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

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability

Do soft tissue augmentation techniques provide stable and favorable peri-implant conditions in the medium and long term? A systematic review

To review the available literature on the medium- and long-term effects of soft tissue augmentation (STA) at implant sites and to explore the effects of the different approaches on clinical-, patient-reported, and health-related parameters. Materials and Methods A comprehensive electronic and manual search was performed to identify prospective clinical studies that assessed the medium- and long-term (≥36 months) outcomes following STA, including number of sites maintaining peri-implant health and number of sites developing peri-implant disease, incidence of complications, stability of the clinical, volumetric, and radiographic parameters, and patient-reported outcome measures (PROMs). Results Fifteen studies were included in the qualitative analysis. STA was performed with either a bilaminar- or an apically positioned flap (APF) approach, in combination with autogenous grafts (free gingival graft [FGG] and connective tissue graft [CTG]) or substitutes (acellular dermal matrix [ADM] and xenogeneic cross-linked collagen matrix [CCM]). An overall high survival rate was observed. Most of the augmented implant sites maintained peri-implant health in the medium and long term, with the incidence of peri-implant mucositis and peri-implantitis ranging from 0% to 50% and from 0% to 7.14%, respectively. The position of the soft tissue margin following APF + FGG and bilaminar approaches involving CTG or CCM was found to be stable over time. No substantial changes were reported for plaque score/index, bleeding on probing/bleeding index, and probing depth between early time points and following visits. CTG-based STA procedures resulted in a stable or increased dimension of keratinized mucosa width (KMW) and mucosal thickness (MT)/volumetric outcomes over time, when compared with early follow-ups. Most of the included studies described stable marginal bone levels at the grafted implant sites over time. No substantial changes for patient-reported outcomes and professionally assessed esthetic results were reported at different time points.Conclusions Implants that received STA showed overall high survival rate and relatively low incidence of peri-implantitis in the medium and long term. Augmented sites seem to maintain the level of soft tissue margin and marginal bone over time, while non-augmented implants may exhibit apical shift of the soft tissue margin. The overall favorable early outcomes obtained with STA are maintained in the medium and long term, with an increase in KMW and MT that may be expected over time at CTG-augmented sites

Association between previous infection with SARS CoV-2 and the risk of self-reported symptoms after mRNA BNT162b2 vaccination: Data from 3,078 health care workers

Background: Health care workers (HCWs) are at high risk of contracting an infection by SARS CoV-2 and thus they are a priority for vaccination. We hereby aim to investigate whether the risk of severe and moderate systemic symptoms (MSS) after vaccination is higher in HCWs with a history of previous COVID-19. Methods: An online questionnaire was offered to the cohort all HCWs undergoing anti-SARS CoV-2 mRNA BNT162b2 vaccination between January 4th and February 9th 2021 in two large tertiary hospitals (ASST Santi Paolo and Carlo) in Milan, Italy. Previous SARS-CoV-2 infection/COVID-19 was recorded. Local and systemic symptoms after each of the two doses were reported. MSS were those either interfering with daily activities or resulting in time off-work. Factors associated to MSS were identified by logistic regression. Findings: 3,078 HCW were included. Previous SARS-CoV-2 infection/COVID-19 occurred in 396 subjects (12·9%). 59·6% suffered from ≥1 local or systemic symptom after the first and 73·4% after the second dose. MSS occurred in 6·3% of cases (14·4% with previous vs 5·1% with no COVID-19 p<0·001) and in 28·3% (24·5% in COVID-19 vs 28·3% no COVID, p = 0·074) after the first and second dose, respectively. Subjects already experiencing COVID-19 had an independent 3-fold higher risk of MSS after the first and a 30% lower risk after the second dose. No severe adverse events were reported. Interpretation: Our data confirm in a real-world setting, the lack of severe adverse events and the short duration of reactogenicity in already infected HCWs. Possible differences in immune reactivity are drivers of MSS among this group of HCWs, as well as among females and younger individuals. Funding: None

Impact of COVID-19 pandemic on retention in care of native and migrant people with HIV in the ICONA cohort

Background: COVID-19 pandemic challenged the UNAIDS 90-90-90 targets. How the COVID-19 pandemic affected HIV retention in care and whether it has disproportionally affected migrant people with HIV (PWH) remained to be investigated. Methods: PWH in ICONA Cohort in follow-up in each of the study periods were included: 01/09/2019-29/02/2020 (pandemic period) and 01/03/2018-31/08/2018 (historical period, as a control). Risk of temporary loss to follow-up (LTFU, defined as no data recorded for a person for one year) was analyzed by logistic regression, with migrant status as the main exposure variable. Difference in difference (DID) analysis was applied to evaluate the effect of COVID-19 pandemic in the different risk of LTFU between natives and migrants. Results: 8864 (17.1% migrants) and 8071 (16.8% migrants) PWH constituted the pandemic and the historical period population, respectively. Proportion of PWH defined as LTFU in the pandemic period was 10.5% in native and 19.6% in migrant PWH. After controlling for age, sex and geographical location of enrolling site, risk of temporary LTFU was higher for migrants than native PWH [adjusted odds ratio 1.85 (95%CI 1.54–2.22)] in pandemic period. In PWH contributing to both periods, LTFU was 9.0% (95% CI 8.3–9.8) in natives vs 17.0% (95% CI 14.7–19.4) in migrants during the pandemic. Instead, LTFU was 1.2% (95%CI 0.9, 1.5) in natives vs 2.2% (95% CI 1.3–3.1) in migrants during the historical period, with a resulting DID of 7.0% (95% CI 4.4–9.6). Conclusions: A greater proportion of LTFU in migrant PWH was observed in both periods, which remained unaltered over time. Interventions to reduce LTFU of migrants are necessary

Impact of HCV Eradication on Lipid Metabolism in HIV/HCV Coinfected Patients: Data from ICONA and HepaICONA Foundation Cohort Study

Objectives: HCV shows complex interactions with lipid metabolism. Our aim was to examine total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) changes in HIV/HCV coinfected patients, after achieving sustained virological response (SVR), according to different HCV genotypes and specific antiretroviral use. Methods: HIV/HCV coinfected patients, enrolled in the ICONA and HepaICONA cohorts, who achieved DAA-driven SVR were included. Paired t-tests were used to examine whether the pre- and post-SVR laboratory value variations were significantly different from zero. ANCOVA regression models were employed to estimate the causal effect of SVR and of PI/r use on lipid changes. The interaction between the effect of eradication and HCV genotype was formally tested. Results: six hundred and ninety-nine HIV/HCV coinfected patients were enrolled. After HCV eradication, a significant improvement in liver function occurred, with a significant decrease in AST, ALT, GGT, and total plasmatic bilirubin. TC and LDL-C significantly increased by 21.4 mg/dL and 22.4 mg/dL, respectively (p < 0.001), after SVR, whereas there was no evidence for a change in HDL-C (p = 0.45) and triglycerides (p = 0.49). Notably, the TC and LDL-C increase was higher for participants who were receiving darunavir/ritonavir, and the TC showed a more pronounced increase among HCV genotype 3 patients (interaction-p value = 0.002). Conclusions: complex and rapid changes in TC and LDL-C levels, modulated by HCV genotype and PI/r-based ART combinations, occurred in HIV/HCV coinfected patients after SVR. Further studies are needed to evaluate the clinical impact of these changes on the long-term risk of cardiovascular disease

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 Naïve Antiretrovirals (ICONA). 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 one 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 and 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

Virological response and retention in care according to time of starting ART in Italy: data from the Icona Foundation Study cohort

OBJECTIVES: To describe: (i) factors associated with rapid and delayed ART initiation; (ii) rates of 12 week virological response; and (iii) virologically controlled retention in care by 1 year from ART initiation according to timing of start in a real-life setting. METHODS: All individuals in the Icona cohort diagnosed with HIV in 2016-17 who initiated ART were grouped according to the time between HIV diagnosis and ART initiation: Group 1, ≤7 days; Group 2, 8-14 days; Group 3, 15-30 days; Group 4, 31-120 days; and Group 5, >120 days. Multivariable logistic regression models were used to identify factors associated with: (i) the probability of rapid (Group 1) and very delayed (Group 5) ART initiation; (ii) the 12 week virological response (by a modified snapshot algorithm); and (iii) the probability of retention in care at 1 year (on ART with HIV-RNA <50 copies/mL). RESULTS: A total of 1247 individuals were included [82 (6.6%) in Group 1, 115 (9.2%) in Group 2, 267 (21.4%) in Group 3, 641 (51.4%) in Group 4 and 142 (11.4%) in Group 5]. Main predictors of rapid ART start (Group 1) were low CD4 cell count and high HIV-RNA at first contact with the infectious diseases centre. There was no association between probability of virological response and timing of ART initiation. Overall, 90% of individuals remained on ART after 1 year, 91% with undetectable HIV-RNA. Participants of Italian nationality, those with higher CD4 cell count and lower HIV-RNA at ART initiation were more likely to be retained in care after 1 year. CONCLUSIONS: In our high-income observational setting, we did not observe differences in the 1 year rate of virological response and retention in care according to timing of ART initiation