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Introduction: HIV treating physicians in the Netherlands follow the guidelines of the Department of Health and Human Services (DHHS). Most of these recommended initial regimens are single-tablet regimens (STRs), which incur higher costs. By the end of 2017, generic NRTI backbones had become widely available, offering a potentially cheaper multi-tablet regimen. This study aimed to evaluate guideline compliance in people with HIV who started antiretroviral therapy (ART), the uptake of generic multi-tablet regimens (gMTRs), and associated medication costs. Methods: This retrospective cohort study used data from the Dutch HIV Monitoring Foundation to determine the proportion of treatment-naïve people entering care who initiated ART according to the DHHS and type of ART regimens prescribed between January 2016 and December 2020. We analyzed ART prescriptions, both at the national level and per individual HIV treatment centers. We calculated the monthly ART costs based on Dutch medicine prices listed on www.medicijnkosten.nl for each calendar year. Results: In 2016, an integrase inhibitor-containing regimen was initiated in 77.3% which increased to 87.8% in 2020. The compliance rate to DHHS-recommended initial regimens ranged from 82.8% in 2016 to 90.9% in 2020. Most patients received single-tablet regimens, 81.3% in 2016 to 60.3% in 2020. After the introduction the gMTRs showed a steady increase from 17.8% in 2018 to 37.8% in 2020. The cost of the first-line regimen per patient decreased by 22.9% in 2020 compared with 2017. The decrease was larger in centers where treatment-naïve individuals with HIV were preferentially initiated on a gMTR. Conclusions: There was a high compliance to the "DHHS-recommended initial regimens for most people with HIV" in the Netherlands. Most people who initiated ART received STRs, although the percentage of people who started on STRs gradually decreased over time. The use of gMTRs increased over time and was associated with lower medication costs. [ABSTRACT FROM AUTHOR]

Background Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use. Methods Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA–suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin. Results The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: −3.78% [95% confidence interval {CI}, −7.49% to.08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, –.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued. Conclusions In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice. Clinical Trials Registration NCT04707326. [ABSTRACT FROM AUTHOR]

Objectives: To provide an overview of the demographics, treatment characteristics and long-term outcomes of children with perinatal HIV-1 infection (PHIV) living in the Netherlands (NL) and to specifically investigate whether outcomes differ by children's adoption status. Design: A prospective population-based open cohort including children with PHIV in NL. Methods: We included children with PHIV who had entered HIV care in NL since 2007, in view of a sharp increase in the number of adopted children with PHIV since that year. We compared the proportion with virologic suppression and CD4+T-cell count over time between the following groups of children with PHIV: adopted and born outside NL, non-adopted born in NL, and non-adopted born outside NL, using generalized estimating equations and linear mixed effects models, respectively. To account for the variation in cohort inclusion, we analyzed data of children exposed to at least one year of antiretroviral therapy (ART). Results: We included 148 children (827.5 person-years of follow-up, 72% adopted, age at start care in NL 2.4 (0.5–5.3)). Under-18 mortality was zero. Over the years, a boosted PI-based regimen was most often prescribed. The use of integrase inhibitors increased since 2015. Non-adopted children born in NL were less likely to achieve virological suppression compared to adopted children (OR 0.66, 95%CI 0.51–0.86, p = 0.001), which disappeared after excluding one child with suspected treatment nonadherence (OR 0.85, 95%CI 0.57–1.25, p = 0.400). CD4+T-cell Z-score trajectories were not significantly different between groups. Conclusions: Despite considerable and increasing diversity of the population of children with PHIV in NL, geographical origin and adoption status do not seem to pose important challenges in achieving good immunological and virological outcomes. [ABSTRACT FROM AUTHOR]

Background Long-term viral suppression on antiretroviral therapy (ART) is not established among all people with human immunodeficiency virus (PWH). Young adults (18–24 years) are recognized as a group vulnerable for suboptimal virological treatment outcomes. The aim of this study is to evaluate longitudinal virological treatment outcomes and to identify risk factors for virological failure (VF) among young adults with non-perinatally and perinatally acquired human immunodeficiency virus (HIV) in the Netherlands. Methods We included individuals registered in the national ATHENA observational cohort from 2000 until 2020 who had entered care before the age of 25 years, who had received ART for at least 6 months with at least 2 available HIV ribonucleic acid measurements between the age of 18 and 24 years. We compared VF between age groups 12–17, 18–24, and 25–30 years. A multivariable generalized linear mixed model was used to evaluate risk factors for VF. Analyses were stratified by HIV acquisition mode. Results In total, 1174 non-perinatally PWH and 157 perinatally PWH were included. In 2020, VF rate was 7% in non-perinatally PWH young adults and 19% in perinatally PWH young adults. The adjusted risk for VF was significantly higher in those aged 18–24 compared to 25–30 years in both non-perinatally PWH (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.07–1.50) and perinatally PWH (OR, 2.34; 95% CI, 1.48–3.71). Conclusions Young adulthood is a vulnerable period, with increased risk for VF, especially for perinatally PWH. The probability of VF decreased over time, but less for perinatally PWH compared to non-perinatally PWH. [ABSTRACT FROM AUTHOR]

Background We determined the frequency of and factors associated with ≥10% weight gain and its metabolic effects in virally suppressed people with human immunodeficiency virus (PWH) from the Dutch national AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort switching to tenofovir alafenamide (TAF) and/or integrase strand transfer inhibitor (INSTI). Methods We identified antiretroviral therapy–experienced but TAF/INSTI-naive PWH who switched to a TAF and/or INSTI-containing regimen while virally suppressed for >12 months. Individuals with comorbidities/comedication associated with weight change were excluded. Analyses were stratified by switch to only TAF, only INSTI, or TAF + INSTI. Factors associated with ≥10% weight gain were assessed using parametric survival models. Changes in glucose, lipids, and blood pressure postswitch were modeled using mixed-effects linear regression and compared between those with and without ≥10% weight gain. Results Among 1544 PWH who switched to only TAF, 2629 to only INSTI, and 918 to combined TAF + INSTI, ≥10% weight gain was observed in 8.8%, 10.6%, and 14.4%, respectively. Across these groups, weight gain was more frequent in Western and sub-Saharan African females than Western males. Weight gain was also more frequent in those with weight loss ≥1 kg/year before switching, age <40 years, and those discontinuing efavirenz. In those with ≥10% weight gain, 53.7% remained in the same body mass index (BMI) category, while a BMI change from normal/overweight at baseline to obesity at 24 months postswitch was seen in 13.9%, 11.7%, and 15.2% of those switching to only TAF, only INSTI, and TAF + INSTI, respectively. PWH with ≥10% weight gain showed significantly larger, but small increases in glucose, blood pressure, and lipid levels. Lipid increases were limited to those whose switch included TAF, whereas lipids decreased after switching to only INSTI. Conclusions Weight gain of ≥10% after switch to TAF and/or INSTI was common in virally suppressed PWH, particularly in females and those starting both drugs simultaneously. Consequent changes in metabolic parameters were, however, modest. [ABSTRACT FROM AUTHOR]

Evidence-based guidelines in HIV care aim to improve patients' health outcomes, quality of care, and cost-effectiveness. Laboratory monitoring plays an important role in assessing clinical status of patients and forms an integral part of HIV treatment guidelines. The Dutch HIV monitoring foundation (Stichting HIV Monitoring) previously observed variation between HIV treatment centres in the Netherlands in terms of compliance with guidelines for performing laboratory tests. Drawing on qualitative research methods, this article aims to describe factors that influence guideline compliance for laboratory monitoring in outpatient HIV care in the Netherlands. Twelve semi-structured in-depth interviews were conducted with a convenience sample of physicians from four HIV treatment centres. In general, physicians perceived laboratory guidelines as useful. However, unclear online visual representation of the guidelines, a lack of set reminders for tests, and assessment of patients' risk behaviour, which differs per patient, were identified as barriers to guideline compliance. The compartmentalisation of the Dutch healthcare system was viewed as hampering guideline compliance. A clinical-decision-support tool could possibly facilitate compliance with laboratory monitoring guidelines. Moreover, better alignment of HIV outpatient care, municipal health services and primary care, in terms of laboratory testing, could optimize efficiency, increase cost-effectiveness, and improve quality of HIV care. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Methods and Findings: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1:1:1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1:1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm³ or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. Conclusions: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection. [ABSTRACT FROM AUTHOR]

Objectives: We investigated occurrence of and risk factors for severe COVID-19 outcomes in people with HIV (PWH) in the Netherlands., Design: An ongoing prospective nationwide HIV cohort study., Methods: COVID-19 diagnoses and outcomes with other relevant medical information were prospectively collected from electronic medical records in all HIV treatment centers in the Netherlands, from the start of the COVID-19 epidemic until December 31, 2021. Risk factors for COVID-19 related hospitalization and death were investigated using multivariable logistic regression, including demographics, HIV-related factors, and comorbidities., Results: The cohort comprises 21 289 adult PWH, median age 51.2 years, 82% male, 70% were of Western origin, 12.0% were of sub-Saharan African and 12.6% Latin American/Caribbean origin, 96.8% had HIV-RNA less than 200 copies/ml, median CD4 + cell count 690 (IQR 510-908) cells/μl. Primary SARS-CoV-2 infections were registered in 2301 individuals, of whom 157 (6.8%) required hospitalization and 27 (1.2%) ICU admission. Mortality rates were 13 and 0.4% among hospitalized and nonhospitalized individuals, respectively. Independent risk factors for severe outcomes (COVID-19-related hospitalization and death) were higher age, having multiple comorbidities, a CD4 + cell count less than 200 cells/μl, uncontrolled HIV replication, and prior AIDS diagnosis. Migrants from sub-Saharan Africa, Latin America, and the Caribbean were at an increased risk of severe outcomes independently of other risk factors., Conclusion: In our national cohort of PWH, risk of severe COVID-19 outcomes was increased in individuals with uncontrolled HIV replication, low CD4 + cell count, and prior AIDS diagnosis, independently of general risk factors such as higher age, comorbidity burden and migrants originating from non-Western countries., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In two Dutch observational cohorts of people with HIV, the use of TDF, ETR, or INSTIs was not independently associated with either the risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes, as was suggested by previous observational and molecular docking studies. Our findings do not support a strategy of modifying antiretroviral therapy to include these agents to protect against SARS-CoV-2 infection and severe COVID-19 outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Achieving and maintaining viral suppression in young adults (18-24 years) living with HIV is challenging. Overall HIV viral suppression rates are lower in young as compared to older adults. Longitudinal data provide valuable insight on dynamics of viral suppression and variables of potential influence on HIV virological failure (VF), but is scarce in young adults living with HIV on combination antiretroviral therapy (cART). We evaluated longitudinal virological outcomes of behaviorally young adults (18-24 years) living with HIV in the Netherlands over a period of 15 years.We analyzed data from the Dutch national HIV database of 816 young adults living with HIV on cART in the Netherlands from 2000 to 2015. VF was defined as 2 consecutive detectable plasma HIV-1 viral load (VL) measurements > 200 copies/ml. Generalized linear mixed model analyses were used to assess HIV VF over time and identify risk factors associated with VF.VF during the study follow-up occurred at least once in 26% of cases. The probability of experiencing VF decreased over the study period per calendar year (OR 0.78, 95% confidence interval [CI];0.72; 0.85). Factors significantly associated with VF were being infected through heterosexual contact (OR 5.20, CI 1.39;19.38) and originating from Latin America or the Caribbean (OR 6.59, CI 2.08;20.92). Smaller, yet significant risk factors for VF were being infected through a blood transfusion or a needle accident (OR9.93, CI 1.34;73.84, and having started with cART with a nadir CD4 count >500 cells/μl (OR 11.36, CI 2.03;63.48).In our large cohort of young adults, the risk of VF has diminished over 15 years. Specific subgroups were identified to be at risk for suboptimal treatment.

Background: Whether continued, accelerated liver fibrosis progression occurs following acute hepatitis C virus infection (AHCVI) in HIV-positive MSM is unknown., Design and Methods: HIV-positive MSM from the AIDS Therapy Evaluation in the Netherlands and MSM Observational Study for Acute Infection with Hepatitis C-cohorts with primary AHCVI and at least one fibrosis-4 (FIB-4) measurement less than 2 years before and 1 year after estimated AHCVI were included. Mixed-effect linear models were used to evaluate (time-updated) determinants of FIB-4 levels over time. Determinants of transitioning to and from FIB-4 ≤ 1.45 and > 1.45 were examined using multistate Markov models., Results: Of 313 MSM, median FIB-4 measurements per individual was 12 (interquartile range  = 8-18) and median follow-up following AHCVI was 3.5 years (interquartile range = 1.9-5.6). FIB-4 measurements averaged at 1.00 [95% confidence interval (CI) = 0.95-1.05] before AHCVI, 1.31 (95% CI = 1.25-1.38) during the first year of AHCVI and 1.10 (95% CI = 1.05-1.15) more than 1 year after AHCVI. Mean FIB-4 more than 1 year after AHCVI was higher for chronically infected patients compared with those successfully treated (P = 0.007). Overall FIB-4 scores were significantly higher with older age, lower CD4 cell count, longer duration from HIV-diagnosis or AHCVI, and nonresponse to HCV-treatment. At the end of follow-up, 60 (19.2%) and eight MSM (2.6%) had FIB-4 between 1.45-3.25 and ≥ 3.25, respectively. Older age, lower CD4 cell count and detectable HIV-RNA were significantly associated with higher rates of progression to FIB-4 > 1.45, whereas older age, longer duration from HIV-diagnosis and nonresponse to HCV-treatment were significantly associated with lower rates of regression to FIB-4 ≤ 1.45., Conclusion: In this population of HIV-positive MSM, FIB-4 scores were higher during the first year of AHCVI, but FIB-4 ≥ 3.25 was uncommon by the end of follow-up. Well controlled HIV-infection appears to attenuate FIB-4 progression.

Background: The risk of venous thrombotic events is elevated in people with HIV, but overall risk estimates and estimates specific to immune status and antiretroviral medication remain i mprecise. In this study, we aimed to estimate these parameters in a large cohort of people with HIV in the Netherlands., Methods: In this retrospective cohort study, we used the Dutch ATHENA cohort to estimate crude, age and sex standardised, and risk period-specific incidences of a first venous thrombotic event in people with HIV aged 18 years or older attending 12 HIV treatment centres in the Netherlands. Crude and standardised incidences were compared with European population-level studies of venous thrombotic events. We used time-updated Cox regression to estimate the risk of a first venous thrombotic event in association with HIV-specific factors (CD4 cell count, viral load, recent opportunistic infections, antiretroviral medication use) adjusted for traditional risk factors for venous thrombotic events., Findings: With data collected from Jan 1, 2003, to April 1, 2015, our study cohort included 14 389 people with HIV and 99 762 person-years of follow-up, with a median follow-up of 7·2 years (IQR 3·3-11·1). During this period, 232 first venous thrombotic events occurred, yielding a crude incidence of 2·33 events per 1000 person-years (95% CI 2·04-2·64) and an incidence standardised for age and sex of 2·50 events per 1000 (2·18-2·82). CD4 counts less than 200 cells per μL were independently associated with higher risk of a venous thrombotic event: adjusted hazard ratio (aHR) 3·40 (95% CI 2·28-5·08) relative to counts of 500 cells per μL. A high viral load (aHR 3·15, 95% CI 2·00-5·02; >100 000 copies per mL vs <50 copies per mL) and current or recent opportunistic adverse events (2·80, 1·77-4·44) were also independently associated with higher risk of a venous thrombotic event. There were no associations between any specific antiretroviral drugs and risk of a venous thrombotic event. Rates associated with pregnancy (9·4, 95% CI 4·6-17·3), malignancy (16·7, 10·6-25·1), and hospitalisation (24·4, 19·1-30·6) were lower than primary thromboprophylaxis thresholds suggested by the respective guidelines., Interpretation: Our findings support neither prescribing primary outpatient thromboprophylaxis nor avoiding any type of antiretroviral medication in people with HIV at high risk of a venous thrombotic event., Funding: Dutch Ministry of Health, Welfare and Sport., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: In 1998, the AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort was established to demonstrate the lifesaving effectiveness of triple combination antiretroviral therapy, including HIV-protease inhibitors, that had recently been made available for clinical use. Subsequently, the HIV Monitoring Foundation was established by the Dutch Ministry of Health, Welfare and Sport to continue ATHENA as an open cohort in order to continue the registration and monitoring of all HIV-positive people as an integral part of HIV care in all 26 HIV treatment centres in the Netherlands., Participants: To date, a total of 25 036 participants have been enrolled in the cohort, with 263 600 person-years of follow-up. As of 1 January 2017, 19 035 HIV-1-positive participants were known to be in care: 18 824 adults (81% men and 19% women) and 211 children (47% boys and 53% girls). The remaining 6001 participants had either died (46%), were lost to care (29%) or had moved abroad (25%)., Findings to Date: Today, with over 20 years of follow-up, the ATHENA cohort has provided extensive knowledge on HIV treatment, comorbidities and coinfections and created insight into the transmission dynamics of the HIV epidemic., Future Plans: ATHENA continues to enrol and monitor HIV positive people entering HIV care in the Netherlands. Future research will continue to provide tangible input into HIV care and prevention policies in the Netherlands and internationally., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Monitoring of renal function becomes increasingly important in the aging population of HIV-1 infected patients. We compared Cockroft & Gault (C&G), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Cystatin C- and 24 h urine-based estimated GFR (eGFR) with the gold standard, measured GFR (mGFR) using [125I]-iothalamate., Methods: Substudy within a randomized, multinational trial comparing continuing zidovudine/ lamivudine with switching to tenofovir/ emtricitabine in patients with suppressed HIV-1 infection. Accuracy (defined as the mean difference between eGFR and mGFR) and precision (defined as standard deviation (SD) of the mean difference between eGFR and mGFR) of the eGFRs were calculated using linear regression and Bland & Altman analysis., Results: We included 19 patients, 18 men, 15 Caucasian, mean (SD) age 46.0 y (± 8.9) and BMI 23.9 kg/m2 (± 3.0). Mean (SD) mGFR was 102 ml/min/1.73 m2 (± 19), 4 patients had mild renal dysfunction. All eGFRs tended to underestimate true GFR, with best accuracy for C&G (-1 ml/min/1.73 m2), CKD-EPI (-1 ml/min/1.73 m2), 24 hcreatinine clearance (-2 ml/min/1.73 m2) and MDRD-6 (0 ml/min/1.73 m2), and worst for cystatin C-based (-9 ml/min/1.73 m2) and MDRD-4 estimations (-10 ml/min/1.73 m2). Accuracy worsened at higher mGFR, but was not significantly influenced by age. C&G tended to overestimate at higher BMI. Precision was comparable for all GFR estimations., Conclusions: In this limited number of patients with preserved renal function and suppressed HIV-infection C&G and CKD-EPI appeared to be the best reflection of real GFR and most practical tool for monitoring GFR.