All-cause and AIDS-related mortality among people with HIV across Europe from 2001 to 2020: impact of antiretroviral therapy, tuberculosis and regional differences in a multicentre cohort study.

Background: All-cause and AIDS-mortality in Europe has been decreasing between 1996 and 2020. However, regional differences as well as their drivers remain unclear. This study investigates mortality differences and their drivers, including usage of and response to antiretroviral therapy (ART) and active tuberculosis (TB), among people with HIV across Europe. Methods: People with HIV enrolled in EuroSIDA were followed from 2001 through 2020. Immunologic-virologic status (IVS) was categorized as poor (CD4-cell count ≤350 cells/mm3 and viral load (VL) > 200 copies/ml), good (CD4 ≥ 500 and VL < 200), or intermediate (remaining combinations). Participants missing either CD4-cell count or VL were categorized as unknown. Regional differences in mortality were analyzed using multivariable Poisson regression with interaction analyses between regions of Europe and IVS, ART, or TB status. Findings: 20,364 people with HIV were included: 13,715/20,346 (67.3%) from Western, 3020/20,364 (14.8%) from Central Eastern, and 3629/20,364 (17.8%) from Eastern Europe. At enrolment, median age was 40 years (inter-quartile range (IQR): 33-48), median CD4-cell count 449 cells/mm3 (IQR: 291-638), and most were male 14,993/20,346 (73.3%). A total of 2639 died during 192,591 person-years of follow-up (crude mortality rate 13.7/1000 person-years, 95% CI: 13.2-14.2), 519/2639 (19.7%) from AIDS (2.7/1000 person-years, 2.5-2.9). All-cause and AIDS-mortality rates decreased over time but remained higher in Eastern Europe after adjusting for confounders. Being off ART (aIRR 2.42; 95% CI 2.14-2.74), poor IVS (aIRR 4.2; 95% CI 3.39-5.20) and prior TB (aIRR 3.33; 95% CI 2.75-4.03) were associated with higher all-cause mortality. For all-cause mortality the effect of ART (test for interaction: p < 0.001) and IVS (p = 0.02), but not TB (p = 0.5) varied across regions. Interpretation: Overall mortality and AIDS-mortality rates decreased over time, but remained higher in Eastern Europe. A poor IVS, being off ART and prior active TB were related to higher mortality. Eastern Europe had the highest proportion of people with poor or unknown IVS, emphasizing the continued need to improve HIV care with a focus on early diagnosis, ART initiation, and adherence. Funding: EuroSIDA has received funding from ViiV Healthcare LLC, Janssen Scientific Affairs, Janssen R&D, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp, Gilead Sciences and the European Union's Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement n˚ 260694. The study is also supported by a grant from the Danish National Research Foundation and by the International Cohort Consortium of Infectious Disease (RESPOND).

Survival among people with HIV and their families in Denmark 1995-2021: a nationwide population-based cohort study.

Background: Survival among people with HIV (PWH) has vastly improved globally over the last few decades but remains lower than among the general population. We aimed to estimate time trends of survival among PWH and their families from 1995 to 2021. Methods: We conducted a registry-based, nationwide, population-based, matched cohort study. We included all Danish-born PWH from 1995 to 2021 who had been on antiretroviral therapy for 90 days, did not report intravenous drug use, and were not co-infected with hepatitis C (n = 4168). We matched population controls from the general population 10:1 to PWH by date of birth and sex (n = 41,680). For family cohorts, we identified siblings, mothers, and fathers of PWH and population controls. From Kaplan-Meier tables with age as time scale, we estimated survival from age 25. We compared PWH with population controls and families of PWH with families of population controls to calculate mortality rate ratios adjusted for sex, age, comorbidities, and education (aMRR). Findings: The median age of death among PWH increased from 27.5 years in 1995-1997 to 73.9 years (2010-2014), but thereafter survival increased only marginally. From 2015 to 2021, mortality was increased among PWH (aMRR 1.87 (95% CI: 1.65-2.11)) and siblings (aMRR: 1.25 (95% CI: 1.07-1.47)), mothers (aMRR: 1.30 (95% CI: 1.17-1.43)), and fathers (aMRR: 1.15 (95% CI: 1.03-1.29)) of PWH compared to their respective control cohorts. Mortality among siblings of PWH who reported heterosexual route of HIV transmission (aMRR: 1.51 (95% CI: 1.16-1.96)) was higher than for siblings of PWH who reported men who have sex with men as route of HIV transmission (aMRR 1.19 (95% CI: 0.98-1.46)). Interpretation: Survival among PWH improved substantially until 2010, after which it increased only marginally. This may partly be due to social and behavioural factors as PWH families also had higher mortality. Funding: Preben and Anna Simonsen's Foundation and Independent Research Fund Denmark.

Questioning risk compensation: pre-exposure prophylaxis (PrEP) and sexually transmitted infections among men who have sex with men, capital region of Denmark, 2019 to 2022.

BackgroundPre-exposure prophylaxis (PrEP) effectively prevents HIV, but its association with sexually transmitted infections (STIs) has raised concerns about risk compensation, potentially impacting the expansion of PrEP programmes.AimWe examined the relationship between PrEP and the incidence of chlamydia, gonorrhoea and syphilis.MethodsIn this prospective cohort study, we compared STI rates before and after PrEP initiation among users in the capital region of Denmark (2019-2022), calculating incidence rate ratios adjusted for age and testing frequency (aIRR). To pinpoint when increases began, we plotted weekly STI rates, adjusting the timeline to correspond with PrEP initiation.ResultsThe study included 1,326 PrEP users with a median age of 35 years. The STI incidence rate per 100,000 person-years rose from 35.3 before to 81.2 after PrEP start, with an aIRR of 1.35 (95% CI: 1.18-1.56). Notably, this increase preceded PrEP initiation by 10-20 weeks. Specific aIRR for chlamydia, gonorrhoea and syphilis were 1.23 (95% CI: 1.03-1.48), 1.24 (95% CI: 1.04-1.47) and 1.15 (95% CI: 0.76-1.72), respectively. In subanalyses for anatomical sites aIRR was 1.26 (95% CI: 1.01-1.56) for rectal chlamydia and 0.66 (95% CI: 0.45-0.96) for genital gonorrhoea.ConclusionWe found a 35% increase in STI incidence associated with PrEP use. It started before PrEP initiation, challenging the assumption that PrEP leads to risk compensation. Instead, the data suggest that individuals seek PrEP during periods of heightened sexual risk-taking. Consequently, PrEP programmes should include sexual health consultations, STI testing, treatment and prevention strategies to prevent HIV and improve sexual health.

Treatment of hepatitis C in children with direct-acting antiviral drugs.

The primary purpose of treating chronic hepatitis C (HCV) is to prevent the development of liver fibrosis, cirrhosis, and cancer. In the last decade, direct-acting antiviral medicine (DAA) has been approved to treat children with HCV. This treatment has a higher efficacy, shorter duration, and milder side effects than the previously approved treatment. In this review, it is recommended to track down children who might be infected with HCV to enhance early treatment to prevent transmission of the virus and the possible complications.

Cancer risk and temporal trends in people with HIV during a quarter of a century - a nationwide population-based matched cohort study.

BACKGROUND: It is important to understand current trends in cancer risk among people living with HIV (PLWH) to improve outcomes and to commission and delivery appropriate services. METHODS: Nationwide, population-based, matched cohort study on all adult PLWH treated at Danish HIV health care centres since 1 January 1995 and a comparison cohort, randomly selected from the background population and matched on sex and date of birth. RESULTS: We included 6327 PLWH and 63,270 individuals in the comparison cohort - 74% were men and median age was 37 (interquartile range: 30-46). For both smoking related cancers, virological cancers and other cancers, incidence was substantially higher in the first year of observation for PLWH than for the remaining observation period. The risk of smoking related cancer remained stably increased throughout the observation period, whereas the relative risk of virological cancers decreased, especially in the first year of follow up. Finally, the risk of other cancers for PLWH decreased to a level below that of the background population during the study period. CONCLUSION: The fact that the risk of other cancers was probably not higher among PLWH than in the comparison cohort is encouraging, as the excess risk of virological and smoking related cancers is potentially preventable by timely treatment of HIV and smoking cessation.

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Changes in weight, body composition and metabolic parameters after switch to dolutegravir/lamivudine compared with continued treatment with dolutegravir/abacavir/lamivudine for virologically suppressed HIV infection (The AVERTAS trial): a randomised, open-label, superiority trial in Copenhagen, Denmark.

INTRODUCTION: With longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with an increased risk of myocardial infarction, but the mechanism is unknown. Additionally, abacavir may be obesogenic which could mediate an additional risk factor of CVD. We aim to investigate if discontinuation of abacavir will have a favourable impact on body weight and cardiac parameters in PLWH. METHODS AND ANALYSIS: Randomised, controlled, superiority trial of virologically suppressed PLWH on dolutegravir, abacavir and lamivudine (DTG/ABC/3TC) for ≥6 months. In total, 70 PLWH will be randomised 1:2 to either continue DTG/ABC/3TC or to switch to dolutegravir and lamivudine (DTG/3TC) providing the power of 80% at alpha 5% to detect a mean difference in weight change of 2 kg (Δ) given an SD of 2.7 kg. Follow-up will be 48 weeks. Data will be collected at baseline and week 48. Primary outcome will be change in mean body weight from baseline to week 24 and 48 evaluated in a linear mixed model. Secondary outcomes will be changes in cardiac, inflammatory and metabolic parameters, fat distribution, coagulation, endothelial, platelet function, quality of life and virological control from baseline to week 48. Measurements include CT of thorax and abdomen, external carotid artery ultrasound, liver elastography and dual energy X-ray absorptiometry and blood analysis. Plasma HIV RNA will be measured at baseline, week 4, 24 and 48. Forty participants (20 from each arm) will be included in a substudy involving cardiac MRI at baseline and week 48. Twenty non-HIV-infected controls will be included with a single scan to compare with baseline scan data. ETHICS AND DISSEMINATION: Result from this study will lead to a better understanding of the association between antiretroviral therapy and the impact on weight and risk of CVD. Findings will be useful for both clinicians and PLWH in the guidance of a more individualised HIV treatment. Results from the main study and the substudies will be submitted for publication in a peer-reviewed journal(s). The AVERTAS study is approved by the Ethics Committee of the Capital Region, Denmark (H-20011433), Danish Medicines Agency (EudraCT no. 2019-004999-19) and Regional Data Protection Centre (P-2020-207). TRIAL REGISTRATION NUMBER: Pre-results registration at ClinicalTrials.gov Identifier: NCT04904406, registered 27 May 2021. PROTOCOL VERSION: Protocol version 9.0, 4 April 2023, approved 10-05-2023 by Ethics Committee of the Capital Region, Denmark (H-20011433). Danish Medicines Agency (EudraCT no. 2019-004999-19). Regional Data Protection Centre (P-2020-207) ClinicalTrials.gov.

Peripheral T-cell activation, Th17 cells, regulatory T-cells, and aortic aneurysm in people with HIV.

Here, we investigate if peripheral T-cell activation and proportion of Th17 and T-regulatory cells (Tregs) are associated with aortic aneurysm or aortic diameter in people with HIV. Aorta was examined by computed tomography scans and T-cells by flow cytometry in 428 participants, and aortic aneurysm was found in 32 participants. None of the T-cell subsets were associated with aortic aneurysm, but activated T-cells and Tregs had opposite association to aorta diameter indicating an inverse impact.

Risk of Depression in People With Human Immunodeficiency Virus: A Nationwide Population-based Matched Cohort Study.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with depression. However, previous studies have not addressed familial factors. METHODS: Nationwide, population-based, matched cohort study of people with HIV (PWH) in Denmark between 1995 and 2021 who were matched on sex and date of birth with a comparison cohort randomly selected from the Danish population. Family-related factors were examined by inclusion of siblings of those in the cohorts. We calculated hazard ratios (HRs) for depression, receipt of antidepressants, electroconvulsive therapy (ECT), and suicide, as well as the yearly proportions of study cohorts with psychiatric hospital contact due to depression and receipt of antidepressants from 10 years before to 10 years after study inclusion. RESULTS: We included 5943 PWH and 59 430 comparison cohort members. Median age was 38 years, and 25% were women. We observed an increased risk of depression, receipt of antidepressants, ECT, and suicide among PWH in the 2 first years of observation (HR, 3.3; 95% confidence interval [CI]: 2.5-4.4), HR, 3.0 (95% CI: 2.7-3.4), HR, 2.8 (95% CI: .9-8.6), and HR, 10.7 (95% CI: 5.2-22.2), thereafter the risk subsided but remained increased. The proportions of PWH with psychiatric hospital contact due to depression and receipt of antidepressants were increased prior to and especially after HIV diagnosis. Risk of all outcomes was substantially lower among siblings of PWH than among PWH (HR for receipt of antidepressants, 1.1; 95% CI: 1.0-1.2). CONCLUSIONS: PWH have an increased risk of depression. Family-related factors are unlikely to explain this risk.

Coronary Artery Disease in Persons With Human Immunodeficiency Virus Without Detectable Viral Replication.

Background: We aimed to determine the prevalence of coronary artery disease (CAD) in persons with human immunodeficiency virus (HIV; PWH) and investigate whether inflammatory markers, including interleukin 6, IL-1ß, and high-sensitivity C-reactive protein (hsCRP), were associated with CAD. Methods: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included virologically suppressed PWH who underwent coronary computed tomographic (CT) angiography. Any atherosclerosis was defined as >0% stenosis, and obstructive CAD as ≥50% stenosis. Results: Among 669 participants (mean age [standard deviation], 51 [11] years; 89% male), 300 (45%) had atherosclerosis, and 119 (18%) had obstructive CAD. The following risk factors were associated with any atherosclerosis and with obstructive CAD: age, male sex, hypertension, diabetes, smoking, dyslipidemia, time with HIV, and current protease inhibitor use. Interleukin 6 (IL-6) and hsCRP levels >2 mg/L were associated with any atherosclerosis and with obstructive CAD in univariable analyses but not after adjustment for traditional risk factors. IL-1ß was not associated with CAD. Conclusions: In a large population of PWH without viral replication, almost half had angiographically verified atherosclerosis. High concentrations of IL-6 and hsCRP were associated with CAD in univariable analyses, but adjustment for cardiovascular risk factors attenuated the association, suggesting that inflammation may mediate the association between traditional risk factors and CAD.

Humoral and cellular immune responses eleven months after the third dose of BNT162b2 an mRNA-based COVID-19 vaccine in people with HIV - a prospective observational cohort study.

BACKGROUND: We investigated long-term durability of humoral and cellular immune responses to third dose of BNT162b2 in people with HIV (PWH) and controls. METHODS: In 378 PWH with undetectable viral replication and 224 matched controls vaccinated with three doses of BNT162b2, we measured IgG-antibodies against the receptor binding domain of SARS-CoV-2 spike protein three months before third dose of BNT162b2, and four and eleven months after. In 178 PWH and 135 controls, the cellular response was assessed by interferon-γ (IFN-γ) release in whole blood four months after third dose. Differences in antibody or IFN-γ concentrations were assessed by uni- and multivariable linear regressions. FINDINGS: Before the third dose the concentration of SARS-CoV-2 antibodies was lower in PWH than in controls (unadjusted geometric mean ratio (GMR): 0.68 (95% CI: 0.54-0.86, p = 0.002). We observed no differences in antibody concentrations between PWH and controls after four (0.90 (95% CI: 0.75-1.09), p = 0.285) or eleven months (0.89 (95% CI: 0.69-1.14), p = 0.346) after the third dose. We found no difference in IFN-γ concentrations four months after the third dose between PWH and controls (1.06 (95% CI: 0.71-1.60), p = 0.767). INTERPRETATION: We found no differences in antibody concentrations or cellular response between PWH and controls up to eleven months after third dose of BNT162b2. Our findings indicate that PWH with undetectable viral replication and controls have comparable immune responses to three doses of the BNT162b2 vaccine. FUNDING: This work was funded by the Novo Nordisk Foundation (NFF205A0063505, NNF20SA0064201), the Carlsberg Foundation (CF20-476 0045), the Svend Andersen Research Foundation (SARF2021), and Bio- and Genome Bank Denmark.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Peripheral Artery Disease and Markers of Endothelial Dysfunction and Platelet Activation in People With HIV.

BACKGROUND: People with HIV (PWH) have an increased risk of peripheral artery disease (PAD), but the pathogenesis is unknown. We aimed to determine the associations between markers of endothelial dysfunction and platelet activation and both PAD at baseline and de novo PAD in PWH. METHODS: In total, 1012 PWH from the longitudinal Copenhagen Comorbidity in HIV-infection (COCOMO) study and 57 age-matched and sex-matched population controls were included. Plasma samples were collected at baseline and analyzed for soluble thrombomodulin, syndecan-1, and CD40 ligand (sCD40L). The ankle-brachial index was measured at baseline and two-year follow-up in PWH. Logistic and Poisson regression models were used to test associations. RESULTS: PWH had higher concentrations of soluble thrombomodulin ( P = 0.03) and syndecan-1 ( P < 0.001) and lower concentration of sCD40L ( P < 0.001) compared with controls. High concentration of soluble thrombomodulin, but not syndecan-1 or sCD40L, was associated with lower odds of PAD in PWH at baseline after adjustments (adjusted odds ratio: 0.50 [0.28, 0.90], P = 0.02). None of the markers were associated with de novo PAD. CONCLUSIONS: PWH had higher concentrations of soluble thrombomodulin and syndecan-1 and lower concentration of sCD40L compared with controls. Soluble thrombomodulin was associated with lower odds of PAD at baseline. Further studies are needed to elucidate the pathogenesis of PAD in people with HIV.

Aortic aneurysms and markers of platelet activation, hemostasis, and endothelial disruption in people living with HIV.

Introduction: People living with HIV (PLWH) are at twice the risk of developing cardiovascular diseases and have more than four times higher odds of aortic aneurysm (AA) than the uninfected population. However, biomarkers of AA in PLWH are yet to be discovered. We aimed to investigate whether circulating biomarkers reflecting platelet activation, hemostasis and endothelial disruption, i.e. sCD40L, D-dimer, syndecan-1, and thrombomodulin, were associated with AA in PLWH. Methods: Five hundred seventy one PLWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) study ≥40 years of age with an available contrast-enhanced CT scan as well as available biomarker analyses were included. The biomarkers were analyzed on thawed plasma. For each biomarker, we defined high level as a concentration in the upper quartile and low level as a concentration below the upper quartile. For D-dimer, the cut-off was defined as the lower limit of detection. Using unadjusted and adjusted logistic and linear regression models, we analyzed associations between AA and sCD40L, D-dimer, syndecan-1, and thrombomodulin, respectively in PLWH. Results: PLWH had median (IQR) age 52 years (47-60), 88% were male, median (IQR) time since HIV diagnosis was 15 years (8-23), and 565 (99%) were currently on antiretroviral treatment. High level of sCD40L was associated with lower odds of AA in both unadjusted (odds ratio, OR, 0.23 (95% CI 0.07-0.77; P=0.017)) and adjusted models (adjusted OR, aOR, 0.23 (95% CI 0.07-0.78; P=0.019)). Detectable level of D-dimer was associated with higher odds of AA in both unadjusted (OR 2.76 (95% CI 1.34-5.67; P=0.006)) and adjusted models (aOR 2.22 (95% CI 1.02-4.85; P=0.045)). Conclusions: SCD40L was associated with lower odds of AA whereas D-dimer was independently associated with higher odds of AA in PLWH. This calls for further investigations into specific biomarkers to aid early diagnosis of AA in PLWH.

Incidence of Childbirth, Pregnancy, Spontaneous Abortion, and Induced Abortion Among Women With Human Immunodeficiency Virus in a Nationwide Matched Cohort Study.

BACKGROUND: Reproductive health in women with human immunodeficiency virus (HIV) (WWH) has improved in recent decades. We aimed to investigate incidences of childbirth, pregnancy, spontaneous abortion, and induced abortion among WWH in a nationwide, population-based, matched cohort study. METHODS: We included all WWH aged 20-40 years treated at an HIV healthcare center in Denmark from 1995 to 2021 and a matched comparison cohort of women from the general population (WGP). We calculated incidence rates per 1000 person-years and used Poisson regression to calculate adjusted incidence rate ratios (aIRRs) of childbirth, pregnancy, spontaneous abortion, and induced abortion stratified according to calendar periods (1995-2001, 2002-2008, and 2009-2021). RESULTS: We included 1288 WWH and 12 880 WGP; 46% of WWH were of African origin, compared with 1% of WGP. Compared with WGP, WWH had a decreased incidence of childbirth (aIRR, 0.6 [95% confidence interval, .6-.7]), no difference in the incidence of pregnancy (0.9 [.8-1.0]) or spontaneous abortion (0.9 [.8-1.0]), but an increased incidence of induced abortion (1.9 [1.6-2.1]) from 1995 to 2021. The aIRRs for childbirth, pregnancy, and spontaneous abortion increased from 1995-2000 to 2009-2021, while the aIRR for induced abortion remained increased across all time periods for WWH. CONCLUSIONS: From 1995 to 2008, the incidences of childbirth, pregnancy, and spontaneous abortion were decreased among WWH compared with WGP. From 2009 to 2021, the incidence of childbirth, pregnancy, and spontaneous abortion no longer differed among WWH compared with WGP. The incidence of induced abortions remains increased compared with WGP.

Potential drug-drug interactions between antiretroviral drugs and comedications, including dietary supplements, among people living with HIV: A clinical survey.

OBJECTIVE: Age-related comorbidities, polypharmacy and thereby the risk of potential drug-drug interactions (PDDIs) among people living with HIV (PLWH) have increased over the years. We estimated the prevalence of comedications, including dietary supplements, and evaluated PDDIs among PLWH receiving antiretroviral therapy (ART) in Denmark in an outpatient setting. METHODS: Information on prescription medication, over-the-counter medication and dietary supplements was obtained from adult PLWH receiving ART attending two outpatient clinics in Denmark. The PDDIs were identified using the University of Liverpool's drug interaction database. Associations between PDDIs and relevant variables were compared using logistic regression models. RESULTS: A total of 337 PLWH receiving ART with a median age of 53 years (interquartile range: 45-61) were included; 77% were male and 96% had a HIV-RNA viral load < 50 copies/mL. Twenty-six per cent of participants received five or more comedications and 56% consumed dietary supplements. Co-administration of drugs requiring dose adjustment or monitoring was identified in the medication lists of 52% of participants, and 4.5% were on drugs that should not be co-administered. Male sex [odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.0-3.4], being on a protease inhibitor (OR = 4.3, 95% CI: 1.9-9.7), receiving five or more comedications (OR = 3.3, 95% CI: 1.5-7.2), taking over-the-counter medications (OR = 1.9, 95% CI: 1.1-3.3) and dietary supplements (OR = 2.0, 95% CI: 1.2-3.3) were independent predictors of PDDIs. CONCLUSION: Potential drug-drug interactions were common among our study population Our study confirms that polypharmacy and being on a protease inhibitor-based regimen increase the risk of PDDIs considerably and highlights the importance of questioning PLWH about dietary supplement intake.

Outcomes following severe acute respiratory syndrome coronavirus 2 infection among individuals with and without HIV in Denmark.

OBJECTIVE: To compare the risk of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and coronavirus disease 2019 (COVID-19) outcomes in people with HIV (PWH) with the general population, and estimate the association with vaccination status. DESIGN: A nationwide, population based, matched cohort study. METHODS: We included all Danish PWH ≥18 years ( n  = 5276) and an age and sex-matched general population cohort ( n  = 42 308). We used Cox regression analyses to calculate (adjusted) incidence rate ratios [(a)IRR] and further stratified and restricted the analyses. RESULTS: We observed no major difference in risk of first positive SARS-CoV-2 test [aIRR: 0.8 (95% confidence interval (CI): 0.8-0.9)], but a higher risk of first hospital contact with COVID-19 and hospitalization with severe COVID-19 for PWH vs. controls [IRR: 2.0; (1.6-2.5), 1.8 (1.4-2.3)]. Risk of first hospitalization decreased substantially in PWH with calendar time [first half of year 2022 vs. 2020 IRR: 0.3; (0.2-0.6)], whereas the risk compared to population controls remained almost twofold increased. We did not observe increased risk of death after SARS-CoV-2 infection [aIRR: 0.7 (95% CI: 0.3-2.0)]. Compared to PWH who had received two vaccines PWH who receiving a third vaccine had reduced risk of first positive SARS-CoV-2 test, death (individuals ≥60years) and hospitalization [aIRR: 0.9 (0.7-1.0); 0.2 (0.1-0.7); 0.6 (0.2-1.2)]. CONCLUSION: PWH have almost the same risk of a positive SARS-CoV-2 test as the general population. Although risk of hospital contacts and severe outcomes following SARS-CoV-2 infection is increased, the risk of death does not seem to be substantially increased. Importantly, a third vaccine is associated with reduced risk of infection, and death.

Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV.

INTRODUCTION: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis. METHODS: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts. RESULTS: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants. CONCLUSION: Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Incidence of Hepatocellular Carcinoma and Decompensated Liver Cirrhosis and Prognostic Accuracy of the PAGE-B HCC Risk Score in a Low Endemic Hepatitis B Virus Infected Population.

Purpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population. Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first. Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0-15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0-12.3) and 0.2% (95% CI 0.1-0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5-1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5-1.8), and 8.7 (95% CI 1.0-16.4) in persons scoring <10, 10-17 and >17, respectively (c-statistic 0.91 (95% CI 0.84-0.98)). Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.