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 > 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 < 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 >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 <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

Chronic suppressive antibiotic treatment for staphylococcal bone and joint implant–related infections

: Prosthetic joint infection (PJI) and fracture-related infection (FRI) are difficult-to-treat conditions in patients with severe comorbidity or significant surgical risk. In cases not eligible for standard strategy, debridement procedures with the retention of prosthesis or internal fixation device, combined with long-term antibiotic treatment and subsequent indefinite chronic oral antimicrobial suppression (COAS), can be the only reasonable choice. The aim of this study was to investigate the role of COAS and its follow-up in the management of these cases. We retrospectively analyzed a cohort of 16 patients with a follow-up of at least 6 months (mean age 75 yo, 9F, 7M, 11 PJI, 5 FRI). All microbiological isolates were tetracycline-susceptible staphylococci and for this reason a minocycline-based COAS was adopted after debridement and 3 months of antibiogram-guided antibiotic treatment. Patient monitoring was carried out on a clinical basis, with bimonthly execution of the inflammation indices and serial radiolabeled leukocyte scintigraphy (LS). The overall median time of COAS follow-up was 15 months (min 6-max 30). Moreover, 62.5% of patients were still taking COAS with no relapse after cure at the last evaluation available. Clinical failure with a relapse of the infection was observed in 37.5% of patients; interestingly, 50% of them had previously stopped COAS due to side effects of the antibiotic used. In the COAS follow-up, a combination of clinical, laboratory and LS evaluation seems to monitor the infection properly. COAS can be considered as an interesting approach in patients not suitable for standard treatments of PJI or FRI but it requires careful monitoring

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort

Objectives: To evaluate the incidence and risk factors for liver enzyme elevations (LEE) in patients initiating first-line ART in the ICONA prospective observational cohort, between June 2009 and December 2017. Patients and methods: In total, 6575 ART-naive patients were selected, initiating two NRTIs with the third drug being a boosted PI (n=2436; 37.0%), an NNRTI (n=2384; 36.3%) or an integrase strand transfer inhibitor (INSTI) (n=1755; 26.7%). HBV surface antigen and HCV RNA were detected in 3.9% and 5.8% of the study population. Inverse probability weighted Cox regression analysis was used to calculate the HRs, according to first-line regimen, for LEE, defined as ALT or AST increases of ≥2.5× upper limit of normal (ULN) for patients with normal baseline values or ≥2.5× baseline for patients with higher baseline values. Results: One hundred and eighty-three LEE occurred over 20722 patient-years of follow-up. After adjusting for the main confounders, the risk of LEE halved with INSTIs compared with NNRTIs (HR 0.46, 95% CI 0.25-0.86), with a significant reduction in the raltegravir group (HR 0.11, 95% CI 0.02-0.84 using the NNRTI class as reference). HRs for LEE were significantly higher in subjects with HBV or HCV coinfection, in patients with poorly controlled HIV infection and in those who acquired HIV through homosexual transmission. Conclusions: In our study, INSTI use almost halved the risk of LEE compared with other regimens. This finding could be particularly important for choosing ART in patients with risk factors for liver toxicity such as HCV and HBV coinfections

Switching from TDF to TAF or dual therapy (DT)-based regimens in HIV-infected individuals with viral load <= 50 copies/ml: does eGFR matter?

reserved98noOur aim was to evaluate the association between recent eGFR values and risk of switching from TDF to TAF or dual therapy (DT) in real life. HIV-positive patients achieving HIV-RNA ≤50 copies/mL for the first time after starting a TDF-based regimen were included. Kaplan–Meier (KM) curves and Cox regression models were used to estimate the time from TDF to switch to TAF or DT. 1486 participants were included: median (IQR) age 36 (30–42) years; baseline CKD-EPI eGFR 99.92 (86.47–111.4) mL/min/1.73m2. We observed a consistently higher proportion of people with HIV-RNA ≤50 copies/mL who switched from TDF to TAF rather than to DT. By competing risk analysis, at 2 years from baseline, the probability of switching was 3.5% (95% CI 2.6–4.7%) to DT and 46.7% (42.8–48.5%) to TAF. A significantly higher probability of switching to TAF was found for patients receiving INSTI at baseline versus NNRTIs and PI/b [KM, 65.6% (61.7–69.4%) vs. 4.0% (1.8–6.1%) and 59.9% (52.7–67.2%), respectively; P &lt; 0.0001]. eGFR &lt;60 mL/min/1.73m2 both as time-fixed covariate at baseline or as current value was associated with a higher risk of switching to DT [aHR 6.68 (2.69–16.60) and 8.18 (3.54–18.90); P &lt; 0.001] but not to TAF-based cART [aHR 0.94 (0.39–2.31), P = 0.897; and 1.19 (0.60–2.38), P = 0.617]. Counter to our original hypothesis, current eGFR is used by clinicians to guide switches to DT but does not appear to be a key determinant for switching to TAF.mixedA Vergori, R Gagliardini, N Gianotti, A Gori, M Lichtner, A Saracino, A De Vito, A Cascio, A Di Biagio, A d'Arminio Monforte, A Antinori, A Cozzi-Lepri on behalf of the ICONA Foundation Study Network, A. Giacometti, A. Costantini, V. Barocci; G. Angarano, L. Monno, E. Milano; F. Maggiolo, C. Suardi ; P. Viale, V. Donati, G. Verucchi ; F. Castelnuovo, C. Minardi, E. Quiros Roldan ; B. Menzaghi, C. Abeli ; L. Chessa, F. Pes ; B. Cacopardo, B. Celesia ; J. Vecchiet, K. Falasca (Chieti); A. Pan, S. Lorenzotti ; L. Sighinolfi; Daniela Segala ; P. Blanc, F. Vichi ; G. Cassola, M. Bassetti, A. Alessandrini, N. Bobbio, G. Mazzarello ; M. Lichtner, L. Fondaco (Latina); P. Bonfanti, C. Molteni ; A. Chiodera, P. Milini ; G. Nunnari, G. Pellicanò ; A. d’Arminio Monforte, M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. Castagna, E.S. Cannizzo, M.C. Moioli, R. Piolini, D. Bernacchia, A. Poli, C. Tincati, C. Mussini, C. Puzzolante ; C. Migliorino, G. Lapadula ; V. Sangiovanni, G. Borgia, V. Esposito, G. Di Flumeri, I. Gentile, V. Rizzo ; A.M. Cattelan, S. Marinello ; A. Cascio, C. Colomba ; D. Francisci, E. Schiaroli; G. Parruti, F. Sozio ; C. Lazzaretti, R. Corsini ; M. Andreoni, A. Antinori, R. Cauda, A. Cristaudo, V. Vullo, R. Acinapura, S. Lamonica, M. Capozzi, A. Mondi, A. Cingolani, M. Rivano Capparuccia, G. Iaiani, A. Latini, G. Onnelli, M.M. Plazzi, G. De Girolamo, A. Vergori; M. Cecchetto, F. Viviani; G. Madeddu, A. De Vito ; B. Rossetti, F. Montagnani ; A. Franco, R. Fontana Del Vecchio ; C.Di Giuli; P. Caramello, G. Di Perri, S. Bonora, G.C. Orofino, M. Sciandra; C. Tascini, A. Londer; V. Manfrin, G. Battagin ; G. Starnini, A. IalungoVergori, A; Gagliardini, R; Gianotti, N; Gori, A; Lichtner, M; Saracino, A; De Vito, A; Cascio, A; Di Biagio, A; d'Arminio Monforte, A; Antinori, A; Cozzi-Lepri on behalf of the ICONA Foundation Study Network, A; Giacometti, A.; Costantini, A.; Barocci, V.; Angarano, G.; Monno, L.; Milano, E.; C. Suardi, F. Maggiolo; Viale, P.; Donati, V.; Verucchi, G.; Castelnuovo, F.; Minardi, C.; Quiros Roldan, E.; C. Abeli, B. Menzaghi; F. Pes, L. Chessa; B. Celesia, B. Cacopardo; K. Falasca (Chieti), J. Vecchiet; S. Lorenzotti, A. Pan; Sighinolfi, L.; Segala, Daniela; F. Vichi, P. Blanc; Cassola, G.; Bassetti, M.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; L. Fondaco (Latina), M. Lichtner; C. Molteni, P. Bonfanti; P. Milini, A. Chiodera; G. Pellicanò, G. Nunnari; d’Arminio Monforte, A.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; Castagna, A.; Cannizzo, E. S.; Moioli, M. C.; Piolini, R.; Bernacchia, D.; Poli, A.; Tincati, C.; Mussini, C.; Puzzolante, C.; G. Lapadula, C. Migliorino; Sangiovanni, V.; Borgia, G.; Esposito, V.; Di Flumeri, G.; Gentile, I.; Rizzo, V.; S. Marinello, A. M. Cattelan; C. Colomba, A. Cascio; E. Schiaroli, D. Francisci; F. Sozio, G. Parruti; R. Corsini, C. Lazzaretti; Andreoni, M.; Antinori, A.; Cauda, R.; Cristaudo, A.; Vullo, V.; Acinapura, R.; Lamonica, S.; Capozzi, M.; Mondi, A.; Cingolani, A.; Rivano Capparuccia, M.; Iaiani, G.; Latini, A.; Onnelli, G.; Plazzi, M. M.; De Girolamo, G.; Vergori, A.; F. Viviani, M. Cecchetto; A. De Vito, G. Madeddu; F. Montagnani, B. Rossetti; R. Fontana Del Vecchio, A. Franco; Di Giuli, C.; Caramello, P.; Di Perri, G.; Bonora, S.; Orofino, G. C.; Sciandra, M.; A. Londer, C. Tascini; G. Battagin, V. Manfrin; A. Ialungo, G. Starnin

Evaluation of HIV transmission clusters among natives and foreigners living in Italy

We aimed at evaluating the characteristics of HIV-1 molecular transmission clusters (MTCs) among natives and migrants living in Italy, diagnosed between 1998 and 2018. Phylogenetic analyses were performed on HIV-1 polymerase (pol) sequences to characterise subtypes and identify MTCs, divided into small (SMTCs, 2-3 sequences), medium (MMTCs, 4-9 sequences) and large (LMTCs, ≥10 sequences). Among 3499 drug-naïve individuals enrolled in the Italian Cohort Naive Antiretroviral (ICONA) cohort (2804 natives; 695 migrants), 726 (20.8%; 644 natives, 82 migrants) were involved in 228 MTCs (6 LMTCs, 36 MMTCs, 186 SMTCs). Migrants contributed 14.4% to SMTCs, 7.6% to MMTCs and 7.1% to LMTCs, respectively. HIV-1 non-B subtypes were found in 51 MTCs; noteworthy was that non-B infections involved in MTCs were more commonly found in natives (n = 47) than in migrants (n = 4). Factors such as Italian origin, being men who have sex with men (MSM), younger age, more recent diagnosis and a higher CD4 count were significantly associated with MTCs. Our findings show that HIV-1 clustering transmission among newly diagnosed individuals living in Italy is prevalently driven by natives, mainly MSM, with a more recent diagnosis and frequently infected with HIV-1 non-B subtypes. These results can contribute to monitoring of the HIV epidemic and guiding the public health response to prevent new HIV infections

Evaluation of HIV transmission clusters among natives and foreigners living in Italy

We aimed at evaluating the characteristics of HIV-1 molecular transmission clusters (MTCs) among natives and migrants living in Italy, diagnosed between 1998 and 2018. Phylogenetic analyses were performed on HIV-1 polymerase (pol) sequences to characterise subtypes and identify MTCs, divided into small (SMTCs, 2-3 sequences), medium (MMTCs, 4-9 sequences) and large (LMTCs, ≥10 sequences). Among 3499 drug-naïve individuals enrolled in the Italian Cohort Naive Antiretroviral (ICONA) cohort (2804 natives; 695 migrants), 726 (20.8%; 644 natives, 82 migrants) were involved in 228 MTCs (6 LMTCs, 36 MMTCs, 186 SMTCs). Migrants contributed 14.4% to SMTCs, 7.6% to MMTCs and 7.1% to LMTCs, respectively. HIV-1 non-B subtypes were found in 51 MTCs; noteworthy was that non-B infections involved in MTCs were more commonly found in natives (n = 47) than in migrants (n = 4). Factors such as Italian origin, being men who have sex with men (MSM), younger age, more recent diagnosis and a higher CD4 count were significantly associated with MTCs. Our findings show that HIV-1 clustering transmission among newly diagnosed individuals living in Italy is prevalently driven by natives, mainly MSM, with a more recent diagnosis and frequently infected with HIV-1 non-B subtypes. These results can contribute to monitoring of the HIV epidemic and guiding the public health response to prevent new HIV infections

The impact of DAA-mediated HCV eradication on CD4+ and CD8+ T lymphocyte trajectories in HIV/HCV coinfected patients: Data from the ICONA Foundation Cohort

HCV infection has been hypothesized as a contributor of poor CD4+ recovery in patients living with HIV (PLWHIV). Aim of this study was to evaluate CD4+, CD8+ cells and CD4/CD8 ratio trends before and after HCV treatment with direct acting agents (DAA) in PLWHIV. HIV/HCV patients enrolled in ICONA and HepaICONA cohorts with HIV-RNA 6450&nbsp;copies/ml who achieved a sustained viral response after DAA treatment were studied. A linear regression model was used to investigate CD4+, CD8+ and CD4/CD8 changes 12&nbsp;months before and after DAA treatment. A total of 939 HIV/HCV patients were included, 225 (24.0%) female, median age: 53&nbsp;years (IQR 50\u201356). At DAA initiation, CD4+ T cell count was &lt;350&nbsp;cells/mm3 in 164 patients (17.5%), and 246 patients (26.2%) had liver stiffness&gt;12.5&nbsp;kPa. Trends of CD4+ and CD4/CD8 ratio were similar before and after DAA in all study populations (CD4+ change +17.6 cells/mm3 (95%CI 1233.5; 69.4, p&nbsp;=&nbsp;0.494); CD4/CD8 change 0.013 (95%CI 120.061; 0.036, p&nbsp;=&nbsp;0.611). However, patients treated with ribavirin (RBV)-free DAA showed a significant decrease in CD8+ cells ( 12204.3 cells/mm3, 95%CI 12375.0;-33.4, p&nbsp;=&nbsp;0.019), while patients treated with RBV experienced CD8+ cell increase (+141.2 cells/mm3, 95%CI 40.3; 242.1, p&nbsp;=&nbsp;0.006). In conclusion, HCV eradication following DAA treatment does not seem to have an impact on CD4+ T cell recovery in PLWHIV. However, a fast decline of CD8+T cells has been observed in patients treated without RBV, suggesting a favourable effect of HCV clearance on the general state of immune activation

The impact of DAA-mediated HCV eradication on CD4+ and CD8+ T lymphocyte trajectories in HIV/HCV coinfected patients: Data from the ICONA Foundation Cohort

HCV infection has been hypothesized as a contributor of poor CD4+ recovery in patients living with HIV (PLWHIV). Aim of this study was to evaluate CD4+, CD8+ cells and CD4/CD8 ratio trends before and after HCV treatment with direct acting agents (DAA) in PLWHIV. HIV/HCV patients enrolled in ICONA and HepaICONA cohorts with HIV-RNA≤50&nbsp;copies/ml who achieved a sustained viral response after DAA treatment were studied. A linear regression model was used to investigate CD4+, CD8+ and CD4/CD8 changes 12&nbsp;months before and after DAA treatment. A total of 939 HIV/HCV patients were included, 225 (24.0%) female, median age: 53&nbsp;years (IQR 50–56). At DAA initiation, CD4+ T cell count was &lt;350&nbsp;cells/mm3 in 164 patients (17.5%), and 246 patients (26.2%) had liver stiffness&gt;12.5&nbsp;kPa. Trends of CD4+ and CD4/CD8 ratio were similar before and after DAA in all study populations (CD4+ change +17.6 cells/mm3 (95%CI −33.5; 69.4, p&nbsp;=&nbsp;0.494); CD4/CD8 change 0.013 (95%CI −0.061; 0.036, p&nbsp;=&nbsp;0.611). However, patients treated with ribavirin (RBV)-free DAA showed a significant decrease in CD8+ cells (−204.3 cells/mm3, 95%CI −375.0;-33.4, p&nbsp;=&nbsp;0.019), while patients treated with RBV experienced CD8+ cell increase (+141.2 cells/mm3, 95%CI 40.3; 242.1, p&nbsp;=&nbsp;0.006). In conclusion, HCV eradication following DAA treatment does not seem to have an impact on CD4+ T cell recovery in PLWHIV. However, a fast decline of CD8+T cells has been observed in patients treated without RBV, suggesting a favourable effect of HCV clearance on the general state of immune activation

HBcAb Positivity Increases the Risk of Severe Hepatic Fibrosis Development in HIV/HCV-Positive Subjects From the ICONA Italian Cohort of HIV-Infected Patients

The aim of this study was to investigate the impact of anti-HBc (HBcAb) positivity on the progression of liver fibrosis (Fibrosis-4 score &gt;3.25) in the Italian cohort of HIV-infected individuals na\uefve to antiretroviral treatment (ICONA)