OBJECTIVE:The aim of this study was to improve understanding of biological pathways underlying inadequate CD4 + T-cell restoration after initiating antiretroviral treatment as these so called Immunological nonresponders are at increased risk for morbidity and mortality while treatment options are lacking. DESIGN:We compared baseline multiomics data from 88 Immunological nonresponders and 1467 immunological responders that participated in the 2000HIV study, separated into a discovery and validation cohort. METHODS:We measured expression levels of 2367 plasma proteins, comparing the immunological responders and nonresponders. As this highlighted low Src kinase-associated phosphoprotein 1 (SKAP1) levels in Immunological nonresponders, we measured intracellular SKAP1 levels in CD4 + T-cells, investigated DNA methylation and assessed single-nucleotide polymorphisms (SNPs). We also explored whether HIV or CMV infection may influence SKAP1 expression. RESULTS:SKAP1 plasma levels were significantly lower in Immunological nonresponders in both cohorts. SKAP1 plasma concentrations reflected intracellular levels in CD4 + T-cells. DNA methylation analysis showed significant hypermethylation at the SKAP1 promotor region. Three SNPs close to the SKAP1 gene were associated with poor Immunological response. Preliminary data suggest that HIV or CMV may influence SKAP1 levels. CONCLUSION:Our data show decreased SKAP1 concentrations in immunological nonresponders, potentially driven by hypermethylation of the SKAP1 promoter. Downregulation of SKAP1, which is known to play a role in T cell proliferation and migration, may therefore contribute to the poor restoration of CD4 + cell count after ART.

Background Suriname has an estimated human immunodeficiency virus (HIV) prevalence of 1.6% among adults aged 15 to 49 years. Women living with HIV (WLWH) have a higher risk of developing cervical cancer or dysplasia. The World Health Organization (WHO) guidelines advise cervical screening once every three years, starting at age 25, when using visual inspection with acetic acid (VIA). Objective The primary objective of this study was to determine how often WLWH in Suriname undergo cervical screening. The secondary objective was to explore factors associated with cervical screening participation. Methodology In this single-center study, data were collected from all WLWH visiting the HIV outpatient clinic of the Academic Hospital Paramaribo during six weeks in 2023. The last cervical screening date was registered. To explore factors associated with the cervical screening rate, these women were asked to fill out a questionnaire. Results During the study period, 195 WLWH visited the outpatient department. Of these, 134 (68.7%) had ever gone for cervical screening, and 77 (39.5%) had gone for cervical screening in the past three years. A total of 134 WLWH participated in the questionnaire. Of those women, 99 (73.9%) were not aware of the higher risk of cervical cancer in WLWH. Conclusions Although a majority of WLWH had done cervical screening at least once in their lives, less than 40% were screened in the last three years in accordance with WHO guidelines. Strategies to increase the number of women going for cervical cancer screening should be explored in the coming years.

Background The COVID-19 pandemic has been associated with an increase in mental health problems and a decline in health-related quality of life (HRQoL). It has been hypothesized that disease severity of COVID-19 pneumonia may increase the risk for long-term anxiety, depressive and posttraumatic stress symptoms. This exploratory study investigates the relationship between the severity of COVID-19 infection in admitted and non-admitted patients and the prevalence of anxiety, depressive and post-traumatic stress symptoms as well as quality of life up to 2 years post COVID-19. Method COVID-19 survivors were categorized in three subgroups: “moderate” (no need for hospitalization), “severe” (hospitalization requiring oxygen), and “critical” cases (respiratory failure and intensive care unit admission). Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI) and HRQoL (Short Form SF-36 health survey) were studied at 3, 6, 12 and 24 months follow-up visits. Data were analysed using (repeated measures) linear mixed-effects models. Results A high burden of disease persists two years after COVID, manifested by mental health symptoms and reduced quality of life across all subgroups. No significant differences were observed in the development of mental health symptoms over time between the three subgroups, except less posttraumatic stress symptoms in critically ill COVID patients compared to severe or moderate COVID patients after 2 years. Conclusions Up to 2 years after COVID-19 pneumonia, mental health symptoms and decreased quality of life are prevalent, but this is not related to the severity of COVID-19 pneumonia.

BACKGROUND:Starting antiretroviral treatment (ART) at higher CD4 cell counts is associated with reduced non-AIDS-defining malignancy (NADM) risk. We studied whether starting ART within 1 year after acquiring human immunodeficiency virus type 1 (HIV-1) reduces this risk while also adjusting for socioeconomic status. METHODS:We included individuals (≥18 years) from the Dutch national ATHENA cohort diagnosed with human immunodeficiency virus (HIV) and having started ART between 2000 and 2022 without prior NADM with ≥6 months of follow-up. "Early ART" initiators were defined as starting ART <365 days following a negative HIV test or primary HIV infection, all others as "late-ART" starters. Hazard ratios (HR) for NADM were estimated using Cox regression, adjusted for a priori selected confounders (age, sex at birth, smoking, alcohol use, calendar time, HIV transmission route, region of origin, nadir CD4 cell count, HIV-1 viral copy-years), and socioeconomic status (SES) using data from Statistics Netherlands. RESULTS:Compared to "late-ART" (n = 17 965) participants, "early-ART" participants (n = 1858) were younger (median 34.8 vs 39.0 years), with a higher nadir CD4 count (median 478 vs 260 cells/µL). NADM were diagnosed in 25 "early-ART" and 869 "late-ART" starters resulting in an incidence rate of 2.22/1000 person-years (PY) (95% confidence interval [CI] = 1.50-3.28) and 4.87/1000 PY (95% CI = 4.56-5.21), respectively. "Early-ART" initiation was associated with a reduced risk of any NADM (HR = 0.60 [95% CI = .40-.91]) and infection-unrelated NADM (HR = 0.60 [95% CI = .37-.98]), but not of infection-related NADM (HR = 0.58 [95% CI = .27-1.28]). Additional adjustment for SES only minimally changed the hazard ratios. CONCLUSIONS:Starting ART within 1 year of HIV acquisition is associated with a reduced NADM risk compared to starting ART later.

HIV is a highly stigmatized condition, and negative beliefs about HIV and people with HIV are frequently internalized. This paper describes how we designed, implemented, and evaluated RESET, an intervention aiming to reduce internalized HIV stigma among people with HIV in the Netherlands. This face-to-face, three-session workshop series for people with HIV was designed, implemented, and evaluated with Intervention Mapping, a systematic approach to behavior change that uses theory and evidence, as well as participatory processes, in the planning of interventions. Intervention Mapping comprises six steps: 1) conducting a needs assessment and drafting a logic model of the problem; 2) specifying intervention outcomes and objectives, and drafting a logic model of change; 3) designing the intervention by selecting theory and evidence-based methods for behavior change and then developing their practical applications; 4) producing and pre-testing the intervention; 5) planning for implementation; and 6) planning process and effect evaluation. For each step, we describe the tasks involved and how we approached each task as we designed, implemented, and evaluated RESET. By transparently reporting how RESET was developed, we illuminate success and challenges in designing, implementing, and evaluating HIV stigma interventions. We also demonstrate how Intervention Mapping can be leveraged to develop effective interventions for reducing stigma, including internalized HIV stigma.

Background:Little is known about the effect of hepatitis C virus (HCV) treatment on sexual risk behavior among men who have sex with men (MSM) with HIV by treatment type (interferon [IFN]-based vs direct-acting antiviral [DAA]-based).Setting:MSM with HIV and recently acquired HCV infection enrolled in the MSM Observational Study of Acute Infection with hepatitis C (MOSAIC) cohort.Methods:Using data from 2009 to 2018, we evaluated risk behavior through a validated HCV risk score (where >= 2 indicated high risk) and its individual risk behaviors. Levels of risk behavior before, during, and after treatment were modeled for each treatment episode using linear and logistic regression with Generalized Estimating Equations adjusting for DAA availability and number of reinfections.Results:One hundred forty MSM with a median age of 45 years (interquartile range = 40-49) yielded 180 treatment episodes (n = 131 IFN-based, n = 49 DAA-based). Adjusted mean risk score before, during, and after treatment was 2.4 (95% confidence interval [CI] = 2.1 to 2.6), 0.9 (95% CI = 0.8 to 1.0), and 1.7 (95% CI = 1.5 to 1.8), respectively. Before treatment, no differences in mean HCV risk score or proportion of specific behaviors were found between the regimen groups. During treatment, MSM treated with DAAs had a higher average risk score and proportion of receptive condomless anal sex, sharing toys and unprotected fisting than those treated with IFN. After treatment, the proportion sharing straws were significantly higher in MSM treated with DAAs than in MSM treated with IFN.Conclusions:MSM treated with DAAs, compared with MSM treated with IFN, had higher levels of HCV-related risk behavior during treatment. The higher risk of HCV reinfection in the DAA-era underscores the need for ongoing HCV testing and behavioral interventions against HCV.

BACKGROUND:Although guidelines for COVID-19 additional vaccination strategies generally prioritise people with advanced HIV infection, recommendations vary globally, with some countries recommending an annual vaccination for all people with HIV (PWH), while others restrict this to PWH with a CD4+ T-cell count < 200 cells per µL. METHODS:We conducted a prospective cohort study in 448 adult PWH. The primary outcome was the SARS-CoV-2 spike (S1)-specific IgG antibody level at 1, 6, 12, 18, and 24 months after completing a primary COVID-19 vaccination series (two doses of BNT162b2, mRNA-1273, or ChAdOx1-S, or one dose of Ad26.COV2.S). We compared the antibody kinetics over two years between PWH with a baseline CD4+ T-cell count < 200 cells per µL (n = 16) vs. ≥ 200 cells per µL (n = 432) with a mixed-effects model. Secondary outcomes included variables associated with the kinetics of S1-specific antibody levels and the incidence of breakthrough infections. RESULTS:The median most recent CD4+ T-cell count prior to primary vaccination was 140 (IQR 80-165) in the < 200 cells per µL group, and 688 (IQR 520-899) in the ≥ 200 cells per µL group at the time of primary vaccination. S1-specific antibodies were lower in PWH with a CD4+ T-cell count < 200 vs. ≥ 200 cells per µL during the two-year follow-up, with predicted S1-specific antibody levels of 514 (95% CI 456-578) vs. 2758 (95% CI 1488-5110) BAU per mL at 12 months (p < 0.001) and 839 (95% CI 732-959) vs. 3505 (95% CI 1712-7175) BAU per mL at 24 months (p < 0.001). The overall incidence of SARS-CoV-2 infections was 55% and comparable between groups. A CD4+ T-cell count < 200 cells per µL, higher age, and a vector-based primary vaccination series were negatively associated with S1-specific antibody levels over time. CONCLUSION:Long-term humoral responses were lower in PWH with a CD4+ T-cell count < 200 cells per µL compared to those with a CD4+ T-cell count ≥ 200 cells per µL. National COVID-19 vaccine guidelines recommending booster vaccines for all PWH, should therefore specifically emphasise the need for booster vaccines in those with a CD4+ T-cell count < 200 cells per µL. Trial registration: The trial was registered on the International Clinical Trials Platform (registration number: EUCTR2021-001054-57-N).

Certain key populations have a high risk of hepatitis C virus (HCV) reinfection, which includes men who have sex with men (MSM) with HIV who continue to engage in behaviors associated with HCV acquisition following clearance. Among MSM with HIV, we aimed to identify longitudinal sexual behavior patterns and estimate reinfection risk within identified patterns. MSM with HIV from the longitudinal, prospective Dutch MOSAIC study (2009-2018) at risk for HCV reinfection were included. Follow-up started following HCV clearance. Risk behavior was assessed using the HCV-MOSAIC score (range = 0.0-7.0), where ≥2 indicates high risk of reinfection. Classes were inferred from the mean HCV-MOSAIC score over time using a latent process mixed-effects model with the covariates age, group sex and casual partnership. The association between classes and HCV reinfection risk was assessed using a joint survival model. In total, 123 MSM were included with a median follow-up of 2.7 years [interquartile range (IQR) = 1.2-4.7]. Two classes were identified: one with mostly lower (C1, n = 67) and one with mostly higher risk behavior (C2, n = 56). During follow-up, both classes had considerable variation in HCV-MOSAIC scores (C1, median = 1.1, IQR = 0.0-2.1 and C2, median = 3.0, IQR = 2.0-3.5). HCV reinfection probability was similar between both classes at year 3 of follow-up [C1, 17%, 95% confidence interval (CI) = 11%-35% and C2, 18%, 95%CI = 15%-47%], but became higher in C2 than C1 at year 5 (C1, 22%, 95%CI = 13%-39% and C2, 37%, 95%CI = 28%-69%). The variation in risk over time suggests that behavioral assessment is continually needed for early testing, treatment and offering behavioral inventions.

Reduced diffusion capacity (DLCO) after COVID 19 pneumonia was reported in hospitalised patients after discharge. Here, we studied the restoration of DLCO over a 24 months period in COVID-19 pneumonia survivors (n = 317), who were categorised into "moderate" cases (no oxygen supply; no need for hospitalisation), "severe" cases (respiratory frequency > 30/min and/or peripheral oxygen SpO2 < 93%), and "critical" cases (respiratory failure and admission into the intensive care unit). COVID-19 pneumonia survivors with a decreased DLCO (<80%) at 3 months (n = 133) were invited for 6- and 24-months follow-up. At 3 months, impairment of DLCO was more severe in critical case (p < .01). Over time, the subgroups showed a similar level of improvement; and, there was no difference in recovery over time between the subgroups. At 24 months, the DLCO did not differ between the subgroups, with a mean DLCO of 73% for all patients. At 24 months, 65% of patients still had a DLCO < 80%, and in 40% of patients DLCO was <70% of predicted. Regardless the initial disease severity, all COVID-19 survivors showed improvement in DLCO during follow-up; however, DLCO had not normalised in the majority of patients with a DLCO <80% 3 months after hospital discharge.

IntroductionAnti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART.Methods and analysisB-Free is a multistage, randomised, multicentre, open-label, non-inferiority trial, embedded within the Swiss HIV Cohort Study and conducted in collaboration with cohorts of PWH in the Netherlands and France. Cohort participants with a history of ART change due to virologic failure and who maintain HIV virologic suppression with an ART regimen consisting of a pharmacological booster and at least two drugs from classes other than nucleoside reverse transcriptase inhibitors are included. Patients with major drug resistance mutations against DTG or DOR and individuals with chronic hepatitis B virus infection are not eligible for the study. Individuals are randomised 1:1 to either receiving co-formulated DTG/3TC and DOR once daily or continuing their boosted ART regimen. The primary outcome is the proportion of individuals lacking virologic control (HIV-RNA ≥50 cp/mL) at 48 weeks, according to the Food and Drug Administration snapshot algorithm. Changes in DDI burden (assessed using a DDI score), treatment satisfaction (assessed using the HIV Treatment Satisfaction Questionnaire), quality of life and mental health represent key secondary outcomes. Additional secondary outcomes include the proportion of individuals developing new resistance-associated mutations and changes in quality of life and mental health. In a qualitative substudy, we will conduct semistructured interviews with a subset of participants to assess their expectations and experiences towards HIV treatment and clinical research in general. Enrolling 210 individuals will provide 80% power to demonstrate non-inferiority, defined as less than 8% absolute increase in loss of viral suppression in individuals randomised to DOR/DTG/3TC (one-sided type I error rate of 0.025).Ethics and disseminationThe study was approved by the competent ethics committees (reference number BASEC 2023–01060) and the regulatory authority Swissmedic (reference number 701655) in Switzerland before the enrolment of the first participant. Approval by the European Medicines Agency and local ethical committees in the Netherlands and France will be obtained prior to including participants in these countries. Participant’s written informed consent is obtained by the investigators before enrolment. The results of all major B-Free study outcomes will be submitted to peer-reviewed journals that enable Open Access publication.Trial registration numberSwiss National Clinical Trials Portal (SNCTP000005686, registered on 06 November 2023) and Clinicaltrials.gov (NCT06037564, registered on 07 September 2023).

Objectives:Antiretroviral therapy (ART) accounts for a considerable proportion of HIV care expenses. In June 2021, a Dutch healthcare insurer implemented a mandatory policy to de-simplify branded RPV/TDF/FTC (Eviplera) into a two-tablet regimen containing rilpivirine (Edurant) and generic TDF/FTC as part of cost-saving measures. The objectives of this study were to evaluate the acceptance of this policy, the trends in ART dispensation, and cost developments.Design:A retrospective database study.Methods:In this study, medication dispensation data were obtained from the Dutch Foundation for Pharmaceutical Statistics (SFK). This database covers 98% of all medication dispensations from Dutch pharmacies including people with HIV who receive ART. We received pseudonymized data exclusively from individuals insured by the insurer for the years 2020-2022. Costs were calculated using Dutch drug prices for each year.Results:In June 2021, 128 people with HIV were on branded RPV/TDF/FTC. Following the policy implementation, 59 (46%) had switched to RPV + generic TDF/FTC, but after 1.5 years, only 17 of 128 individuals (13%) used the proposed two-tablet regimen. The other 111/128 used RPV/TDF/FTC with prescriptions for 'medical necessity' (n = 29), switched to RPV/TAF/FTC (n = 51), or other ART (n = 31). Despite expectations of cost-savings, costs increased from 72 988 in May 2021 to 75 649 in May 2022.Conclusion:A mandatory switch from an STR to a TTR in people with HIV proved unsuccessful, marked by low acceptance, and increased costs after 1 year. This underscores the necessity of incorporating patient and prescriber involvement in changing medication policies.

BACKGROUND:Antiretroviral therapy (ART), which is increasingly used by people with HIV, accounts for significant care costs, particularly because of single-tablet regimens (STRs). This study explored de-simplification to a two-tablet regimen (TTR) for cost reduction. The objectives of this study were: (1) acceptance of de-simplification, (2) patient-reported outcomes, and (3) cost savings. METHODS:All individuals on Triumeq®, Atripla® or Eviplera® in five HIV clinics in the Netherlands were eligible. Healthcare providers informed individuals of this study. After inclusion, individuals were free to de-simplify. An electronic questionnaire was sent to assess study acceptance, adherence, quality of life (SF12) and treatment satisfaction (HIVTSQ). After 3 and 12 months, questionnaires were repeated. Cost savings were calculated using Dutch drug prices. RESULTS:In total, 283 individuals were included, of whom 55.5% agreed to de-simplify their ART, with a large variability between treatment centres: 41.1-74.2%. Individuals who were willing to de-simplify tended to be older, had a longer history of HIV diagnosis, and used more co-medication than those who preferred to remain on an STR regimen. Patient-reported outcomes, including quality of life and treatment satisfaction, showed no significant difference between people with HIV who switched to a TTR and those who remained on an STR regimen. Furthermore, we observed a 17.8% reduction in drug costs in our cohort of people with HIV who were initially on an STR. CONCLUSIONS:De-simplification from an STR to a TTR within the Dutch healthcare setting has been demonstrated as feasible, leads to significant cost reductions and should be discussed with every eligible person with HIV in the Netherlands.

BACKGROUND:Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV. METHODS:We did a nationwide, matched, prospective cohort study of people with HIV without previous virological failure and stable for at least 12 months on non-doravirine-containing triple or dual ART switching to doravirine before Sept 1, 2020 (exposed group). Participants in the exposed group were matched 1:2 to individuals continuing stable non-doravirine-containing ART, on age, sex, HIV acquisition category, time since ART initiation, calendar time, pre-ART CD4-count, pre-ART plasma viral load (PVL) and anchor drug class before switching. The primary outcome was protocol-defined virological failure (PDVF; PVL of ≥200 copies per mL) in the intention-to-treat (ITT) population at week 104, with participants modifying their regimen or becoming lost to follow-up considered as PDVF (non-inferiority margin +5%). In contrast, in the on-treatment population, those who modified their regimen or became lost to follow-up were censored from that moment onwards. Tolerability was a secondary outcome. FINDINGS:In total, 590 participants in the exposed group and 1180 participants in the unexposed group (of whom 55·3% used integrase strand transfer inhibitor-based regimens) were included. In the ITT analysis, PDVF occurred in 135 (22·9%) exposed participants and in 295 (25·0%) unexposed participants (risk difference -2·12%, upper limit of the one-sided 95% CI +1·40%). In the on-treatment analysis, 10 (2·2%) of 455 non-censored exposed participants and 26 (2·9%) of 885 non-censored unexposed participants had PDVF (risk difference -0·70%, upper limit of the one-sided 95% CI +0·73%). All exposed participants with a PVL of 200 copies or more per mL resuppressed without regimen modification: no confirmed virological failure (two consecutive PVLs of ≥200 copies per mL) was observed. 104 (17·6%) exposed participants and 211 (17·9%) unexposed participants modified their regimen. 73 (12.4%) exposed participants discontinued doravirine due to adverse events: abnormal dreams (1·7%) and insomnia (1·5%) were most common. INTERPRETATION:Switching to doravirine in well suppressed people with HIV without previous virological failure was non-inferior compared with continuing non-doravirine-containing regimens after 2 years in a real-world setting. FUNDING:None.

IntroductionImmunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects.MethodsThe 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli.ResultsThe discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production.ConclusionsINR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

Background:Doravirine is a non-nucleoside reverse transcriptase inhibitor with demonstrated efficacy as a third agent in treatment-naive and treatment-experienced people living with HIV (PLWH) in registration studies. However, limited real-world data are available.Methods:By searching electronic health care records, PLWH using doravirine-based regimens were selected with at least 1 year of follow-up after their first prescription. All stable PLWH who were switched to a doravirine-based regimen were included in the analysis. The primary outcome was the durability of a doravirine-based regimen 1 year after prescription. Reasons for stopping were also collected. Secondary outcomes for PLWH continuing a doravirine-based regimen after 1 year were routine laboratory assessment, body mass index, and differences in medication costs compared with their previous cART.Results:A total of 687 patients (92% men) were included from September 2019 to August 2022: 97.7% switched to doravirine/tenofovir/lamivudine (DOR/TDF/3TC). After 1 year, 94/687 (13.6%) PLWH stopped this therapy. The main reason for discontinuation was patient-reported adverse events in 70/687 (10.2%). Medical reasons for discontinuation included increased alanine tranaminase levels in 6/687 (0.9%), decreased estimated glomerular filtration rate in 3/687 (0.4%), and precautions after diagnosis of osteoporosis in 2/687 (0.3%) patients. Virologic failure occurred in 4/687 cases (0.6%), and 1 case demonstrated resistance mutations. The secondary outcomes demonstrated a statistically significant increase in alanine tranaminase levels and decrease in LDL-c levels. The switch to a doravirine-based regimen in the Netherlands reduced medication costs by 27%.Conclusions:This study demonstrated that switching to a doravirine-based regimen, mostly DOR/TDF/3TC, was highly effective and generally well tolerated, with substantial cost savings.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to ‘lipid and lipid-like molecules’, ‘organic acids and derivatives’ and ‘organoheterocyclic compounds’. In pathway analysis, perturbed ‘vitamin B1 (thiamin) metabolism’, ‘de novo fatty acid biosynthesis’, ‘bile acid biosynthesis’ and ‘pentose phosphate pathway’ were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.

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.

Objective:We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH).Design:Prospective observational cohort study.Methods:PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those <45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1 : 2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses and cytokine responses up to 180 days post-vaccination.Results:Forty PWH received mRNA-1273.214 (N = 35) or BNT162b2 (N = 5) following mRNA-based (N = 29) or vector-based (N = 11) primary vaccination. PWH were predominantly male (87% vs. 26% of non-PWH) and median 57 years [interquartile range (IQR) 53–59]. Their median CD4+T-cell count was 775 (IQR 511–965) and the plasma HIV-RNA load was <50 copies/ml in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH [4.48, 95% confidence interval (CI) 3.24–6.19] and non-PWH (4.07, 95% CI 3.42–4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. Interferon-γ, interleukin (IL)-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH.Conclusion:A bivalent BA.1 booster vaccine was immunogenic in well treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH.

We assessed the predictive capacity of the HCV-MOSAIC risk score, originally developed for primary early HCV infection, as a screening tool for HCV reinfection in 103 men who have sex with men (MSM) with HIV using data from the MOSAIC cohort, including MSM with HIV/HCV-coinfection who became reinfected (cases, n = 27) or not (controls, n = 76) during follow-up. The overall predictive capacity of the score was assessed using the area under the receiver operating characteristic (AUROC) curve. The effects of covariates on the receiver operating characteristic (ROC) curve were assessed using parametric ROC regression. The score cut-off validated for primary early infection (≥2.0) was used, from which the sensitivity and specificity were calculated. The AUROC was 0.74 (95% confidence interval (CI) = 0.63–0.84). Group sex significantly increased the predictive capacity. Using the validated cut-off, sensitivity was 70.4% (95%CI = 49.8–86.2%) and specificity was 59.2% (95%CI: 47.3–70.4%). External validation from a cohort of 25 cases and 111 controls, all MSM with HIV, resulted in a sensitivity of 44.0% (95%CI = 24.4–65.1) and specificity of 71.2% (95%CI = 61.8–79.4). The HCV-MOSAIC risk score may be useful for identifying individuals at risk of HCV reinfection. In sexual health or HIV-care settings, this score could help guide HCV-RNA testing in MSM with a prior HCV infection.