The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study.

PURPOSE: Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID. METHODS: This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection. RESULTS: A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16-8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30-3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21-0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25-0.92). CONCLUSIONS: We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.

ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment.

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

Dynamics of the seroprevalence of SARS-CoV-2 antibodies among healthcare workers at a COVID-19 referral hospital in Milan, Italy.

OBJECTIVES: Healthcare workers (HCWs) are at high risk of developing SARS-CoV-2 infection. The aim of this single-centre prospective study was to evaluate the trend of SARS-CoV-2 seroprevalence in HCWs working at the primary referral centre for infectious diseases and bioemergencies (eg, COVID-19) in Northern Italy and investigate the factors associated with seroconversion. METHODS: Six hundred and seventy-nine HCW volunteers were tested for anti-SARS-CoV-2 antibodies three times between 4 March and 27 May 2020 and completed a questionnaire covering COVID-19 exposure, symptoms and personal protective equipment (PPE) training and confidence at each time. RESULTS: SARS-CoV-2 seroprevalence rose from 3/679 to 26/608 (adjusted prevalence: 0.5%, 95% CI 0.1 to 1.7% and 5.4%, 95% CI 3.6 to 7.9, respectively) between the first two time points and then stabilised, in line with the curve of the COVID-19 epidemic in Milan. From the first time point, 61.6% of the HCWs had received training in the use of PPE and 17 (61.5%) of those who proved to be seropositive reported symptoms compatible with SARS-CoV-2 infection. Contacts with ill relatives or friends and self-reported symptoms were independently associated with an increased likelihood of seroconversion (p<0.0001 for both), whereas there was no significant association with professional exposure. CONCLUSION: The seroprevalence of SARS-CoV-2 among the HCWs at our COVID-19 referral hospital was low at the time of the peak of the epidemic. The seroconversions were mainly attributable to extrahospital contacts, probably because the hospital readily adopted effective infection control measures. The relatively high number of asymptomatic seropositive HCWs highlights the need to promptly identify and isolate potentially infectious HCWs.

Clinical Features and Outcomes of Patients With Human Immunodeficiency Virus With COVID-19.

Little is known about the clinical outcomes of patients with human immunodeficiency virus infected with SARS-CoV-2. We describe 47 patients referred to our hospital between 21 February and 16 April 2020 with proven/probable COVID-19, 45 (96%) of whom fully recovered and 2 who died.

Association of HIV Infection with Epilepsy and Other Comorbid Conditions.

Here, we aimed to investigate the associations of comorbidities in HIV patients given antiepileptic drugs. HIV patients given antiepileptic drugs for at least 6 months were considered. Comorbidities of the epileptic, HIV-positive patients were stratified according to patients' age and causes of epilepsy. Seventy-four of the 97 HIV patients identified had at least one comorbidity. Patients more than 50-years old had more comorbidities (1.9 ± 1.5 vs. 1.1 ± 1.2, p < 0.01) compared with younger subjects. The distribution of the psychiatric disorders was comparable between age-related categories. A marginally significant trend for higher frequency of psychiatric disorders was observed in patients with idiopathic epilepsy versus other causes of epilepsy (43% vs. 24%), Because the presence of comorbid disorders is a major driver for premature mortality both in HIV infection and epilepsy, strategies aimed at favoring prevention, early identification, and adequate treatment in these clinical settings should be pursued at all levels of care.

The impact of time since SARS-Cov-2 vaccination, age, sex and comorbidities on COVID-19 outcome in hospitalized patients with SARS-CoV-2 infection.

We evaluated the impact of COVID-19 vaccination on disease outcome in hospitalized patients with SARS-CoV-2 infection with a prospective study. 745 vaccinated and 451 unvaccinated patients consecutively admitted to a COVID-19 Hospital from 1st September 2021 to 1st September 2022 were included. Compared with unvaccinated cases, vaccinated patients were older, had more comorbidities, but had a lower risk of O2 need (odds ratio, OR, 0.46; 95 % CI 0.32-0.65) by logistic regression analysis adjusted for age, sex, comorbidity and WHO COVID-19 Clinical Progression Scale at admission. The ORs for O2 need were 0.38 (0.24-0.61), 0.50 (0.30-0.83) and 0.57 (0.34-0.96) in patients vaccinated 14-120, 121-180 and > 180 days prior to hospitalization, respectively. An anti-spike Ig titer higher than 5000 U/ml was associated with a reduced risk of O2 need (OR 0.52; 95 % CI 0.30-0.92). This study shows that COVID-19 vaccination has a significant impact on COVID-19 outcomes in hospitalized patients.

Polypharmacy and Aging in People Living with HIV: 6 Years of Experience in a Multidisciplinary Outpatient Clinic.

BACKGROUND: Despite the availability of potent antiretroviral drugs, the management of human immunodeficiency virus (HIV) infection still presents some important challenges, especially in older patients who often experience age-related comorbidities and complex polypharmacy. OBJECTIVE: To describe the results of our 6 year experience with the outpatient clinic [Gestione Ambulatoriale Politerapie (GAP)] for the management of polypharmacy in people living with HIV (PLWH). METHODS: Demographic characteristics, antiretroviral regimens, and number and type of comedications were collected in all PLWH included in the database of GAP from September 2016 to September 2022. Therapies were stratified based on the number of anti-HIV drugs (dual versus triple regimens) and on the presence of pharmacokinetic boosters (ritonavir or cobicistat). RESULTS: A total of 556 PLWH were included in the GAP database. Overall, the enrolled patients were administered 4.2 ± 2.7 drugs (range 1-17) in addition to antiretroviral therapies. The number of comedications greatly increased with age (3.0 ± 2.2 versus 4.1 ± 2.5 versus 6.3 ± 3.2 in PLWH aged < 50 versus 50-64 versus > 65 years; p < 0.001 for all comparisons). PLWH on dual antiretroviral therapies were significantly older (58 ± 9 versus 54 ± 11 years; p < 0.001) and were concomitantly treated with more drugs (5.1 ± 3.2 versus 3.8 ± 2.5; p < 0.001) compared with those on triple therapies. A significant reduction of boosted antiretroviral regimens (53% versus 23%; p < 0.001) and in the number of comedications (4.0 ± 2.9 versus 3.1 ± 2.2 drugs; p < 0.001) was observed in the subgroup of patients (n = 198) with two GAP visits. CONCLUSIONS: The high prevalence of polypharmacy in PLWH, especially among older adults, place these patients at high risk for clinically relevant drug-drug interactions (DDIs). A multidisciplinary approach involving physicians and clinical pharmacologists could help to optimize medication regimens associated with reduced risk.

Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings.

BACKGROUND AND OBJECTIVES: Liver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART). OBJECTIVE: We aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital. METHODS: We searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. RESULTS: Ten HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable. CONCLUSIONS: The management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.

Evaluation of the concentrations of psychotropic drugs in HIV-infected versus HIV-negative patients: Potential implications for clinical practice.

Objectives: The management of psychiatric illness in HIV-infected patients is clinically challenging because of the risk of potential drug-drug interactions. Here, we aimed to measure the antidepressant and/or antipsychotic drug concentrations in HIV-infected patients during routine outpatient visits.Methods: Six hundred HIV-infected patients were screened during the first 15 months after the introduction of our outpatient polytherapy management service in a search for subjects treated with psychotropic drugs for at least 3 months. The distribution of psychotropic drug concentrations in HIV-infected patients was compared with that observed in a control group of HIV-negative patients monitored over the same period.Results: The search identified 82 HIV-infected patients concomitantly receiving antiretroviral and psychotropic drug treatment, 55% of whom had plasma psychotropic drug concentrations that were below minimum effective levels. The same result was found in only 26% of the samples taken from HIV-negative patients. These results were not affected by patients' gender, age, adherence to therapies or drug-drug interactions.Conclusions: A higher rate of sub-therapeutic antidepressant and/or antipsychotic drugs concentrations were found in HIV-infected patients. The creation of multidiscliplinary specialist teams may contribute to improving the management of such complex patients.

Corrigendum: Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection.

[This corrects the article DOI: 10.3389/fimmu.2019.01648.].

Endoplasmic Reticulum Associated Aminopeptidase 2 (ERAP2) Is Released in the Secretome of Activated MDMs and Reduces in vitro HIV-1 Infection.

Background: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. HapA/HapA homozygous (HomoA) subjects show a reduced susceptibility to HIV-1 infection, probably secondary to the modulation of the antigen processing/presenting machinery. ERAP1 was recently shown to be secreted from the plasma membrane in response to activation; we investigated whether ERAP2 can be released as well and if the secreted form of this enzyme retains its antiviral function. Methods: Human monocyte derived macrophages (MDMs) were differentiated from peripheral blood mononuclear cells (PBMCs) isolated from 6 HomoA healthy controls and stimulated with IFNγ and LPS. ERAP2-FL secretion was evaluated by mass spectrometry. PBMCs (14 HomoA and 16 HomoB) and CD8-depleted PBMCs (CD8-PBMCs) (4 HomoA and 4 HomoB) were in vitro HIV-infected in the absence/presence of recombinant human ERAP2-FL (rhERAP2) protein; p24 viral antigen quantification was used to assess viral replication. IFNγ and CD69 mRNA expression, as well as the percentage of perforin-producing CD8+ T Lymphocytes, were analyzed 3 and 7-days post in vitro HIV-1-infection, respectively. The effect of rhERAP2 addition in cell cultures on T cell apoptosis, proliferation, activation, and maturation was evaluated as well on 24 h-stimulated PBMCs. Results: ERAP2 can be secreted from human MDMs in response to IFNγ/LPS stimulation. Notably, the addition of rhERAP2 to PBMC and CD8-PBMC cultures resulted in the reduction of viral replication, though these differences were statistically significant only in PBMCs (p < 0.05 in both HomoA and HomoB). This protective effect was associated with an increase in IFNγ and CD69 mRNA expression and in the percentage of perforin-expressing CD107+CD8+ cells. RhERAP2 addition also resulted in an increase in CD8+ activated lymphocyte (CD25+HLA-DRII+) and Effector Memory/Terminally differentiated CD8+ T cells ratio. Conclusions: This is the first report providing evidence for the release of ERAP2 in the secretome of immunocompetent cells. Data herein also indicate that exogenous ERAP2-FL exerts its protective function against HIV-1 infection, even in HomoB subjects who do not genetically produce it. Presumably, this defensive extracellular feature is only partially dependent on immune system modulation.

Assessment of Antiepileptic Drug Concentrations in HIV-Infected versus HIV-Negative Patients: A Retrospective Analysis.

INTRODUCTION: A higher rate of subtherapeutic psychotropic drug concentrations was recently found in HIV-infected versus HIV-negative patients. In this study, we sought to investigate if this trend could also apply to antiepileptic drugs. METHODS: Overall, 700 HIV-infected patients were screened during the first 2 years after the introduction of our outpatient polytherapy management service (Gestione Ambulatoriale Politerapie [GAP]) in the search for subjects with antiepileptic drug trough concentration assessments. The distribution of such concentrations was compared with that in HIV-negative patients monitored over the same period. RESULTS: The search identified 97 HIV-infected patients concomitantly receiving antiretroviral and antiepileptic drugs, for a total of 310 drug measurements. Overall, 30%, 64% and 6%, versus 28%, 65% and 7%, of the antiepileptic concentrations measured in HIV-infected versus HIV-negative patients (1090 patients, for a total of 3488 antiepileptic concentrations measured) were below, within, or above the therapeutic targets, respectively. The antiepileptic drug valproate was associated with the highest risk of subtherapeutic drug concentrations, with 57% and 46% of determinations below the therapeutic range in HIV-positive and HIV-negative patients, respectively. Remarkably, the concentrations of valproate were significantly lower in HIV-infected versus HIV-negative patients (47.9 ± 21.2 versus 53.9 ± 21.6 mg/L; p < 0.05). CONCLUSION: In our retrospective study, most HIV-infected patients had antiepileptic drug concentrations falling within the therapeutic targets, with the exception of valproate, which was associated with a higher rate of subtherapeutic concentrations compared with other antiepileptic drugs.

Effect of Cobicistat on Tenofovir Disoproxil Fumarate (TDF): What Is True for TAF May Also Be True for TDF.

BACKGROUND: The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting. METHODS: HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons. RESULTS: Patients were given TDF with protease inhibitors/ritonavir (n = 212), non-nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation. CONCLUSIONS: Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.

Dolutegravir plasma concentrations according to companion antiretroviral drug: unwanted drug interaction or desirable boosting effect?

BACKGROUND: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. METHODS: Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. RESULTS: All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012). CONCLUSIONS: Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.

When food can make the difference: The case of elvitegravir-based co-formulation.

Stribild should be administered under fed conditions to optimize drugs exposure. Here we assessed to what extent this advice is applied in the real life scenario by therapeutic drug monitoring in 75 HIV-infected patients given Stribild-based antiretroviral therapy. Fifty-three percent of our patients took Stribild at lunch/supper time, 23% in the morning with breakfast, and 24% middle in the morning or late in the evening. Twelve out of the 75 patients had unquantifiable elvitegravir concentrations, whereas in the remaining the levels were largely distributed. Wide inter-individual variability in the tenofovir, cobicistat and darunavir trough concentrations was also observed. In real life settings a significant proportion of patients took Stribild without food, namely in the mid-morning or late in the evening. This resulted in a wide inter-individual variability of antiretroviral drug trough concentrations. To avoid the risk for patients to experience suboptimal drug exposure, it is important that health professionals more convincingly advise their patients to take Stribild in fed conditions. On the other hand, the role of patient education and patient responsibility to correctly take the therapy should not be underestimated.

Metabolic and kidney disorders correlate with high atazanavir concentrations in HIV-infected patients: is it time to revise atazanavir dosages?

INTRODUCTION: Ritonavir-boosted atazanavir (ATV/r) is a relatively well tolerated antiretroviral drug. However, side effects including hyperbilirubinemia, dyslipidemia, nephrolithiasis and cholelithiasis have been reported in the medium and long term. Unboosted ATV may be selected for some patients because it has fewer gastrointestinal adverse effects, less hyperbilirubinemia and less impact on lipid profiles. METHODS: We investigated the distribution of ATV plasma trough concentrations according to drug dosage and the potential relationship between ATV plasma trough concentrations and drug-related adverse events in a consecutive series of 240 HIV-infected patients treated with ATV/r 300/100 mg (68%) or ATV 400 mg (32%). RESULTS: 43.9% of patients treated with ATV/r 300/100 mg had ATV concentrations exceeding the upper therapeutic threshold. A significant and direct association has been observed between the severity of hyperbilirubinemia and ATV plasma trough concentrations (ATV concentrations: 271 [77-555], 548 [206-902], 793 [440-1164], 768 [494-1527] and 1491 [1122-1798] ng/mL in patients with grade 0, 1, 2, 3 and 4 hyperbilirubinemia, respectively). In an exploratory analysis we found that patients with dyslipidemia or nephrolitiasis had ATV concentrations significantly higher (582 [266-1148], and 1098 [631-1238] ng/mL, respectively) (p<0.001), as compared with patients with no ATV-related complications (218 [77-541] ng/mL). CONCLUSIONS: A significant proportion of patients treated with the conventional dosage of ATV (300/100) had plasma concentrations exceeding the upper therapeutic threshold. These patients that are at high risk to experience ATV-related complications may benefit from TDM-driven adjustments in ATV dosage with potential advantages in terms of costs and toxicity.