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 coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. METHODS: The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. RESULTS: Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60-66), 86% were male, and median CD4+ T-cell count was 650/µL (IQR, 423-941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24-46) to 4317 BAU/mL (95% CI, 3275-5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed. CONCLUSIONS: An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination. Clinical Trials Registration. EUCTR2021-001054-57-N.

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.].

Can ultrasound of the major salivary glands differentiate Sjögren's disease from its major mimics?

OBJECTIVES: Ultrasound of the major salivary glands (SGUS) is widely used to assess the major salivary glands in Sjögren's disease (SjD). Little is known, however, regarding the diagnostic accuracy of SGUS to differentiate SjD from its mimics. This study aims to investigate the diagnostic accuracy of SGUS in differentiating SjD from other diseases with salivary gland involvement. METHODS: SGUS was performed in 20 consecutive patients with SjD and 20 consecutive patients with well-established systemic disease, i.e., with either sarcoidosis, amyloidosis, HIV infection or chronic HCV infection. Images were scored independently by two blinded observers using the Hocevar scoring system. Diagnostic accuracy to discriminate between the patient (sub-)groups was explored. RESULTS: The accuracy of SGUS to differentiate SjD from other systemic diseases was excellent (area under ROC curve of 0.91). The optimal cut-off value to define positive or negative ultrasound for SS was 15. Sensitivity, specificity, positive predictive value and negative predictive value were high, varying from 85-90%, and diagnostic odds ratio was 51. SGUS was positive in the vast majority of SjD patients (n=18), but also in 2 patients with HIV infection and one patient with sarcoidosis. SGUS score differed significantly between patients with SjD and other systemic diseases (median 27 vs. 10, p<0.001) as well as between SjD patients and patients with either sarcoidosis, amyloidosis, HIV or HCV infection (all p<0.05). CONCLUSIONS: This study indicates that SGUS has a potentially high diagnostic accuracy to discriminate SjD from systemic diseases which can also cause salivary gland involvement.

Immune markers and microbial factors are related with periodontitis severity in people with HIV.

OBJECTIVE: The objective of the study is to assess systemic immune markers and microbial factors related to periodontitis severity in people living with HIV. METHODS: Eighty people living with HIV (PLWH), who exhibited in the last two viral load measurements < 40 copies/mL, underwent full-mouth periodontal examinations and sub-gingival plaque sampling. Periodontitis was classified according to the CDC-AAP case definition. Inflammation, immune-activation, and immunosenescence markers were assessed, microbiological analyses were performed, and oral care routines and HIV characteristics were noted. RESULTS: From our group of PLWH, 42.5% and 57.5% suffered from moderate and severe periodontitis, respectively. Oral care habits did not differ between PLWH with moderate and severe periodontitis. Bacterial subgingival plaque loads were higher, and Porphyromonas gingivalis was more prevalent in PLWH with severe periodontitis than with moderate periodontitis (53% vs 7%, respectively). Mean C-reactive protein levels [CRP, 1.6 mg/L versus 0.8 mg/L, p = 0.020] and percentages of senescent CD28-CD57 + CD8 + T-cells in peripheral blood [16.5 versus 8.9, p = 0.035] were higher with severe periodontitis. Infection duration, CD4 count, CD4/CD8 ratio and type of antiretroviral therapy did not differ between both groups. CONCLUSIONS: Periodontitis severity is related to increased prevalence of Porphyromonas gingivalis, elevated CRP levels, and higher frequencies of circulating CD8 + senescent cells in PLWH.

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.

Darunavir Population Pharmacokinetic Model Based on HIV Outpatient Data.

BACKGROUND: Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice. METHODS: Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing-Bablok regression and Bland-Altman analyses. RESULTS: In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing-Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland-Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23-0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement. CONCLUSIONS: A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.

Risk factors contributing to a low darunavir plasma concentration.

Darunavir is an efficacious drug; however, pharmacokinetic variability has been reported. The objective of this study was to find predisposing factors for low darunavir plasma concentrations in patients starting the once- or twice-daily dosage. Darunavir plasma concentrations from January 2010 till December 2014 of human immunodeficiency virus-infected individuals treated in the outpatient clinic of the University Medical Center Groningen were retrospectively reviewed. The first darunavir plasma concentration of patients within 8 weeks after initiation of darunavir therapy was selected. A dichotomous logistic regression analysis was conducted to select the set of variables best predicting a darunavir concentration below median population pharmacokinetic curve. In total 113 patients were included. The variables best predicting a darunavir concentration besides food intake included age together with estimated glomerular filtration rate (Hosmer-Lemeshow test P = 0.945, Nagelkerke R2  = 0.284). Systematic evaluation of therapeutic drug monitoring results may help to identify patients at risk for low drug exposure.

Food intake and darunavir plasma concentrations in people living with HIV in an outpatient setting.

AIMS: Patients receiving darunavir are advised to take it concomitantly with food. The objectives of the present cross-sectional study were to evaluate the actual concomitant food intake of patients visiting an HIV outpatient clinic. METHODS: Sixty participants treated with darunavir/ritonavir once daily were subjected to a food recall questionnaire concerning their last concomitant food intake with darunavir. Darunavir trough concentrations were calculated. RESULTS: The median food intake was 507 (0-2707) kcal; protein intake, 20 (0-221)g; carbohydrate intake, 62 (0-267)g; fat intake: 14 (0-143)g; and dietary fibre: 4 (0-30)g. Twenty-five patients (42%) ingested their drug with between-meal snacks. No relationship was found between food intake and trough concentrations. CONCLUSIONS: Clear advice on the optimal caloric intake is needed, to avoid high caloric intake in patients who already have an increased risk of cardiovascular disease due to their HIV infection.

Boceprevir, peginterferon and ribavirin for acute hepatitis C in HIV infected patients.

BACKGROUND & AIMS: Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy. METHODS: We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint. RESULTS: One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers. CONCLUSION: With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495.

Periodontal inflammation as a potential driver of HIV low level viremia.

HIV can be successfully suppressed to undetectable levels by antiretroviral therapy (ART) in most people with HIV (PWH). However, a small proportion continues to have persistent low-level viremia (LLV) during ART. A presumed source of LLV is production or replication from viral reservoirs, which are maintained in the presence of ART. It is unknown whether the oral cavity can be considered an HIV reservoir. As periodontal inflammation is a common problem in PWH, we hypothesize that periodontal inflammation in the oral cavity activates (latently) infected cells and thus might be associated with LLV. We included 11 individuals with HIV LLV, and compared HIV-RNA levels in saliva and plasma at baseline and at week 24 after switch of ART. We compared the LLV-group at baseline with 11 age-matched controls with suppressed viremia. To investigate the severity of periodontitis we used Periodontal Inflamed Surface Areas (PISA) by measuring probing depth, gingival recession, bleeding on probing and clinical attachment level. Severity of periodontitis was classified according to the CDC-AAP case definition. Additional insights in periodontal inflammation were obtained by comparing immune activation markers and the presence of periodontal pathogens. In four individuals of the LLV group, residual levels of HIV-RNA were detected in saliva at baseline (N = 1) or at week 24 (N = 2) or both (N = 1). Of the four individuals with LLV, three had residual levels of HIV-RNA in saliva. All 22 individuals had moderate to severe periodontitis. PISA was not significantly different between cases with LLV and controls. Similarly, periodontal pathogens were frequently observed in both groups. Total activated HLA-DR+CD38+ CD4+ cells and CD8+ cells were significantly higher in the LLV group than in the control group (p = <0.01). No immune markers were associated with LLV. In conclusion, periodontal inflammation is an unlikely driver of HIV LLV compared to HIV suppressed individuals.

COVID-19 epidemiology and performance of the WHO clinical algorithm to diagnose COVID-19 in people with HIV from Ukraine.

BACKGROUND: The two main objectives were to evaluate the COVID-19 point prevalence and the test performance of the WHO case definition to diagnose COVID-19 clinically in people with HIV in West Ukraine. METHODS: Multicenter cross-sectional study in Lviv, Ukraine, from October 2020-November 2021. COVID-19 unvaccinated people with HIV were included regardless of COVID-19 symptoms at routine clinical visits and had standardized medical, quality of life (EQ(5D)) and SARS-CoV-2 serology assessments. Reported symptoms indicating potential COVID-19 events at inclusion or between March 2020 and inclusion were classified by the WHO case definition as suspected, probable or confirmed. A clinical COVID-19 case was defined as being SARS-CoV-2 seropositive with at least a suspected COVID-19 according to the WHO case definition. The primary endpoints were the clinical COVID-19 prevalence and the test characteristics of the WHO case definition with SARS-CoV-2 serology as reference. (Clinicaltrials.gov:NCT04711954). RESULTS: The 971 included people with HIV were median 40 years, 38.8% women, 44.8% had prior AIDS, and 55.6% had comorbidities. SARS-CoV-2 seroprevalence was 40.1% (95%CI:37.0-43.1) and 20.5% (95%CI:18.0-23.1) had clinical COVID-19 median 4 months (IQR:2-7) before inclusion. Clinical COVID-19 occurred less frequently in people with HIV with tuberculosis history, injecting drug use, CD4+ T-cells <200/mL and unemployment. The quality of life was not impacted after COVID-19. An at least probable COVID-19 classification by the WHO case definition had 44.1% sensitivity (95%CI:38.7-49.7), 85.2% specificity (95%CI:81.5-88.4), 66.6% positive predictive value (95%CI:59.8-73.0) and 69.5% negative predictive value (95%CI:65.5-73.3) to diagnose COVID-19. CONCLUSIONS: COVID-19 unvaccinated people with HIV from Ukraine had a significant COVID-19 rate and using the WHO case definition had insufficient diagnostic accuracy to diagnose these cases. The lower burden in vulnerable people with HIV was unexpected but might reflect a shielding effect.

Dynamics of Low-Level Viremia and Immune Activation after Switching to a Darunavir-Based Regimen.

There is an ongoing debate regarding whether low-level viremia (LLV), in particular persistent LLV, during HIV treatment with optimal adherence originates from low-level viral replication, viral production, or both. We performed an observational study in 30 individuals with LLV who switched to a boosted darunavir (DRV)-based therapy. In-depth virological analyses were used to characterize the viral population and the (activity) of the viral reservoir. Immune activation was examined using cell-bound and soluble markers. The primary outcome was defined as the effect on HIV-RNA and was categorized by responders (<50 cp/mL) or non-responders (>50 cp/mL). At week 24, 53% of the individuals were considered responders, 40% non-responders, and 7% could not be assigned. Sequencing showed no evolution or selection of drug resistance in the non-responders. Production of defective virus with mutations in either the protease (D25N) or RT active site contributed to persistent LLV in two individuals. We show that in about half of the study participants, the switch to a DRV-based regimen resulted in a viral response indicative of ongoing low-level viral replication as the cause of LLV before the switch. Our data confirm that in clinical management, high genetic barrier drugs like DRV are a safe choice, irrespective of the source of LLV.

Dolutegravir/Lamivudine Is Noninferior to Continuing Dolutegravir- and Non-Dolutegravir-Based Triple-Drug Antiretroviral Therapy in Virologically Suppressed People With Human Immunodeficiency Virus: DUALING Prospective Nationwide Matched Cohort Study.

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

Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients.

BACKGROUND: Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens. METHODS: Genotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated. RESULTS: Phylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92%). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response. CONCLUSIONS: Long-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.

Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium.

BACKGROUND: Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe. METHODS: Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated. RESULTS: Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain. CONCLUSIONS: Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment.Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.

Psychological distress among frontline workers during the COVID-19 pandemic: A mixed-methods study.

BACKGROUND: Novel virus outbreaks, such as the COVID-19 pandemic, may increase psychological distress among frontline workers. Psychological distress may lead to reduced performance, reduced employability or even burnout. In the present study, we assessed experienced psychological distress during the COVID-19 pandemic from a self-determination theory perspective. METHODS: This mixed-methods study, with repeated measures, used surveys (quantitative data) combined with audio diaries (qualitative data) to assess work-related COVID-19 experiences, psychological need satisfaction and frustration, and psychological distress over time. Forty-six participants (nurses, junior doctors, and consultants) completed 259 surveys and shared 60 audio diaries. Surveys and audio diaries were analysed separately. RESULTS: Quantitative results indicated that perceived psychological distress during COVID-19 was higher than pre-COVID-19 and fluctuated over time. Need frustration, specifically autonomy and competence, was positively associated with psychological distress, while need satisfaction, especially relatedness, was negatively associated with psychological distress. In the qualitative, thematic analysis, we observed that especially organisational logistics (rostering, work-life balance, and internal communication) frustrated autonomy, and unfamiliarity with COVID-19 frustrated competence. Despite many need frustrating experiences, a strong connection with colleagues and patients were important sources of relatedness support (i.e. need satisfaction) that seemed to mitigate psychological distress. CONCLUSION: The COVID-19 pandemic resulted in an increase of psychological distress among frontline workers. Both need frustration and need satisfaction explained unique variance of psychological distress, but seemed to originate from different sources. Challenging times require healthcare organisations to better support their professionals by tailored formal and informal support. We propose to address both indirect (e.g. organisation) and direct (e.g. colleagues) elements of the clinical and social environment in order to reduce need frustration and enhance need satisfaction.

Perioperative SARS-CoV-2 infections increase mortality, pulmonary complications, and thromboembolic events: A Dutch, multicenter, matched-cohort clinical study.

BACKGROUND: A direct comparison of severe acute respiratory syndrome coronavirus 2 positive patients with a severe acute respiratory syndrome coronavirus 2 negative control group undergoing an operative intervention during the current pandemic is lacking, and a reliable estimate of the assumed difference in morbidity and mortality between both patient categories remains unknown. METHODS: We included all consecutive patients with a confirmed pre- or postoperative severe acute respiratory syndrome coronavirus 2 positive status (operated in 27 hospitals) and negative control patients (operated in 4 hospitals) undergoing emergency or elective operations. A propensity score-matched comparison of clinical outcomes was performed between severe acute respiratory syndrome coronavirus 2 positive and negative tested patients (control group). Primary outcome was overall 30-day mortality rate between both groups. Main secondary outcomes were overall, pulmonary, and thromboembolic complications. RESULTS: In total, 161 severe acute respiratory syndrome coronavirus 2 positive and 342 control severe acute respiratory syndrome coronavirus 2 negative patients were included in this study. The 30-day overall postoperative mortality rate was greater in the severe acute respiratory syndrome coronavirus 2 positive cohort compared with the negative control group (16% vs 4% respectively; P = .007). After propensity score matching, the severe acute respiratory syndrome coronavirus 2 positive group consisted of 123 patients (median 70 years of age [interquartile range 59-77] and 55% male) were compared with 196 patients in the matched control group (median 69 years (interquartile range 58-75] and 53% male). The 30-day mortality rate and risk were greater in the severe acute respiratory syndrome coronavirus 2 positive group compared with the matched control group (12% vs 4%; P = .009 and odds ratio 3.4 [95% confidence interval 1.5-8.5]; P = .005, respectively). Overall, pulmonary and thromboembolic complications occurred more often in severe acute respiratory syndrome coronavirus 2 positive patients (P < .01). CONCLUSION: Patients diagnosed with perioperative severe acute respiratory syndrome coronavirus 2 have an increased risk of 30-day mortality, pulmonary complications, and thromboembolic events. These findings serve as an evidence-based argument to postpone elective surgery and selected emergency cases.

Protease inhibitors atazanavir, lopinavir and ritonavir are potent blockers, but poor substrates, of ABC transporters in a broad panel of ABC transporter-overexpressing cell lines.

OBJECTIVES: A possible mechanism for HIV therapy failure is the efflux of HIV drugs from viral target cells or certain body compartments by ATP-binding cassette (ABC) transporters, allowing ongoing viral replication. Here, we investigated the interaction between protease inhibitors (PIs) and ABC transporters. METHODS: To explore the potential blocking capacity of PIs, we exposed cells overexpressing multidrug resistance 1 P-glycoprotein (MDR1 P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP) to established cytotoxic substrates with or without one of the PIs atazanavir, lopinavir or ritonavir. Furthermore, to assess whether PIs serve as substrates, cell growth-inhibitory effects of these PIs were evaluated on cells overexpressing 1 of 11 ABC transporters and their parental counterparts. RESULTS: Atazanavir, lopinavir and ritonavir were highly effective in reversing resistance against established substrates in cells overexpressing MDR1 P-gp and MRP1, and, to a lesser extent, BCRP. Concurrently, however, PIs appeared to be relatively poor substrates for ABC transporters. Only a moderate level of resistance to atazanavir was observed in cells overexpressing MRP6 and MRP9 [resistance factor (RF): 2.0-2.6]. Cells overexpressing MDR1 P-gp, MRP3, MRP4 and MRP5 displayed low levels of resistance to atazanavir (RF: 1.3-1.7); MRP7- and MRP9-overexpressing cells to lopinavir (RF: 1.4-1.5); and MRP9-overexpressing cells to ritonavir (RF: 1.4). CONCLUSIONS: PIs can act as potent blockers of MDR1 P-gp, MRP1 and BCRP, but they are poor substrates for 11 ABC transporters. Consequently, ABC transporters are unlikely to play a major role in PI failure, but still may contribute to drug-specific adverse events and drug-drug interactions.