COVID-19 in people with HIV in the Netherlands, the ATHENA cohort study.

OBJECTIVES: We investigated occurrence of and risk factors for severe COVID-19 outcomes in PWH in the Netherlands. DESIGN: 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 31 December 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 <200 copies/mL, median CD4 count 690 (IQR 510-908) cells/mm3. Primary SARS-CoV-2 infections were registered in 2,301 individuals, of whom 157 (6.8%) required hospitalization and 27 (1.2%) ICU admission. Mortality rates were 13% and 0.4% amongst hospitalized and non-hospitalized individuals, respectively. Independent risk factors for severe outcomes (COVID-19-related hospitalization and death) were higher age, having multiple comorbidities, a CD4 count <200 cells/mm3, uncontrolled HIV replication and prior AIDS diagnosis. Migrants from sub-Saharan Africa, Latin America and the Caribbean were at increased risk of severe outcomes independently of other risk factors. CONCLUSIONS: In our national cohort of PWH, risk of severe COVID-19 outcomes was increased in individuals with uncontrolled HIV replication, low CD4 count and prior AIDS diagnosis, independently of general risk factors like higher age, comorbidity burden and migrants originating from non-Western countries.

Immunogenicity of an additional mRNA-1273 SARS-CoV-2 vaccination in people with HIV with hyporesponse after primary vaccination.

BACKGROUND: The COVIH-study is a prospective SARS-CoV-2 vaccination study in 1154 people with HIV (PWH), of whom 14% showed a reduced or absent antibody response after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. METHODS: Consenting hyporesponders received an additional 100µg mRNA-1273 vaccination. The primary endpoint was the increase in antibodies 28 days thereafter. Secondary endpoints were the correlation between participant characteristics and antibody response, levels of neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. RESULTS: Of the 66 participants, 40 previously received two doses ChAdOx1-S, 22 two doses BNT162b2, and four a single dose Ad26.COV2.S. The median age was 63[IQR:60-66], 86% were male, pre-vaccination CD4+ T-cell count was median 650/µL[IQR:423-941] and 96% had HIV-RNA < 50 copies/mL. The mean S1-specific antibody level increased from 35 BAU/mL (95%CI:24-46) to 4317 BAU/mL (95%CI:3275-5360) post-vaccination (p < 0.0001). Of all participants, 97% showed an adequate response (>300 BAU/mL) and the 45 antibody negative participants all seroconverted (>33.8 BAU/mL). A significant increase in the proportion of PWH with detectable ancestral S-specific CD4+ T-cells (p = 0.04) and S-specific B-cells (p = 0.02) was observed. CONCLUSION: An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.

Correction: Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003979.].

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study.

BACKGROUND: Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH. METHODS AND FINDINGS: We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/µL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/µL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/µL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients. CONCLUSIONS: After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.

The 2000HIV study: Design, multi-omics methods and participant characteristics.

Background: Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets. Methods: The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort. Results: Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine. Conclusion: The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

Pulmonary function and Quality of Life in a prospective cohort of (non-) hospitalized COVID-19 pneumonia survivors up to six months.

OBJECTIVES: A decrease of both diffusion capacity (DLCO) and Quality of Life (QoL) was reported after discharge in hospitalized COVID-19 pneumonia survivors. We studied three and 6 month outcomes in hospitalized and non-hospitalized patients. METHODS: COVID-19 pneumonia survivors (n = 317) were categorized into non-hospitalized "moderate" cases (n = 59), hospitalized "severe" cases (n = 180) and ICU-admitted "critical" cases (n = 39). We studied DLCO and QoL (Short Form SF-36 health survey) 3 and 6 months after discharge. Data were analyzed using (repeated measures) ANOVA, Kruskal-Wallis or Chi-square test (p < .05). RESULTS: At 3 months DLCO was decreased in 44% of moderate-, 56% of severe- and 82% of critical cases (p < .003). Mean DLCO in critical cases (64±14%) was lower compared to severe (76 ± 17%) and moderate (81±15%) cases (p < .001). A total of 159/278 patients had a decreased DLCO (<80%), of whom the DLCO improved after 6 months in 45% (71/159). However the DLCO did not normalize in the majority (89%) of the cases (63 ± 10% vs 68±10%; p < .001). At 3 months, compared to critical cases, moderate cases scored lower on SF-36 domain "general health" (p < .05); both moderate and severe cases scored lower on the domain of "health change" (p < .05). At 6 months, there were no differences in SF-36 between the subgroups. Compared to 3 months, in all groups "physical functioning" improved; in contrast all groups scored significantly lower on "non-physical" SF-36 domains. CONCLUSION: Three months after COVID-19 pneumonia, DLCO was still decreased in the more severely affected patients, with an incomplete recovery after 6 months. At 3 months QoL was impaired. At 6 months, while "physical functioning" improved, a decrease in "non-physical" QoL was observed but did not differ between the moderate and severely affected patients.

Ethnic Differences in Coronavirus Disease 2019 Hospitalization and Hospital Outcomes in a Multiethnic Population in the Netherlands.

Background: Evidence from the United States and United Kingdom suggests that ethnic minority populations are at an increased risk for developing severe coronavirus disease 2019 (COVID-19); however, data from other West-European countries are scarce. Methods: We analyzed data from 1439 patients admitted between February 2020 and January 2021 to 4 main hospitals in Amsterdam and Almere, the Netherlands. Differences in the risk for hospitalization were assessed by comparing demographics to the general population. Using a population-based cohort as reference, we determined differences in the association between comorbidities and COVID-19 hospitalization. Outcomes after hospitalization were analyzed using Cox regression. Results: The hospitalization risk was higher in all ethnic minority groups than in those of Dutch origin, with age-adjusted odds ratios ranging from 2.2 (95% confidence interval [CI], 1.7-2.6) in Moroccans to 4.5 (95% CI, 3.2-6.0) in Ghanaians. Hypertension and diabetes were similarly associated with COVID-19 hospitalization. For all other comorbidities, we found differential associations. Intensive care unit admission and mortality during 21-day follow-up after hospitalization was comparable between ethnicities. Conclusions: The risk of COVID-19 hospitalization was higher in all ethnic minority groups compared to the Dutch, but the risk of adverse outcomes after hospitalization was similar. Our results suggest that these inequalities may in part be attributable to comorbidities that can be prevented by targeted public health prevention measures. More work is needed to gain insight into the role of other potential factors such as social determinants of health, which might have contributed to the ethnic inequalities in COVID-19 hospitalization.

Which outcomes are most important to measure in patients with COVID-19 and how and when should these be measured? Development of an international standard set of outcomes measures for clinical use in patients with COVID-19: a report of the International Consortium for Health Outcomes Measurement (ICHOM) COVID-19 Working Group.

OBJECTIVES: The COVID-19 pandemic has resulted in widespread morbidity and mortality with the consequences expected to be felt for many years. Significant variation exists in the care even of similar patients with COVID-19, including treatment practices within and between institutions. Outcome measures vary among clinical trials on the same therapies. Understanding which therapies are of most value is not possible unless consensus can be reached on which outcomes are most important to measure. Furthermore, consensus on the most important outcomes may enable patients to monitor and track their care, and may help providers to improve the care they offer through quality improvement. To develop a standardised minimum set of outcomes for clinical care, the International Consortium for Health Outcomes Measurement (ICHOM) assembled a working group (WG) of 28 volunteers, including health professionals, patients and patient representatives. DESIGN: A list of outcomes important to patients and professionals was generated from a systematic review of the published literature using the MEDLINE database, from review of outcomes being measured in ongoing clinical trials, from a survey distributed to patients and patient networks, and from previously published ICHOM standard sets in other disease areas. Using an online-modified Delphi process, the WG selected outcomes of greatest importance. RESULTS: The outcomes considered by the WG to be most important were selected and categorised into five domains: (1) functional status and quality of life, (2) mental functioning, (3) social functioning, (4) clinical outcomes and (5) symptoms. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, clinical factors and treatment-related factors. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of care to patients with COVID-19. Their consistent definition and collection could also broaden the implementation of more patient-centric clinical outcomes research.