Cervical cancer screening integrated in routine clinical care of women living with HIV.

OBJECTIVE: To evaluate if integrated cervical cancer screening (CCS) for women living with HIV (WLWH) in routine HIV care resulted in increased adherence to screening, and to describe the prevalence of Human Papillomavirus (HPV)-specific genotypes and the incidence of cellular abnormalities. DESIGN: Cohort study. METHODS: WLWH who accepted the offer of combined CCS and HIV care (Group 1), WLWH who declined the offer (Group 2), and WLWH not offered CCS within HIV care (Group 3) between 2013-2019 were included. Data was collected from The Danish HIV Cohort Study and The Danish Pathology Data Bank. Adherence to the CCS program was defined as fulfilled if WLWH were screened annually. RESULTS: A total of 804 WLWH were included. WLWH who accepted CCS within HIV care (group 1; n = 218) had significantly higher adherence to screening in all study years 22-99% compared to the WLWH who declined CCS (group 2; n = 232) 10-16% and WLWH who were not invited for CCS (group 3; n = 354) 11-25%. There was no significant difference in the prevalence of HPV-specific genotypes and incidence of cellular abnormalities among the three groups. CONCLUSION: Integrating CCS for WLWH in routine HIV care resulted in higher adherence to the CCS guidelines. Combined services thereby represent an opportunity to engage WLWH in HIV care into preventive services.

Clinical trial: An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B.

BACKGROUND: Stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB) may trigger a beneficial immune response leading to HBsAg loss, but clinical trials on re-start strategies are lacking. AIM: To assess whether it is beneficial to undergo a prolonged flare after NA cessation. METHODS: One-hundred-and-twenty-seven patients with HBeAg negative, non-cirrhotic CHB with at least 24 months of viral suppression on NA therapy were included. All study participants stopped antiviral therapy and were randomised to either low-threshold (ALT > 80 U/L and HBV DNA > 2000 IU/mL) or high-threshold (ALT > 100 U/L for >4 months, or ALT > 400 U/L for >2 months) for the re-start of therapy. The primary endpoint was HBsAg loss within 36 months of stopping antiviral treatment. The primary analysis was based on intention-to-treat allocation with last observation carried forward. RESULTS: There was a numerical but not statistically significant difference in HBsAg loss between the low-threshold (3 of 64; 4.7%) and the high-threshold (8 of 63; 12.7%) group (risk difference: 8.0%, 95% CI: -2.3 to 19.6, p = 0.123). None of the patients with end-of-treatment HBsAg > 1000 IU/mL achieved HBsAg loss; among those with end-of-treatment HBsAg < 1000 IU/mL, 8 of 15 (53.3%) achieved HBsAg loss in the high-threshold group compared to 3 of 26 (11.5%) in the low-threshold group. CONCLUSIONS: We could not confirm our hypothesis that a higher threshold for restart of therapy after NA withdrawal improves the likelihood of HBsAg loss within 36 months in patients with HBeAg negative CHB. Further studies including only patients with HBsAg level <1000 IU/mL and/or larger sample size and longer follow-up duration are recommended.

The Adaptive Immune Response in Hepatitis B Virus-Associated Hepatocellular Carcinoma Is Characterized by Dysfunctional and Exhausted HBV-Specific T Cells.

This systematic review investigates the immunosuppressive environment in HBV-associated hepatocellular carcinoma (HCC), characterized by dysfunctional and exhausted HBV-specific T cells alongside an increased infiltration of HBV-specific CD4+ T cells, particularly regulatory T cells (Tregs). Heightened expression of checkpoint inhibitors, notably PD-1, is linked with disease progression and recurrence, indicating its potential as both a prognostic indicator and a target for immunotherapy. Nevertheless, using PD-1 inhibitors has shown limited effectiveness. In a future perspective, understanding the intricate interplay between innate and adaptive immune responses holds promise for pinpointing predictive biomarkers and crafting novel treatment approaches for HBV-associated HCC.

Neutralizing antibody and CD8+ T cell responses following BA.4/5 bivalent COVID-19 booster vaccination in adults with and without prior exposure to SARS-CoV-2.

As severe acute respiratory coronavirus 2 (SARS-CoV-2) variants continue to emerge, it is important to characterize immune responses against variants which can inform on protection efficacies following booster vaccination. In this study, neutralizing breadth and antigen-specific CD8+ T cell responses were analyzed in both infection-naïve and infection-experienced individuals following administration of a booster bivalent Wuhan-Hu-1+BA.4/5 Comirnaty® mRNA vaccine. Significantly higher neutralizing titers were found after this vaccination compared to the pre-third booster vaccination time point. Further, neutralizing breadth to omicron variants, including BA.1, BA.2, BA.5, BQ.1 and XBB.1, was found to be boosted following bivalent vaccination. SARS-CoV-2-specific CD8+ T cells were identified, but with no evidence that frequencies were increased following booster vaccinations. Spike protein-specific CD8+ T cells were the only responses detected after vaccination and non-spike-specific CD8+ T cells were only detected after infection. Both spike-specific and non-spike-specific CD8+ T cells were found at much lower frequencies than CD8+ T cells specific to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and influenza (Flu). Taken together, these results show that the bivalent Wuhan-Hu-1+BA.4/5 Comirnaty® mRNA vaccine boosted the breadth of neutralization to newer SARS-CoV-2 variants and that vaccination is able to induce spike protein-specific CD8+ T cell responses, which are maintained longitudinally.

Barriers to HIV testing and possible interventions to improve access to HIV healthcare among migrants, with a focus on migrant women: Results from a European survey.

BACKGROUND: According to European Centre for Disease Prevention and Control (ECDC) reports, women and migrants are more likely to have delayed HIV diagnosis (CD4 <350 cells/mm3). As a follow-up to a previously published systematic review revealing a range of barriers to HIV testing among migrant women, the aim of the present study was to identify barriers to HIV testing from the perspective of service providers and to formulate possible interventions to improve access to HIV healthcare among migrants in Europe, with an emphasis on migrant women. METHODS: Between November 2021 and February 2022 an online survey, consisting of 20 questions, was forwarded to 178 stakeholders and non-governmental organizations (NGOs) working with migrant populations in 33 countries from the World Health Organization (WHO) European region. RESULTS: Forty-three responses from 14 countries were analysed. Most respondents (70%) judged migrants' access to healthcare as worse than that for the resident native population. Only 2/11 prevention interventions were available to all in at least 50% of participating countries. The three main barriers to accessing healthcare for migrant women and reasons for late HIV diagnosis among migrant women were stigma and discrimination, language barriers, and cultural barriers. CONCLUSIONS: Many HIV prevention interventions are not free of charge for all within Europe. The results of this survey show that migrant women face many barriers to accessing healthcare and that these might contribute to late HIV diagnosis. Simplification of access to free healthcare for all, more awareness raising about HIV screening and prevention among migrant women, and more migrant-focused outreach programmes are suggested to improve migrant women's access to HIV healthcare in Europe.

Perception and Emotional Experiences of Infant Feeding Among Women Living With HIV in a High-Income Setting: A Longitudinal Mixed Methods Study.

BACKGROUND: The recommendation of breastfeeding avoidance for women living with HIV in high-income settings may be influenced by cultural beliefs and come at an emotional cost. This multicenter, longitudinal, convergent mixed methods study aimed to compare differences in attitudes, concerns, and experiences surrounding breastfeeding in women living with HIV of Nordic and non-Nordic origin. SETTING: High-income setting. METHODS: Pregnant women living with HIV in the Nordic countries Denmark, Finland, and Sweden were recruited in 2019-2020. Quantitative data on attitudes surrounding infant feeding were assessed using the Positive Attitudes Concerning Infant Feeding questionnaire completed in the third trimester (T1), and 3 (T2) and 6 (T3) months postpartum. Women who completed the survey were also invited to participate in semistructured interviews at T1 and T3. The findings from the quantitative survey and qualitative interviews were brought together through merging to assess for concordance, complementarity, expansion, or discordance between the data sets and to draw metainferences. RESULTS: In total, 44 women completed the survey, of whom 31 also participated in qualitative interviews. The merged analyses identified three overarching domains representing commonalities across the quantitative and qualitative data: emotional impact, justifying not breastfeeding, and coping strategies. Not being able to breastfeed was emotionally challenging. Cultural expectations influenced the women's experiences and the strategies they used to justify their infant feeding choice. CONCLUSIONS: For women living with HIV in Nordic countries not breastfeeding was a complex, multilayered process substantially influenced by social and cultural expectations.

Full-length sequence analysis of hepatitis C virus genotype 3b strains and development of an in vivo infectious 3b cDNA clone.

IMPORTANCE: HCV genotype 3b is a difficult-to-treat subtype, associated with accelerated progression of liver disease and resistance to antivirals. Moreover, its prevalence has significantly increased among persons who inject drugs posing a serious risk of transmission in the general population. Thus, more genetic information and antiviral testing systems are required to develop novel therapeutic options for this genotype 3 subtype. We determined the complete genomic sequence and complexity of three genotype 3b isolates, which will be beneficial to study its biology and evolution. Furthermore, we developed a full-length in vivo infectious cDNA clone of genotype 3b and showed its robustness and genetic stability in human-liver chimeric mice. This is, to our knowledge the first reported infectious cDNA clone of HCV genotype 3b and will provide a valuable tool to evaluate antivirals and neutralizing antibodies in vivo, as well as in the development of infectious cell culture systems required for further research.

Psychiatric Diagnoses Among HIV-Exposed and HIV-Unexposed Uninfected Children: A Danish Nationwide Cohort Study.

This nationwide registry-based cohort study aimed to compare the risk of psychiatric diagnoses among HIV-exposed uninfected (HEU) children with a matched comparison group of HIV-unexposed uninfected (HUU) children, born in Denmark. We hypothesized that HEU children had an increased risk of psychiatric diagnoses and that this increased risk may differ by sex and age. All HEU children born in Denmark between year 2000 and 2020 were included. Each HEU child was matched by year of birth, maternal age at birth, and maternal immigration status to 10 HUU children. The primary outcome was risk of any psychiatric diagnosis (International Classification of Diseases, 10th Revision F00-F99). Incidence rate ratios (IRRs) were estimated using Poisson regression. Analyses stratifying by sex and age were also conducted. In total, 550 HEU children and 5500 HUU children were included. HEU children had an increased risk of any psychiatric disorder [IRR 1.45; 95% confidence interval (CI): 1.04-2.04] in the unadjusted analysis, but in the adjusted analysis, the risk was only significant for children aged 6-11 years [adjusted incidence rate ratio (aIRR) 1.93; 95% CI: 1.14-3.28]. Stratifying by sex, girls aged 6-11 years had an increased risk of any psychiatric disorder (aIRR 3.04; 95% CI: 1.27-7.28), while boys had an increased risk at age 12-20 years (aIRR 2.47; 95% CI: 1.18-5.17). In conclusion, HEU girls aged 6-11 years and HEU boys aged 12-20 years had an increased risk of any psychiatric disorder compared with HUU girls and boys, respectively. These findings highlight the importance of addressing the mental health needs of HEU children/adolescents.

Patient-reported outcomes in clinical HIV care: protocol for a single-centre, multistage, mixed-methods study in Denmark.

INTRODUCTION: People with HIV-1 (PWH) have worse health-related quality of life (HRQoL) compared with the general population. Using patient-reported outcomes (PROs) may help reorient the focus of HIV care towards improving HRQoL. This study aims to develop, implement and evaluate the use of PROs in HIV care. METHODS AND ANALYSIS: This is a Danish single-centre, multistage mixed-methods study consisting of four substudies (studies I-IV). Study I is a qualitative focus group interview study aiming to identify relevant PRO domains, and barriers and benefits to PRO use. Participants are 5-10 PWH and 5-10 HIV healthcare providers (HCPs). Data are thematically analysed. Results will guide the design of a PRO measure (PROM). Study II is a quantitative study aiming to assess PWH's willingness and ability to engage with PRO. All PWH are consecutively invited to complete the PROMs before their next consultations. Demographic data are collected at enrolment. Differences between PWH who do/do not complete the PROMs are assessed. Study III is a quantitative before-and-after study aiming to assess the impact of PRO use on HCP awareness. Participants are all who complete the PROMs in Study II. In contrast to study II, HCPs are notified of the PROM results. The number of problems documented by the HCP in patients' medical records during studies II and III are compared using χ2 tests. Multiple regression models are used to identify factors associated with HCP awareness. Study IV is a qualitative study aiming to explore PWH and HCP experiences of using PROs. Participants are 15-20 PWH and 10-15 HCP. Data are collected from participant observation of PRO consultations and individual interviews. Data are analysed thematically. ETHICS AND DISSEMINATION: This study is approved by the Danish Data Protection Agency. Participants will provide written consent prior to participation. Results will be published in peer-reviewed journals.

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 .

Peer-delivered point-of-care testing and linkage to treatment for hepatitis C virus infection among marginalized populations through a mobile clinic in Copenhagen, Denmark.

BACKGROUND: Globally, many people with hepatitis C virus (HCV) infection are marginalized and have very limited access to traditional healthcare services, including HCV testing and treatment. Models of care attuned to the needs of the marginalized population at risk are needed. This study aimed to evaluate the testing and treatment uptake of a community-based, peer-led model of care offering point-of-care testing. METHODS: In this interventional cohort study, people at risk of HCV infection were recruited between May 2019 and December 2021 at a community-based, peer-led mobile clinic. During a single visit, participants were offered a point-of-care HCV antibody test, and, if antibodies were detected, an additional RNA test. Participants with detectable HCV RNA were linked with peer-assisted referral to a 'fast-track' clinic at a major hospital. The primary outcomes were the number of people engaged in testing and the proportion who initiated treatment and achieved a sustained virologic response (SVR). RESULTS: We tested 728 individuals. Of those, 208 (29%) were positive for HCV antibodies, and 114 (15%) were HCV RNA detectable. Of the 114, 80 (70%) initiated treatment, and 79 (99%) achieved SVR. The main reason for not initiating treatment was non-Danish citizenship with no legal access to health care. CONCLUSION: This study found that a peer-led point-of-care service is a model of care that can engage marginalized groups in HCV testing and linkage to treatment.

Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide.

RNA viruses have evolved elaborate strategies to protect their genomes, including 5' capping. However, until now no RNA 5' cap has been identified for hepatitis C virus1,2 (HCV), which causes chronic infection, liver cirrhosis and cancer3. Here we demonstrate that the cellular metabolite flavin adenine dinucleotide (FAD) is used as a non-canonical initiating nucleotide by the viral RNA-dependent RNA polymerase, resulting in a 5'-FAD cap on the HCV RNA. The HCV FAD-capping frequency is around 75%, which is the highest observed for any RNA metabolite cap across all kingdoms of life4-8. FAD capping is conserved among HCV isolates for the replication-intermediate negative strand and partially for the positive strand. It is also observed in vivo on HCV RNA isolated from patient samples and from the liver and serum of a human liver chimeric mouse model. Furthermore, we show that 5'-FAD capping protects RNA from RIG-I mediated innate immune recognition but does not stabilize the HCV RNA. These results establish capping with cellular metabolites as a novel viral RNA-capping strategy, which could be used by other viruses and affect anti-viral treatment outcomes and persistence of infection.

Effect of aerobic exercise training on the fat fraction of the liver in persons with chronic hepatitis B and hepatic steatosis: Trial protocol for a randomized controlled intervention trial- The FitLiver study.

BACKGROUND: The global prevalence of chronic hepatitis B is more than 300 million people, and in Denmark, 17,000 people are estimated to have chronic hepatitis B. Untreated, chronic hepatitis B can lead to the development of liver cirrhosis and liver cancer. There is no curable therapy. In persons with obesity and chronic hepatitis B infection, the development of hepatic steatosis imposes a double burden on the liver, leading to an increased risk of cirrhosis and liver cancer. In patients without chronic hepatitis B, exercise interventions have shown beneficial effects on hepatic steatosis through improvements in fat fraction of the liver, insulin resistance, fatty acid metabolism, and glucose metabolism, as well as activation of liver-induced regulatory protein secretion (hepatokines) after the exercise intervention. OBJECTIVE: To investigate in persons with chronic hepatitis B and hepatic steatosis: Primary: Whether exercise will decrease the fat fraction of the liver. Secondary: If exercise will affect hepatokine secretion and if it will improve lipid- and glucose metabolism, liver status, markers of inflammation, body composition, and blood pressure. METHODS: A randomized, controlled, clinical intervention trial consisting of 12 weeks of aerobic exercise training or no intervention. Thirty persons with chronic hepatitis B and hepatic steatosis will be randomized 1:1. Before and after the intervention, participants will undergo an MRI scan of the liver, blood sampling, oral glucose tolerance test, fibroscan, VO2max test, DXA scan, blood pressure measurements, and optional liver biopsy. Lastly, a hormone infusion test with somatostatin and glucagon to increase the glucagon/insulin ratio for stimulating secretion of circulating hepatokines will be performed. The training program includes three weekly training sessions of 40 min/session over 12 weeks. DISCUSSION: This trial, investigating high-intensity interval training in persons with chronic hepatitis B and hepatic steatosis, is the first exercise intervention trial performed on this group of patients. If exercise reduces hepatic steatosis and induces other beneficial effects of clinical markers in this group of patients, there might be an indication to recommend exercise as part of treatment. Furthermore, the investigation of the effect of exercise on hepatokine secretion will provide more knowledge on the effects of exercise on the liver. TRIAL REGISTRATION: Danish Capital Regions committee on health research ethics reference: H-21034236 (version 1.4 date: 19-07-2022) and ClinicalTrials.gov: NCT05265026.

Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial.

OBJECTIVES: The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if pre-emptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14. METHODS: Between 9 June 2021 and 27 January 2022, this randomized, double-blinded, placebo-controlled, single-centre clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomly assigned 1:1 to either amantadine 100 mg or placebo twice daily for 5 days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (a) age ≥40 years, age ≥18 years and (b) at least one comorbidity, or (c) body mass index ≥30. The study protocol was published at www. CLINICALTRIALS: gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22). RESULTS: With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm, respectively. No participants in either group were admitted to hospital or died. The OR of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (CI 1.0-3.3, [p 0.051]). On day 7, one participant was hospitalized in each group; throughout the study, this increased to five and three participants for amantadine versus placebo treatment (p 0.72). Similarly, on day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p 0.84). CONCLUSION: We found no effect of amantadine on disease progression of SARS-CoV-2 infection.

Pre-existing, treatment-specific resistance-associated substitutions in hepatitis C virus genotype 1 and 3 and viral RNA titers during treatment with direct-acting antivirals.

The introduction of direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infected patients has greatly increased treatment success rates. However, viral response kinetics to DAA treatment may depend on pre-existing resistance-associated substitutions (RASs) in HCV. The aim of this study was to describe how pre-existing RASs affect DAA treatment-induced reduction in HCV RNA titers in HCV genotypes 1- and 3-infected individuals. Patients with HCV genotype 1 infection (N = 31) treated with either sofosbuvir/ledipasvir/ribavirin or paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin and HCV genotype 3-infected patients (N = 16) treated with either sofosbuvir/daclatasvir/ribavirin or sofosbuvir/ribavirin were analyzed. HCV RNA levels were determined at baseline and frequently during treatment, and RAS profiles were obtained by deep sequencing at baseline. In total, 33/47 (70.2%) of the patients had baseline RASs. However, treatment-specific RASs were detected at baseline only in 12.9% and 18.8% of HCV genotypes 1- and 3-infected patients, respectively. In genotype 1-infected individuals, reduction in HCV RNA titer during the first week of treatment was not affected by evidence of either treatment-specific RASs or cirrhosis or treatment regimen. In genotype 3-infected individuals receiving sofosbuvir/daclatasvir/ribavirin, the presence of daclatasvir-specific NS5A RASs at baseline correlated with a reduced decline of HCV RNA in the first treatment week. For both genotypes 1- and 3-infected individuals, cirrhosis but not treatment-specific RAS were associated with the time of clearance of HCV RNA. It is, however, important to note that this study involves DAA regimens that were used only during the original introduction of interferon-free DAA-based treatments.

Late HIV diagnosis among migrant women living in Europe - a systematic review of barriers to HIV testing.

Objectives: HIV transmission persists in Europe, with migrants accounting for over two-fifths of new diagnoses. Over half of all women in Europe are diagnosed late - particularly migrant women. Therefore, an updated understanding of migrant women's needs is crucial to inform inclusive and relevant HIV research, services, and policies. Methods: A systematic review relating to factors influencing late HIV diagnoses among migrant women living in Europe in 2011-2021 was conducted, based on data from 12 papers relating to 13 European Union (EU) countries and three non-EU countries. Results: The studies revealed a range of individual, sociocultural, and structural barriers to HIV diagnosis. Individual barriers included low perceived risk of HIV, lack of knowledge about HIV symptoms and HIV services, lack of trust in healthcare systems, and fear of societal implications of an HIV diagnosis. Sociocultural barriers included language and communication challenges, stigma, and lack of community testing opportunities. Structural factors included poverty, poor living conditions, unclear legal rights, administrative barriers to healthcare access, and lack of testing opportunities. Conclusions: Barriers varied according to resident country, healthcare system, and country/region of origin. The studies highlighted the importance of inclusive research and service design and development, to address the needs of migrant women and reduce inequalities, especially given the current climate in Europe and the everchanging patterns of migration.

The Role of CTLA-4 in T Cell Exhaustion in Chronic Hepatitis B Virus Infection.

Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a role in this phenomenon. This systematic review investigates the role of CTLA-4 in the development of T cell exhaustion in CHB. A systematic literature search was conducted on PubMed and Embase on 31 March 2023 to identify relevant studies. Fifteen studies were included in this review. A majority of the studies investigating CD8+ T cells demonstrated increased expression of CTLA-4 in CHB patients, though one study found this only in HBeAg-positive patients. Three out of four studies investigating the expression of CTLA-4 on CD4+ T cells found upregulation of CTLA-4. Several studies showed constitutive expression of CLTA-4 on CD4+ regulatory T cells. CTLA-4 blockade resulted in heterogeneous responses for all T cell types, as it resulted in increased T cell proliferation and/or cytokine production in some studies, while other studies found this only when combining blockade of CTLA-4 with other inhibitory receptors. Although mounting evidence supports a role of CTLA-4 in T cell exhaustion, there is still insufficient documentation to describe the expression and exact role of CTLA-4 in T cell exhaustion in CHB.

Durability and breadth of neutralisation following multiple antigen exposures to SARS-CoV-2 infection and/or COVID-19 vaccination.

BACKGROUND: Given the importance of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the prevention of severe coronavirus disease 2019 (COVID-19), detailed long-term analyses of neutralising antibody responses are required to inform immunisation strategies. METHODS: In this study, longitudinal neutralising antibody titres to an ancestral SARS-CoV-2 isolate and cross-neutralisation to delta and omicron isolates were analysed in individuals previously infected with SARS-CoV-2, vaccinated against COVID-19, or a complex mix thereof with up to two years of follow-up. FINDINGS: Both infection-induced and vaccine-induced neutralising responses against SARS-CoV-2 appeared to follow similar decay patterns. Following vaccination in previously infected individuals, neutralising antibody responses were more durable than prior to vaccination. Further, this study shows that vaccination after infection, as well as booster vaccination, increases the cross-neutralising potential to both delta and omicron SARS-CoV-2 variants. INTERPRETATION: Taken together, these results suggest that neither type of antigen exposure is superior for neutralising antibody durability. However, these results support vaccination to increase the durability and cross-neutralisation potential of neutralising responses, thereby enhancing protection against severe COVID-19. FUNDING: This work was supported by grants from The Capital Region of Denmark's Research Foundation, the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Candys Foundation, and the Danish Agency for Science and Higher Education.

Psychosocial, sexual, reproductive and menopausal health in women with and without HIV in a high-income setting.

OBJECTIVES: To investigate psychosocial, sexual, reproductive and menopausal health in women with HIV (WWH) compared to women without HIV (WWOH) in Denmark. DESIGN: A nationwide cross-sectional study. METHODS: Data was retrieved from the SHARE study , a Danish nationwide cross-sectional survey examining psychosocial, sexual and reproductive health in people with HIV. Data from WWH, collected in 2021-2022, was matched 1:10 on age to a comparison group of WWOH from the nationally representative cohort study Project SEXUS . Associations between HIV status and psychosocial and sexual health outcomes were assessed by adjusted odds ratios (aOR) with 95% confidence intervals (95% CIs) obtained in logistic regression analyses controlling for potential confounding variables. The severity of menopausal symptoms in WWH was compared to published reference norms. RESULTS: Among 144 WWH and 1440 WWOH, recurrent loneliness was significantly more common among WWH (aOR 2.22 [95% CI: 1.25-3.96]), and WWH had significantly fewer children and close friends (aOR 0.52 [95% CI: 0.28-0.96] for 3-9 vs. 0-2 close friends). Symptoms of anxiety and depression did not differ between groups. Lack of sexual desire (aOR 2.90 [95% CI: 1.29-6.50]), low FSFI-6 score indicating sexual dysfunction (aOR 3.40 [95% CI: 1.33-8.69]), lubrication dysfunction (aOR 8.24 [95% CI: 2.83-24.00]) and genital pain dysfunction (aOR 5.13 [95% CI: 1.26-20.86]) were significantly more common in WWH compared to WWOH. No differences were seen in menopausal characteristics. CONCLUSIONS: WWH in Denmark have fewer children and close friends, and more often report recurrent loneliness, lacking sexual desire and sexual dysfunction compared to WWOH. No differences were evident in menopausal characteristics.