Risk of Chronic Kidney Disease among Patients Developing Mild Renal Impairment during Tenofovir-Containing Antiretroviral Treatment

BACKGROUND: Tenofovir (TDF) can cause kidney injury through tubular dysfunction, with or without drop of estimated glomerular filtration rate (eGFR). Whether mild eGFR reductions during treatment should be considered a reason for prompt TDF discontinuation, however, remains unclear. METHODS: Patients with normal pre-TDF eGFR levels, who had developed mild renal impairment (i.e., two consecutive eGFR results between 89-60 ml/min) on TDF, were observed until onset of chronic kidney disease (CKD), defined as two eGFR<60 ml/min 3 to 6 months apart. Multivariable Poisson regression analysis was used to investigate whether outcome was associated with current and cumulative use of TDF (modeled as time-varying covariates). RESULTS: 2023 (29%) out of 6984 patients developed mild renal impairment on TDF. Among them, 191 progressed to CKD. The incidence of CKD did not significantly differ during TDF treatment (2.6 per 100 PYFU; 95%CI 2.2-3.2) or after its discontinuation (2.2 per 100 PYFU; 95%CI 1.8-2.6). However, the rate of CKD was significantly higher among patients continuing with TDF treatment compared to those who had discontinued it within 6 months of occurrence of mild renal impairment (aIRR 4, 95%CI 2.4-6.8). In contrast, among patients who had maintained TDF >6 months despite mild renal impairment, current TDF use was not associated with a significantly higher rate of CKD. Other significant predictors of CKD were older age, intravenous drug use, diabetes, hypertension, lower pre-TDF eGFR, higher eGFR drop since TDF introduction and longer exposure to TDF. CONCLUSIONS: Prompt discontinuation of TDF among patients developing mild renal impairment may prevent further progression of renal damag

GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed

Determinants of worse liver‐related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort

Objectives: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated.Methods: People living with HIV (PLWH) from Italian Foundation cohort Naive antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. Primary end-point: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence.Results: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 &gt; 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 &lt; 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5).Conclusions: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments

Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort

Background and aims: Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown. Methods: Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models. Results: Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence: .48/100 PYFU (95% CI: .36-.65); re-infections incidence: 1.40/100 PYFU (95% CI: .91-2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17-2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR .75, 95% CI .62-.90), HIV-RNA &gt;50 copies/mL (aHR .70, 95% CI .56-.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count &lt;200/mm3 (vs. CD4 ≥200/mm3 aOR .18, 95% CI: .07-.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022. Conclusions: The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort

Lopinavir pharmacokinetic profiles in HIV-infected patients during rifabutin-based anti-mycobacterial therapy

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Photoactivation of corticosteroids in UVB-exposed skin

The photodegradation of flumethasone (FM) and fluocinolone acetonide (FC) was studied in solution and in the pig skin. Both glucocorticosteroids applied to the pig skin were unstable under UVB light. The photoproducts formed in the skin were the lumi-, photolumi- and andro-derivatives for FM, the same found in vitro. Instead, FC hydroperoxide formed in solution was not found in the skin: the reactivity and oxidative ability of this photoproduct towards biological substrates (lipids, proteins) seems the reason of the lack of its detection in the ex vivo model. In fact, it demonstrated to quickly oxidize amino acids and peptides, and to react with BSA both in the dark and under irradiation. Moreover, the presence in the irradiated pig skin of the FC andro-derivative, which usually forms in H-donating environment, seems consistent with the mechanism of Norrish I fragmentation followed by H-abstraction, likely from the surrounding biological substrates. These findings indicate that photoreactivity of these compounds may take place in the skin of patients exposing themselves to sunlight and is a warning about possible skin damage as a result of that. Furthermore, photolability of these drugs in the skin might cause loss of their therapeutic activity

Lopinavir pharmacokinetic profiles in HIV-infected patients during rifabutin-based anti-mycobacterial therapy

Objectives: To evaluate the pharmacokinetic profile of ritonavir-boosted lopinavir in HIV-infected patients during rifabutin-based anti-mycobacterial therapy. Patients and methods: A longitudinal, cross-over pharmacokinetic evaluation of lopinavir with and without rifabutin in HIV-infected subjects with mycobacterial disease was done. All received lopinavir/ritonavir (400/100 mg twice a day) + an adjusted rifabutin dose of 150 mg every other day. Twelve-hour lopinavir pharmacokinetic sampling occurred at 2 weeks (T1) and 6 weeks (T2) after starting combined therapy and 10 weeks after completion of adjusted rifabutin (T3). Plasma was assayed using an HPLC method; lopinavir plasma concentration-time data were analysed using non-compartmental methods. Results: In 10 patients with complete lopinavir curves at T1, T2 and T3 pharmacokinetic values were, respectively: AUC0-12, 187.5, 161.8 and 121.1 μg h/mL; Ctrough, 13.2, 10.0 and 7.7 μg/mL; Cmax, 18.7, 15.9 and 13.3 μg/mL; and apparent oral clearance (CL/F), 0.035, 0.037 and 0.045 L/h/kg. Lopinavir Ctrough and AUC0-12 were significantly higher at T1 compared with T3 while CL/F remained unchanged throughout. Combined treatment was well tolerated and none of the patients experienced moderate to severe lopinavir-related adverse events. Conclusions: Lopinavir serum concentrations are not reduced when the drug is administered together with an adjusted dose of 150 mg of rifabutin every other day. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved

Synthesis and separation of the enantiomers of the neuropeptide S receptor antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68).

This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible

Risk of chronic kidney disease among patients developing mild renal impairment during tenofovir-containing antiretroviral treatment

Background: Tenofovir (TDF) can cause kidney injury through tubular dysfunction, with or without drop of estimated glomerular filtration rate (eGFR). Whether mild eGFR reductions during treatment should be considered a reason for prompt TDF discontinuation, however, remains unclear. Methods: Patients with normal pre-TDF eGFR levels, who had developed mild renal impairment (i.e., two consecutive eGFR results between 89-60 ml/min) on TDF, were observed until onset of chronic kidney disease (CKD), defined as two eGFR6 months despite mild renal impairment, current TDF use was not associated with a significantly higher rate of CKD. Other significant predictors of CKD were older age, intravenous drug use, diabetes, hypertension, lower pre-TDF eGFR, higher eGFR drop since TDF introduction and longer exposure to TDF. Conclusions: Prompt discontinuation of TDF among patients developing mild renal impairmentmay prevent further progression of renal damage