Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort

Introduction: Concerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals. Methods: We performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan–Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation. Results: About 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC-based triple-therapies, aHR = 3.56, p = 0.012 for tenofovir-based) and for toxicity (aHR = 5.26, p = 0.030 for ABC-based, aHR = 6.60, p = 0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group. Conclusions: In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice

Clinical and Epidemiological Study on Tubercular Uveitis in a Tertiary Eye Care Centre in Italy

PURPOSE: To describe frequency, clinical characteristics, and visual prognosis of tubercular uveitis (TBU) in a nonendemic country. METHODS: We retrospectively reviewed 3743 charts of patients with endogenous uveitis visited from 2008 to 2018 at a tertiary referral centre in Rome, Italy. We included immunocompetent patients with diagnosis of TBU. Patients were divided in two groups: patients with history of uveitis without a previous diagnosis of TBU (group A) and patients at their first episode of TB uveitis (group B). RESULTS: TBU was diagnosed in 28 (0.75%) out of 3743 patients. Twelve (42.9%) patients came from tuberculosis endemic areas. All patients received specific antitubercular treatment (ATT) and were evaluated for a mean follow-up of 3.2 ± 2.9 years. Group A showed a greater number of ocular complications when compared with group B. ATT was effective in reducing the frequency of recurrences of uveitis in patients of group B. CONCLUSION: Intraocular inflammation can be the first manifestation of tuberculosis. Our data highlight that early diagnosis and specific treatment of TBU may allow to decrease recurrences and to improve visual outcomes

Impact analysis of SARS-CoV-2 vaccination in patients treated with monoclonal antibodies. A monocentric experience

Background: Since the discovery of SARS-CoV-2, no treatment has been able to completely eradicate the virus. The study aimed to evaluate the virological and clinical impact of the vaccination in SARS-CoV-2 infected patients treated with monoclonal antibodies (mAbs). Methods: This single-centre, observational, retrospective, real-life study was performed on SARS-CoV-2 symptomatic outpatients and inpatients treated with mAbs from March 2021 to November 2022 includes 726 patients. Each patient received available mAbs (bamlanivimab-etesevimab or casirivimab-indevimab or sotrovimab or tixagevimab-cilgavimab) according to the circulating virus strains. Age, comorbidities, vaccination status, death rates, duration of virological clearance, average length of stay, risk factors, and hospitalization or ICU admission were recorded. Results: Of 726 patients with complete data analyzed (median age 64), 516 outpatients and 210 inpatients were included. Vaccination status was known for all participants: 74.4 % and 51.7 % were vaccinated against SARSCoV-2 among inpatients and outpatients, respectively. A shorter duration of virological clearance was observed in the vaccinated group, with a median of 16 days (IQR 15-17), compared to 19 days (IQR 18-21) in the unvaccinated group [HR 1.21; p < 0.032]. Multivariate analysis of virological clearance also showed statistical significance with tixagevimab cilgavimab 300 mg/300 mg (HR 2.73, p value < 0.001). No significant difference was found in worsening [OR 1,29; p = 0.57] and mortality [OR 0.65; p = 0.81] rates between vaccinated and unvaccinated patients treated with mAbs. Conclusions: Key findings include a shorter duration of virological clearance in vaccinated outpatients but no significant differences in worsening or mortality rates between vaccinated and unvaccinated patients treated with mAbs. The study suggests a potential synergistic role of mAbs in accelerating virological clearance in vaccinated patients with mild to moderate COVID-19, with differing effects in hospitalized patients. Therefore, it is essential to implement health surveillance in high-risk patients with comorbidities in order to identify early any variants that might otherwise escape neutralizing antibodies

Is physician assessment of alcohol consumption useful in predicting risk of severe liver disease among people with HIV and HIV/HCV co-infection?

Background: Alcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy. Methods: We included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 > 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD. Results: Among 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03-2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94-1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population. Conclusions: Using a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals

Switching to dual/monotherapy determines an increase in CD8+ in HIV-infected individuals: An observational cohort study

Background: The CD4/CD8 ratio has been associated with the risk of AIDS and non-AIDS events. We describe trends in immunological parameters in people who underwent a switch to monotherapy or dual therapy, compared to a control group remaining on triple antiretroviral therapy (ART). Methods: We included patients in Icona who started a three-drug combination ART regimen from an ART-naïve status and achieved a viral load ≤ 50 copies/mL; they were subsequently switched to another triple or to a mono or double regimen. Standard linear regression at fixed points in time (12-24 months after the switch) and linear mixed model analysis with random intercepts and slopes were used to compare CD4 and CD8 counts and their ratio over time according to regimen types (triple vs. dual and vs. mono). Results: A total of 1241 patients were included; 1073 switched to triple regimens, 104 to dual (72 with 1 nucleoside reverse transcriptase inhibitor (NRTI), 32 NRTI-sparing), and 64 to monotherapy. At 12 months after the switch, for the multivariable linear regression the mean change in the log10 CD4/CD8 ratio for patients on dual therapy was -0.03 (95% confidence interval (CI) -0.05, -0.0002), and the mean change in CD8 count was +99 (95% CI +12.1, +186.3), taking those on triple therapy as reference. In contrast, there was no evidence for a difference in CD4 count change. When using all counts, there was evidence for a significant difference in the slope of the ratio and CD8 count between people who were switched to triple (points/year change ratio = +0.056, CD8 = -25.7) and those to dual regimen (ratio = -0.029, CD8 = +110.4). Conclusions: We found an increase in CD8 lymphocytes in people who were switched to dual regimens compared to those who were switched to triple. Patients on monotherapy did not show significant differences. The long-term implications of this difference should be ascertained

Effectiveness and predictors of treatment discontinuation of long-acting cabotegravir/rilpivirine in virologically suppressed people with HIV: real-life data from the Icona Cohort

Background: Phase 3 studies have shown long-acting (LA) cabotegravir/rilpivirine to be effective and tolerable as maintenance therapy in people with HIV (PWH). However, real-life data on their effectiveness are limited. Methods: All PWH enrolled in the Icona Cohort who started LA cabotegravir/rilpivirine with HIV-RNA < 50 copies/mL were included. Times to treatment discontinuation (TD) and to virological failure (VF50, two consecutive HIV-RNA >50 copies/mL or one >1000 copies/mL followed by ART switch) were estimated by the Kaplan–Meier method. Cox regression models, adjusted for age, sex and mode of HIV transmission and stratified by the centre, were employed. Results: Overall, 583 PWH started LA cabotegravir/rilpivirine. Six VF50 were observed, with a 1 year estimated cumulative probability of virological failure of 1.2% (95% CI, 0.5%–3.0%). Resistance-associated mutations for rilpivirine and cabotegravir were detected in 3/4 and 4/4 participants with VF50, respectively, for which the genotypic resistance test was performed. The 1 year cumulative probability of TD was 11.4% (95% CI, 8.6%–14.9%), mainly caused by toxicity/adverse events (73.2%). Multivariable analysis identified heterosexual intercourse and IV drug use as significant risk factors for TD compared with MSM. Conclusions: This analysis demonstrated the short-term effectiveness of cabotegravir/rilpivirine in a real-life setting showing minimal incidence of virological failure but a notable probability of discontinuation due to toxicity or adverse events

Does Syphilis Increase the Risk of HIV-RNA Elevation >200 Copies/mL in HIV-Positive Patients under Effective Antiretroviral Treatment? Data from the ICONA Cohort

Background:To assess the impact of syphilis infection on the risk of HIV-RNA elevation in people living with HIV (PLWH) with current HIV-RNA ≤50 copies/mL.Setting:The Italian Cohort Naive Antiretrovirals.Methods:All PLWH (2009-2020) under antiretroviral treatment with at least 2 consecutive HIV-RNA values ≤50 copies/mL before the date of syphilis diagnosis and at least 1 HIV-RNA determination after the syphilis event were enrolled. A control group of PLWH without syphilis was matched for mode of HIV transmission. Outcomes were defined using the first HIV-RNA measure in the time window ranging between -2 and +6 months of the diagnosis/index date. The primary outcome used a single value >200 copies/mL to define HIV-RNA elevation associated with risk of transmission. The association between syphilis infection and the protocol defined outcome was evaluated using logistic regression analysis.Results:Nine hundred twenty-six PLWH with a syphilis event were enrolled and matched with a random sample of 1370 PLWH without syphilis. Eighteen of the 926 (1.9%) with syphilis had ≥1 HIV-RNA >200 copies/mL in the window vs. 29/1370 (2.1%) of the not exposed (P = 0.77). In the multivariable analysis adjusted for age, year of diagnosis/index date, and clinical site, syphilis infection was not associated with the risk of HIV-RNA >200 copies/mL (adjusted odds ratio 0.81; 95% confidence interval 0.43-1.52, P = 0.508).Conclusions:We did not find any evidence for an association between syphilis infection and viral elevation >200 copies/mL

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

Effectiveness of dolutegravir-based vs boosted darunavir-based first-line 3-drug regimens in people with HIV with advanced disease: A trial emulation

Background: No randomized comparisons exist between dolutegravir (DTG) and boosted-darunavir (DRV/b) for people initiating treatment with advanced HIV. Methods: Antiretroviral therapy (ART)-naïve people with HIV (PWH) with CD4 < 200 cells/mm3 or AIDS who started a first-line three-drug regimen with DTG or DRV/b were included. The primary outcome was a composite endpoint of newly diagnosed AIDS, serious non-AIDS events (SNAE), death, virological failure (VF), or discontinuation of the anchor drug due to failure or toxicity. A marginal structural Cox regression model was used to estimate the effect of starting DTG vs DRV/b-based regimens. Results: A total of 1323 advanced ART-naïve PWH were included, 895 starting DTG and 428 DRV/b. The unweighted risks of the composite endpoint by 48 months were 21.1% (95% CI: 18.1; 24.1%) for DTG vs 37.9% (95% CI: 32.7; 43.2%) for DRV/b (P < 0.001). First-line treatment with DTG showed a lower risk of experiencing the composite endpoint than DRV/b (wHR of DTG vs DRV/b 0.47, 95% CI: 0.35; 0.64, P < 0.001). Conclusion: Under the stated assumptions, this analysis indicates that in ART-naïve PWH with advanced disease, ART initiation with DTG vs DRV/b-based regimens leads to a 50% reduction in the risk of AIDS/SNAE/death/VF/discontinuation. This observed difference is partly explained by discontinuation of the anchor drug