Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes.

OBJECTIVES: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. METHODS: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). RESULTS: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350 cells/µl or less (vs. 351-500 cells/µl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). CONCLUSION: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.

Experience with sotrovimab treatment of SARS-CoV-2-infected patients in Denmark.

AIMS: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. METHODS: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. RESULTS: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. CONCLUSION: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Antibody response following the third and fourth SARS-CoV-2 vaccine dose in individuals with common variable immunodeficiency.

Background: The antibody response after vaccination is impaired in common variable immunodeficiency (CVID). Objective: We aimed to study the spike receptor-binding domain IgG antibody (anti-S-RBD) levels during a four-dose SARS-CoV-2 vaccination strategy and after monoclonal antibody (mAB) treatment in CVID. Moreover, we assessed the anti-S-RBD levels in immunoglobulin replacement therapy (IgRT) products. Methods: In an observational study, we examined anti-S-RBD levels after the second, third, and fourth dose of mRNA SARS-CoV-2 vaccines. Moreover, we measured anti-S-RBD after treatment with mAB. Finally, anti-S-RBD was assessed in common IgRT products. Antibody non-responders (anti-S-RBD < 7.1) were compared by McNemar's test and anti-S-RBD levels were compared with paired and non-paired Wilcoxon signed rank tests as well as Kruskal-Wallis tests. Results: Among 33 individuals with CVID, anti-S-RBD levels increased after the third vaccine dose (165 BAU/ml [95% confidence interval: 85; 2280 BAU/ml], p = 0.006) and tended to increase after the fourth dose (193 BAU/ml, [-22; 569 BAU/ml], p = 0.080) compared to the previous dose. With increasing number of vaccinations, the proportion of patients who seroconverted (anti-S-RBD ≥ 7.1) increased non-significantly. mAB treatment resulted in a large increase in anti-S-RBD and a higher median level than gained after the fourth dose of vaccine (p = 0.009). IgRT products had varying concentrations of anti-S-RBD (p < 0.001), but none of the products seemed to affect the overall antibody levels (p = 0.460). Conclusion: Multiple SARS-CoV-2 vaccine doses in CVID seem to provide additional protection, as antibody levels increased after the third and fourth vaccine dose. However, anti-S-RBD levels from mAB outperform the levels mounted after vaccination. Clinical Implications: Boosting with SARS-CoV-2 vaccines seems to improve the antibody response in CVID patients. Capsule summary: The third and possibly also the fourth dose of mRNA SARS-CoV-2 vaccine in CVID improve the antibody response as well as stimulate seroconversion in most non-responders.

Tuberculosis incidence and mortality in people living with human immunodeficiency virus: a Danish nationwide cohort study.

OBJECTIVES: To explore changes over time in the epidemiology of tuberculosis (TB) in Denmark in people living with human immunodeficiency virus (HIV) (PLWH). METHODS: In this nationwide, population-based cohort study we included all adult PLWH from the Danish HIV Cohort Study (1995-2017) without previous TB. We estimated TB incidence rate (IR), all-cause mortality rate (MR), associated risk and prognostic factors using Poisson regression. RESULTS: Among 6982 PLWH (73 596 person-years (PY)), we observed 217 TB events (IR 2.9/1000 PY, 95% CI 2.6-3.4: IR 6.7, 95% CI 5.7-7.9 among migrants and IR 1.4, 95% CI 1.1-1.7 among Danish-born individuals; p < 0.001). The IR of concomitant HIV/TB remained high and unchanged over time. The IR of TB diagnosed >3 months after HIV diagnosis declined with calendar time, longer time from HIV diagnosis, and CD4 cell recovery. Independent TB risk factors were African/Asian/Greenland origin (adjusted incidence rate ratio (aIRR) 5.2, 95% CI 3.5-7.6, aIRR 6.5, 95% CI 4.2-10.0, aIRR 7.0, 95% CI 3.4-14.6, respectively), illicit drug use (aIRR 6.9, 95% CI 4.2-11.2), CD4 <200 cells/µL (aIRR 2.7, 95% CI 2.0-3.6) and not receiving antiretroviral therapy (aIRR 3.7, 95% CI 2.5-5.3). Fifty-five patients died (MR 27.9/1000 PY, 95% CI 21.4-36.3), with no improvement in mortality over time. Mortality prognostic factors were Danish-origin (adjusted mortality rate ratio (aMRR) 2.3, 95% CI 1.3-4.3), social burden (aMRR 3.9, 95% CI 2.2-7.0), CD4 <100 cells/µL at TB diagnosis (aMRR 2.6, 95% CI 1.3-4.9), TB diagnosed >3 months after HIV versus concomitant diagnosis (aMRR 4.3, 95% CI 2.2-8.7) and disseminated TB (aMRR 3.3, 95% CI 1.1-9.9). CONCLUSION: Late HIV presentation with concomitant TB remains a challenge. Declining TB rates in PLWH were observed over time and with CD4 recovery, highlighting the importance of early and successful antiretroviral therapy. However, MR remained high. Our findings highlight the importance of HIV and TB screening strategies and treatment of latent TB in high-risk groups.

SARS-CoV-2 viral load as a predictor for disease severity in outpatients and hospitalised patients with COVID-19: A prospective cohort study.

INTRODUCTION: We aimed to examine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) cycle quantification (Cq) value, as a surrogate for SARS-CoV-2 viral load, could predict hospitalisation and disease severity in adult patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a prospective cohort study of adult patients with PCR positive SARS-CoV-2 airway samples including all out-patients registered at the Department of Infectious Diseases, Odense University Hospital (OUH) March 9-March 17 2020, and all hospitalised patients at OUH March 10-April 21 2020. To identify associations between Cq-values and a) hospital admission and b) a severe outcome, logistic regression analyses were used to compute odds ratios (OR) and 95% Confidence Intervals (CI), adjusting for confounding factors (aOR). RESULTS: We included 87 non-hospitalised and 82 hospitalised patients. The median baseline Cq-value was 25.5 (interquartile range 22.3-29.0). We found a significant association between increasing Cq-value and hospital-admission in univariate analysis (OR 1.11, 95% CI 1.04-1.19). However, this was due to an association between time from symptom onset to testing and Cq-values, and no association was found in the adjusted analysis (aOR 1.08, 95% CI 0.94-1.23). In hospitalised patients, a significant association between lower Cq-values and higher risk of severe disease was found (aOR 0.89, 95% CI 0.81-0.98), independent of timing of testing. CONCLUSIONS: SARS-CoV-2 PCR Cq-values in outpatients correlated with time after symptom onset, but was not a predictor of hospitalisation. However, in hospitalised patients lower Cq-values were associated with higher risk of severe disease.

Low morbidity in Danish patients with common variable immunodeficiency disorder infected with severe acute respiratory syndrome coronavirus 2.

BACKGROUND: Manifestations and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not well documented in patients with common variable immunodeficiency disorder (CVID). METHODS: A Danish nationwide retrospective clinician-reported survey. RESULTS: Eleven patients with CVID and SARS-CoV-2 infection were identified. The median age was 50 years (range 22-72). All were on immunoglobulin replacement therapy. Eight patients had other pre-existing co-morbidities. Three patients were asymptomatic during the SARS-CoV-2 infection while seven developed mild coronavirus disease 2019 (COVID-19). One patient had more severe disease with hypoxia and required oxygen therapy. This patient had multiple co-morbidities including well known risk factors for severe COVID-19. All patients recovered. CONCLUSIONS: The results suggest that CVID may not be a risk factor for severe COVID-19. However, further monitoring of this immunodeficient population is needed to confirm our observation.

Low mortality of hospitalised patients with COVID-19 in a tertiary Danish hospital setting.

OBJECTIVES: We aimed to describe clinical characteristics and outcomes of admitted COVID-19 patients in a Danish hospital setting where an early active government intervention was taken. METHODS: Prospective cohort study including all admitted patients to the COVID-19 unit at Odense University Hospital from March 10 to April 21, 2020. Patients were assessed by a multidisciplinary team at admission. Outcome parameters were development of acute respiratory distress syndrome (ARDS), intensive care unit (ICU) admission, death and admission time. RESULTS: We included 83 patients (median age 62 years, 62.7% male). At hospitalization, 31.3% needed oxygen supplementation and the median National Early Warning Score was four. Median admission time was 7 days (Interquartile ranges (IQR) 3-12). In total, ARDS was diagnosed in 33.7% (28/83) of the patients corresponding to an incidence rate of 7.1 per 100 person days (95% CI: 4.1-10.2). Overall 13 patients (15.7%) were transferred to the ICU of whom 11 (84.6%) received corticosteroids.. No patients died while admitted to the ICU. Four patients (4.8%) died during admission. CONCLUSION: Despite similar patient characteristics compared to those reported by others, we found a low overall mortality of < 5%.

Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report.

BACKGROUND: Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. CASE PRESENTATION: We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman's rho: - 0.86, p < 0.001. CONCLUSIONS: To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

Prescription of antimicrobials in primary health care as a marker to identify people living with undiagnosed HIV infection, Denmark, 1998 to 2016.

BackgroundDevelopment of additional diagnostic strategies for earlier HIV diagnosis are needed as approximately 50% of newly diagnosed HIV-infected individuals continue to present late for HIV care.AimWe aimed to analyse antimicrobial consumption in the 3 years preceding HIV diagnosis, assess whether there was a higher consumption in those diagnosed with HIV compared with matched controls and whether the level of consumption was associated with the risk of HIV infection.MethodsWe conducted a nested case-control study, identifying all individuals (n = 2,784 cases) diagnosed with HIV in Denmark from 1998 to 2016 and 13 age-and sex-matched population controls per case (n = 36,192 controls) from national registers. Antimicrobial drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals.ResultsIn the 3 years preceding an HIV diagnosis, we observed more frequent and higher consumption of antimicrobial drugs in cases compared with controls, with 72.4% vs 46.3% having had at least one prescription (p < 0.001). For all antimicrobial classes, the association between consumption and risk of subsequent HIV diagnosis was statistically significant (p < 0.01). The association was stronger with higher consumption and with shorter time to HIV diagnosis.ConclusionHIV-infected individuals have a significantly higher use of antimicrobial drugs in the 3 years preceding HIV diagnosis than controls. Prescription of antimicrobial drugs in primary healthcare could be an opportunity to consider proactive HIV testing. Further studies need to identify optimal prescription cut-offs that could endorse its inclusion in public health policies.

HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) -Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART).

Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/µl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART.