rate of CD4 T cell decline before treatment was used as the phenotype. In addition, we extended previous work on the in vitro susceptibility of purified donor CD4 T cells (n = 125) to HIV-1 infection, and on the susceptibility of HeLa cells that were stably transduced with the different TRIM5 variants. Haplotypes were analysed according to the most parsimonious evolutionary structure, where two main human TRIM5α groups can be defined according to the residue at amino acid 136. Humans present both Q136 and R136 at similar frequency, and additional TRIM5α amino acid variants are almost exclusively derived from R136-carrying haplotypes. RESULTS: We observed modest differences in disease progression for evolutionary branches carrying R136-derived haplotypes, and with the non-synonymous polymorphisms G249D and H419Y. In vitro analysis of susceptibility of donor CD4 T cells, and of the various transduced HeLa cell lines supported the absence of significant differential restriction of HIV-1 infection by the various huTRIM5α alleles. CONCLUSION: Common human variants of TRIM5α have no effect or modest effect on HIV-1 disease progression. These variants occur at sites conserved throughout evolution, and are remote from clusters of positive selection in the primate lineage. The evolutionary value of the substitutions remains unclear

Migrating a Well-Established Longitudinal Cohort Database From Oracle SQL to Research Electronic Data Entry (REDCap): Data Management Research and Design Study

BACKGROUND: Providing user-friendly electronic data collection tools for large multicenter studies is key for obtaining high-quality research data. Research Electronic Data Capture (REDCap) is a software solution developed for setting up research databases with integrated graphical user interfaces for electronic data entry. The Swiss Mother and Child HIV Cohort Study (MoCHiV) is a longitudinal cohort study with around 2 million data entries dating back to the early 1980s. Until 2022, data collection in MoCHiV was paper-based. OBJECTIVE: The objective of this study was to provide a user-friendly graphical interface for electronic data entry for physicians and study nurses reporting MoCHiV data. METHODS: MoCHiV collects information on obstetric events among women living with HIV and children born to mothers living with HIV. Until 2022, MoCHiV data were stored in an Oracle SQL relational database. In this project, R and REDCap were used to develop an electronic data entry platform for MoCHiV with migration of already collected data. RESULTS: The key steps for providing an electronic data entry option for MoCHiV were (1) design, (2) data cleaning and formatting, (3) migration and compliance, and (4) add-on features. In the first step, the database structure was defined in REDCap, including the specification of primary and foreign keys, definition of study variables, and the hierarchy of questions (termed "branching logic"). In the second step, data stored in Oracle were cleaned and formatted to adhere to the defined database structure. Systematic data checks ensured compliance to all branching logic and levels of categorical variables. REDCap-specific variables and numbering of repeated events for enabling a relational data structure in REDCap were generated using R. In the third step, data were imported to REDCap and then systematically compared to the original data. In the last step, add-on features, such as data access groups, redirections, and summary reports, were integrated to facilitate data entry in the multicenter MoCHiV study. CONCLUSIONS: By combining different software tools-Oracle SQL, R, and REDCap-and building a systematic pipeline for data cleaning, formatting, and comparing, we were able to migrate a multicenter longitudinal cohort study from Oracle SQL to REDCap. REDCap offers a flexible way for developing customized study designs, even in the case of longitudinal studies with different study arms (ie, obstetric events, women, and mother-child pairs). However, REDCap does not offer built-in tools for preprocessing large data sets before data import. Additional software is needed (eg, R) for data formatting and cleaning to achieve the predefined REDCap data structure

The Presence of Human Immunodeficiency Virus-Associated Neurocognitive Disorders Is Associated With a Lower Adherence to Combined Antiretroviral Treatment.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are defined according to their diagnostic degrees as follows: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Because high adherence to combined antiretroviral therapy (cART) is required to maintain viral suppression among HIV-infected patients, it is important to investigate the impact of HAND on medication adherence. Our study hypothesis was that patients with HAND had a lower medication adherence than patients who did not have HAND. This was an observational, exploratory, 2-center pilot study of patients who had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015 while also being followed at their respective adherence clinics. Adherence was measured with electronic monitors. Patients' sociodemographic characteristics, HIV viral load, and CD4 counts were retrieved from the Swiss HIV Cohort Study database. At each time t, adherence was computed as the proportion of patients taking medication as prescribed at that time. We included 59 patients, with a median (Q1, Q3) age of 53 years (47-58) and 39 (66%) were male participants. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit (implementation stayed 90% during follow-up). Our findings support the hypothesis that HAND is associated with reduced cART adherence

CD4:CD8 ratio and CD8 cell count and their prognostic relevance for coronary heart disease events and stroke in antiretroviral treated individuals: The Swiss HIV Cohort Study.

INTRODUCTION HIV infection leads to a persistent expansion of terminally CD8T cells and CD8T suppressor-cells, a marker of chronic immune activation leading to a low CD4:CD8 ratio that may persist in the presence of potent ART and regained CD4 helper cells. It remains unclear whether a low CD4:CD8 ratio is associated with cardiovascular diseases (CVD). METHODS We conducted an observational cohort study to investigate the association of immune depression and activation as characterized by the proxy of the CD4:CD8 ratio on the hazard of coronary heart disease (CHD) and stroke among treated individuals living with HIV, while accounting for viral load and known risk factors for CVD and exposure to abacavir or protease inhibitors. We used Cox proportional hazard models with time-dependent cumulative and lagged exposures to account for time-evolving risk factors and avoid reverse causality. RESULTS CD4, CD8 and CD4:CD8 immunological markers were not associated with an increased hazard for CHD. CD8 cell count lagged at 12 months above 1000 cells per μl increased the hazard of stroke, after adjusting for socio-demographics, cardiovascular risk factors and exposure to specific types of antiretroviral drugs. CONCLUSIONS This analysis of treated HIV infected individuals within a large cohort with long-term follow-up does not provide evidence for a prognostic role of immune dysregulation regarding CHD. However, increased CD8 cell count may be a moderate risk factor for stroke. Early detection and treatment of HIV-infected individuals are crucial for an optimal immune restoration and a limited CD8 cells expansion

Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared

Comparing HIV treatment in Switzerland, where drug selection is individualized, and South Africa, where a programmatic approach is used, Matthias Egger and colleagues find similar virologic outcomes over two years

Pregnancy and delivery outcomes of HIV infected women in Switzerland 2003-2008

Objective: Rates of vertical HIV transmission between mother and child are low, allowing many HIV positive women to have children with near impunity. In this study, data from the Swiss Mother and Child HIV Cohort Study were used to describe maternal characteristics and their association with pregnancy outcomes in HIV positive women. Study design: HIV positive women were followed prospectively during their pregnancies and deliveries by anonymous questionnaires between January 2003 and October 2008. Adverse pregnancy outcomes included preterm delivery, preeclampsia and gestational diabetes mellitus. Results: This study included 266 HIV positive women, of which 67 (25.2%) were first diagnosed with HIV during pregnancy. Thirty percent (n=80) of the women had pregnancy complications after 24weeks of gestation. Preterm delivery was noted in 72 (27%) patients. Other complications included preeclampsia (n=7; 2.6%) and gestational diabetes (n=7; 2.6%). Older maternal age was the only risk factor associated with adverse pregnancy outcomes (adjusted odds ratio: 1.06, 95% confidence interval 1.01-1.12, P=0.02). Conclusions: HIV positive women, especially with advanced maternal age, have high-risk pregnancies and should be monitored as in an interdisciplinary setting. The preponderance of initial HIV diagnosis during pregnancy confirms the importance of HIV screening in pregnant wome

Impact of integrase inhibitors on cardiovascular disease events in people with HIV starting antiretroviral therapy.

BACKGROUND Integrase strand transfer inhibitors (INSTI) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with HIV (PWH) using a target trial framework, which reduces the potential for confounding and selection bias. METHODS We included Swiss HIV Cohort Study participants who were ART-naïve after 05/2008, when INSTI became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs. other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (IQR 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increase in CVD events (adjusted hazard ratio 0.80, 95% confidence interval [CI] 0.46-1.39). Adjusted risk differences between individuals who started INSTI and those who started other ART were -0.17% (95% CI -0.37-0.19) after one year, -0.61% (-1.54-0.22) after 5 years, and -0.71% (-2.16-0.94) after 8 years. CONCLUSIONS In this target trial emulation, we found no difference in short or longer term risk for CVD events between treatment-naïve PWH who started INSTI-based and those on other ART

Viral suppression and retention in HIV care during the postpartum period among women living with HIV: a longitudinal multicenter cohort study

BACKGROUND: Low rates of postnatal retention in HIV care and viral suppression have been reported in women living with HIV (WLWH) despite viral suppression at delivery. At the same time, postpartum follow-up is of crucial importance in light of the increasing support offered in many resource-rich countries including Switzerland to WLWH choosing to breastfeed their infant, if optimal scenario criteria are met. METHODS: We longitudinally investigated retention in HIV care, viral suppression, and infant follow-up in a prospective multicentre HIV cohort study of WLWH in the optimal scenario who had a live birth between January 2000 and December 2018. Risk factors for adverse outcomes in the first year postpartum were assessed using logistic and proportional hazard models. FINDINGS: Overall, WLWH were retained in HIV care for at least six months after 94.2% of the deliveries (694/737). Late start of combination antiretroviral therapy (cART) during the third trimester was found to be the main risk factor for failure of retention in HIV care (crude odds ratio [OR] 3.91; 95% confidence interval [CI], 1.50-10.22; p = 0.005). Among mothers on cART until at least one year after delivery, 4.4% (26/591) experienced viral failure, with illicit drugs use being the most important risk factor (hazard ratio [HR], 13.2; 95% CI, 2.35-73.6; p = 0.003). The main risk factors for not following the recommendations regarding infant follow-up was maternal depression (OR, 3.52; 95% CI, 1.18-10.52; p = 0.024). INTERPRETATION: Although the results are reassuring, several modifiable risk factors for adverse postpartum outcome, such as late treatment initiation and depression, were identified. These factors should be addressed in HIV care of all WLWH, especially those opting to breastfeed in resource-rich countries. FUNDING: This study has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project 850 and by the SHCS research foundation

Sexual Behaviour and STI Incidence in Sexually Active MSM Living With HIV in Times of COVID-19.

Despite decreased numbers of sexual partners, the COVID-19 pandemic had limited impact on the prevalence of attending private sex parties, traveling for sex within Switzerland, and practicing chemsex in men with HIV who have sex with men. COVID-19 risk perception was low, and STI-diagnosis incidence rates remained stable over time