Integrase strand transfer inhibitor (INSTI) related changes in BMI and risk of diabetes: a prospective study from the RESPOND cohort consortium.

BACKGROUND: With integrase strand transfer inhibitor (INSTI) use associated with increased body mass index (BMI) and BMI increases associated with higher diabetes mellitus (DM) risk, this study explored the relationship between INSTI/non-INSTI regimens, BMI changes, and DM risk. METHODS: RESPOND participants were included if they had CD4, HIV RNA, and ≥ 2 BMI measurements during follow up. Those with prior DM were excluded. DM was defined as a random blood glucose ≥ 11·1 mmol/L, HbA1c ≥ 6·5%/48 mmol/mol, use of antidiabetic medication, or site reported clinical diagnosis. Poisson regression assessed the association between natural log (ln) of time-updated BMI, current INSTI/non-INSTI, and their interactions, on DM risk. RESULTS: Among 20,865 people with HIV included, most were male (74%) and White (73%). Baseline median age was 45 years (IQR 37-52), with a median BMI of 24 kg/m2 (IQR 22-26). There were 785 DM diagnoses with a crude rate of 0·73 (95%CI 0·68-0·78)/100 PYFU. Ln(BMI) was strongly associated with DM (adjusted incidence rate ratio (aIRR) 16·54 per log increase, 95%CI 11·33-24·13; p<0·001). Current INSTI use associated with increased DM risk (IRR 1·58, 95%CI 1·37-1·82; p<0·001) in univariate analyses, only partially attenuated when adjusted for variables including ln(BMI) (aIRR 1·48, 95%CI 1·29-1·71; p<0·001). There was no interaction between ln(BMI), INSTI and non-INSTI use, and DM (p=0·130). CONCLUSIONS: In RESPOND, compared with non-INSTIs, current use of INSTIs was associated with an increased DM risk, which partially attenuated when adjusted for BMI changes and other variables.

Do we Still Need Eligibility Criteria to Recommend PrEP? Impact of National Prescribing Requirements on Retention in Care and Sexually Transmitted Infections Acquisition.

Italian guidelines recommend HIV pre-exposure prophylaxis (PrEP) only upon satisfying strict eligibility criteria. The objective of this study is to evaluate if PrEP candidates attending a community-based service comply with these criteria and whether these prescribing conditions affect retention in care and sexually transmitted infections (STIs) acquisition. A retrospective analysis was performed on PrEP candidates evaluated from January 2019 to June 2022. Data were collected from self-administered questionnaires and clinical files. The population was divided in subjects with 0/1 (0/1 C) and ≥ 2 (≥ 2 C) criteria. Descriptive statistics and non-parametric tests were employed to describe study population. Incidence of PrEP discontinuation and of STIs was estimated per 100 persons-year of follow up (PYFU), and incidence rate ratio (IRR) was calculated. Univariate and multivariable Cox regression analyses were used to evaluate the association strength between PrEP drop out and other variables. The analyses enrolled 659 individuals: 422 individuals were included in 0/1 C, 237 in ≥ 2 C group, respectively. Inconsistent condom use was the most reported prescribing criteria (399 individuals, 60.6%), followed by a previous STI (186 individuals, 28.2%). 0/1 C exhibited lower STIs incidence. PrEP discontinuation was 29% in 0/1 C and 38% in ≥ 2 C (p = 0.031). Cox model revealed that inconsistent condom use was the only prescribing criteria associated to PrEP persistence. The majority of PrEP candidate did not comply with prescribing conditions. Eligibility criteria failed to identify individuals with better retention in care. Our results suggest that Italian guidelines should be updated removing barriers to prescription.

EuCARE-POSTCOVID Study: a multicentre cohort study on long-term post-COVID-19 manifestations.

BACKGROUND: Post-COVID-19 condition refers to persistent or new onset symptoms occurring three months after acute COVID-19, which are unrelated to alternative diagnoses. Symptoms include fatigue, breathlessness, palpitations, pain, concentration difficulties ("brain fog"), sleep disorders, and anxiety/depression. The prevalence of post-COVID-19 condition ranges widely across studies, affecting 10-20% of patients and reaching 50-60% in certain cohorts, while the associated risk factors remain poorly understood. METHODS: This multicentre cohort study, both retrospective and prospective, aims to assess the incidence and risk factors of post-COVID-19 condition in a cohort of recovered patients. Secondary objectives include evaluating the association between circulating SARS-CoV-2 variants and the risk of post-COVID-19 condition, as well as assessing long-term residual organ damage (lung, heart, central nervous system, peripheral nervous system) in relation to patient characteristics and virology (variant and viral load during the acute phase). Participants will include hospitalised and outpatient COVID-19 patients diagnosed between 01/03/2020 and 01/02/2025 from 8 participating centres. A control group will consist of hospitalised patients with respiratory infections other than COVID-19 during the same period. Patients will be followed up at the post-COVID-19 clinic of each centre at 2-3, 6-9, and 12-15 months after clinical recovery. Routine blood exams will be conducted, and patients will complete questionnaires to assess persisting symptoms, fatigue, dyspnoea, quality of life, disability, anxiety and depression, and post-traumatic stress disorders. DISCUSSION: This study aims to understand post-COVID-19 syndrome's incidence and predictors by comparing pandemic waves, utilising retrospective and prospective data. Gender association, especially the potential higher prevalence in females, will be investigated. Symptom tracking via questionnaires and scales will monitor duration and evolution. Questionnaires will also collect data on vaccination, reinfections, and new health issues. Biological samples will enable future studies on post-COVID-19 sequelae mechanisms, including inflammation, immune dysregulation, and viral reservoirs. TRIAL REGISTRATION: This study has been registered with ClinicalTrials.gov under the identifier NCT05531773.

CD4:CD8 Ratio and CD8 Count as Prognostic Markers for Mortality in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC).

BACKGROUND: We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count. METHODS: We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy (ART)-naive adults who started ART during 1996-2010, who were followed from the date they had CD4 count ≥350 cells/µL and were virologically suppressed (baseline). We used stratified Cox models to estimate unadjusted and adjusted (for sex, people who inject drugs, ART initiation year, and baseline age, CD4 count, AIDS, duration of ART) all-cause and cause-specific mortality hazard ratios for tertiles of CD4:CD8 ratio (0-0.40, 0.41-0.64 [reference], >0.64) and CD8 count (0-760, 761-1138 [reference], >1138 cells/µL) and examined the shape of associations using cubic splines. RESULTS: During 276526 person-years, 1834 of 49865 patients died (249 AIDS-related; 1076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11 (95% confidence interval [CI], 1.00-1.25). The association of CD8 count with all-cause mortality was U-shaped: aHR for higher vs middle tertile was 1.13 (95% CI, 1.01-1.26). AIDS-related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. There was little evidence that CD4:CD8 ratio or CD8 count was prognostic for non-AIDS mortality. CONCLUSIONS: In this large cohort collaboration, the magnitude of adjusted associations of CD4:CD8 ratio or CD8 count with mortality was too small for them to be useful as independent prognostic markers in virally suppressed patients on ART.

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir Combination Treatment in Patients with HIV/HCV Co-Infection: Results of an Italian Compassionate Use Program.

Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are at high risk of liver disease progression. We report a favorable safety profile and SVR12 rates of 96.7% among HIV/HCV co-infected patients participating in an Italian compassionate-use program of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV).

Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events. METHODS AND FINDINGS: We included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%-5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints. CONCLUSIONS: We found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV-positive people.

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.

BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013.

Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010-2013. People aged ≥ 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrollment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count < 350/mm(3) or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm(3) (interquartile range (IQR) 193-555/mm(3)), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p < 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02-1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85-0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent.

Immune activation and microbial translocation in liver disease progression in HIV/hepatitis co-infected patients: results from the Icona Foundation study.

BACKGROUND: We evaluated whether immune activation (IA) and microbial translocation (MT) might play a role in accelerating liver disease progression in HIV-HBV/HCV co-infected patients. METHODS: ART-naïve HIV/viral hepatitis co-infected patients from Icona with a CD4 cell count >200/µl and with a known date of prior HIV neg/pos tests and ≥1 plasma sample stored were included in the study. Plasma MT (LPS, sCD14) and IA (IL-6,TNFα) were measured using ELISA while activated CD8 + CD38 + HLA-DR + were measured by flow cytometry, with one measurement being performed for all patients and two measurements for a smaller group of subjects. The association between these biomarkers and the time to i) a single ALT >200 IU/l and ii) a Fib-4 >1.45 was also investigated. A standard survival analysis with robust standard errors was used for all evaluations. Follow-up was censored at patients' last clinical follow-up. RESULTS: We studied 127 HIV-infected hepatitis viruses co-infected patients (118 HCV, 9 HBV). Overall median (IQR) CD4, VL, age were 596/µl (208-1303), 3.8 log10cp/mL (3-4.3), 34 years (22-56). While heightened TNF-α was associated with a 13-fold increased risk of Fib-4 > 1.45 (RH 13.05, 95% CI 2.43-70; p = 0.003), markers of MT did not show an association with liver illness. Interestingly, higher sCD14 was associated with a decreased risk of Fib-4 > 1.45, independently of other biomarkers considered (RH 0.20, 95% CI 0.04-0,9; p = 0.04). CONCLUSIONS: In HIV/hepatitis virus co-infected ART-naive patients, higher TNF-α plasma levels were associated with a 13-fold increase in the risk of progression to a Fib-4 >1.45, suggesting that the pro-inflammatory status in HIV infection might hasten the course of HCV. In view of the fact that sCD14 may hinder the interaction between LPS and the phagocyte membrane CD14, we herewith propose a model which aims to demonstrate that high sCD14 levels might contribute to shelter liver function through the down-regulation of the inflammatory cascade.

SARS-CoV-2 mRNA vaccination and short-term changes in viral load and CD4/CD8 T-cell counts in people living with HIV.

OBJECTIVES: To investigate whether SARS-CoV-2 messenger RNA (mRNA) vaccination has an impact on HIV-related viro-immunological parameters. METHODS: People with HIV (PWH) in the VAXICONA-ORCHESTRA cohort who received one or more doses of SARS-CoV-2 mRNA vaccine and for whom paired measures of immuno-virological markers (viral load, clusters of differentiation [CD]4, and CD8 count 1 month before and after a vaccine dose [VD]) were available were included. Paired t-test and generalized estimating equation linear regression analyses were used to study changes over ± 1 month around the VD. Subgroup analyses were performed. RESULTS: A total of 510 PWH were enrolled: the median age was 55 years (interquartile range 46-60 years), the CD4 and CD8 count were 489 (287-719) and 790 (59-1104) cells/mm3, respectively, and 81% received three VDs. After a median of 28 (3-53) days from VD, CD4 count increased by +15 cells/mm3 (SD ± 129.7, P = 0.001) and CD8 by +12 (±250.5, P = 0.199) and the viral load decreased by -0.11 log10 (±0.88, P = 0.001). Similar results were observed after restricting the analysis to viro-suppressed PWH, with CD4 ≤200/mm3, more than 6 months of antiretroviral therapy before VD and after excluding previous COVID-19. CONCLUSIONS: A small significant increase in CD4 count and a negligible drop in HIV RNA were observed. Our findings are consistent with the hypothesis that SARS-CoV-2 mRNA vaccine can prime CD4 T spike-specific cells, even in the more immuno-compromised PWH.

Association between SARS-CoV-2 RNAemia, skewed T cell responses, inflammation, and severity in hospitalized COVID-19 people living with HIV.

Severe COVID-19 outcomes have been reported in people living with HIV (PLWH), yet the underlying pathogenetic factors are largely unknown. We therefore aimed to assess SARS-CoV-2 RNAemia and plasma cytokines in PLWH hospitalized for COVID-19 pneumonia, exploring associations with magnitude and functionality of SARS-CoV-2-specific immune responses. Eighteen unvaccinated PLWH (16/18 on cART; median CD4 T cell count 361.5/µL; HIV-RNA<50 cp/mL in 15/18) and 18 age/sex-matched people without HIV were consecutively recruited at a median time of 10 days from symptoms onset. PLWH showed greater SARS-CoV-2 RNAemia, a distinct plasma cytokine profile, and worse respiratory function (lower PaO2/FiO2nadir), all correlating with skewed T cell responses (higher perforin production by cytotoxic T cells as well as fewer and less polyfunctional SARS-CoV-2-specific T cells), despite preserved humoral immunity. In conclusion, these data suggest a link between HIV-related T cell dysfunction and poor control over SARS-CoV-2 replication/dissemination that may in turn influence COVID-19 severity in PLWH.

Clinical and laboratory predictors of mpox severity and duration: an Italian multicentre cohort study (mpox-Icona).

BACKGROUND: Severe and prolonged mpox courses have been described during the 2022-2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids. METHODS: This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model. FINDINGS: A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33-44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/µL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14-2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27-2.99, p = 0.002), lymphadenopathy (2.30; 1.52-3.48, p < 0.001), sore throat (2.14; 1.27-3.59, p = 0.004), and peri-anal lesions (2.91; 1.93-4.37, p < 0.001). There was a significant difference (p = 0.003) between the median Ct-value in the upper respiratory tract for patients presenting with either mild (35.15; IQR 28.77-42.01) or severe infection (31.00; 25.00-42.01). The risk of developing severe disease decreased by approximately 5% per Ct increase (0.95; 0.91-0.98; p = 0.005). The disease lasted longer in the case of proctitis (+4.78 days; 1.95-7.61, p = 0.001), sore throat (+3.12; 0.05-6.20, p = 0.046), extended rash (+3.42; 0.55-6.28, p = 0.020), as well as in PLWH with a low CD4 count (+12.51; 6.79-18.22, p < 0.001). INTERPRETATION: The identification of predictors of severe or prolonged disease and the direct association MPXV Ct-value in the upper respiratory tract and disease severity could be useful in establishing proper management and early treatment of new mpox cases. FUNDING: ICONA Foundation; Italian Ministry of Health "Ricerca Corrente Linea 2", INMI Lazzaro Spallanzani IRCCS.

Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes.

OBJECTIVES: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. METHODS: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). RESULTS: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350 cells/µl or less (vs. 351-500 cells/µl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). CONCLUSION: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.

Clinical Outcome and 7-Day Virological Clearance in High-Risk Patients with Mild-Moderate COVID-19 Treated with Molnupiravir, Nirmatrelvir/Ritonavir, or Remdesivir.

INTRODUCTION: We compared the effectiveness and virological clearance (VC) at day 7 (T7) post-treatment with molnupiravir, nirmatrelvir/ritonavir, and remdesivir in SARS-CoV-2-infected patients at high risk (HR) for clinical progression. METHODS: We conducted a retrospective study enrolling HR patients with mild-to-moderate COVID-19 (Jan-Oct 2022) treated with nirmatrelvir/ritonavir or molnupiravir or 3 days of remdesivir. We investigated clinical recovery at T7 (resolution of symptoms for ≥ 72 h or all-cause death), VC at T7 (PCR/antigenic negative nasopharyngeal swab), and median time to VC (days from symptom onset to the first negative swab). Factors associated with VC were investigated by logistic regression. RESULTS: In the study, 92/376 (43.8%) patients received molnupiravir, 150/376 (24.7%) nirmatrelvir/ritonavir, and 134/376 (31.5%) remdesivir. Forty-nine (13%) patients were unvaccinated or incompletely vaccinated. Patients treated with nirmatrelvir/ritonavir were younger and presented immunodeficiencies more frequently; remdesivir was used more commonly in patients hospitalized for other diseases. A high proportion of patients obtained clinical recovery without differences among the therapies (97.5% for molnupiravir, 98.3% for nirmatrelvir/ritonavir, and 93.6% for remdesivir); 12 (3.7%) patients died. Nirmatrelvir/ritonavir was associated with a higher proportion of T7 VC and a shorter time to VC compared to molnupiravir/remdesivir, also after adjustment for age and immunodeficiency (AOR 0.445 RDV vs. NMV-r, 95% CI 0.240-0.826, p = 0.010; AOR 0.222 MNP vs. NMV-r, 95% CI 0.105-0.472, p < 0.001). CONCLUSIONS: SARS-COV-2 antiviral treatments are an excellent therapeutic strategy in HR patients. Nirmatrelvir/ritonavir showed a higher proportion of VC as early as 7 days after treatment, confirming its likely superiority in indirect comparisons.

Nirmatrelvir-ritonavir, molnupiravir, and a 3-day course of remdesivir are antiviral therapies recommended in patients with a mild-to-moderate COVID-19 disease at high risk of clinical progression. Randomized controlled trials and observational studies have shown their efficacy in reducing all-cause mortality and clinical progression. Few data are available about a direct comparison among the three drugs; furthermore, the possible role of nirmatrelvir-ritonavir in increasing viral clearance and in reducing the duration of viral shedding needs to be further elucidated. We thus investigated the effectiveness, safety, and virological clearance 7 days after treatment with these three antivirals in our retrospective cohort. We included in the analysis patients that have received these treatments from January 2022 and October 2022; we observed that patients receiving nirmatrelvir-ritonavir displayed a shorter median time from symptoms' onset to virological clearance and a higher proportion of virological clearance at day 7, also after adjustment for possible confounders, compared to molnupiravir and remdesivir. Our data might help in understanding which COVID-19 patients may benefit mostly from antiviral therapies and in the choice of antiviral therapy.

Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE).

BACKGROUND: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. METHODS AND FINDINGS: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). CONCLUSIONS: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

Does hepatitis C viremia or genotype predict the risk of mortality in individuals co-infected with HIV?

BACKGROUND & AIMS: The influence of HCV-RNA levels and genotype on HCV disease progression is not well studied. The prognostic value of these markers was investigated in HIV/HCV co-infected individuals from the EuroSIDA cohort. METHODS: EuroSIDA is a prospective cohort of 18,295 HIV-1 infected patients in 105 centres across Europe, Israel, and Argentina. All subjects with known HCV antibody (HCVAb) status (n=13,025) were enrolled in the present study. RESULTS: 4044 (31.0%) patients had detectable HCVAb. After adjustment, HCVAb+ patients had an increased incidence of liver-related death (LRD) compared to HCVAb- individuals (IRR 8.90; 95% CI 5.60-14.14, p<0.0001). Information on HCV-RNA was available for 2709 (67.0%) HCVAb+ patients and 2010 (74.2%) were HCV-RNA+. Of 1907 patients with measured HCV genotype, 1008 (52.9%), 62 (3.3%), 567 (29.7%), and 270 (14.2%) were infected with genotype 1, 2, 3 and 4, respectively. Patients with detectable HCV-RNA had similar incidence of non-LRD, but higher incidence of LRD compared to HCVAb+ aviremic patients (adjusted IRR 1.18; 95% CI 0.93-1.50, p=0.17) and (adjusted IRR 2.11; 95% CI 1.30-3.42, p=0.0025), respectively. In patients with HCV viremia, HCV-RNA levels and HCV genotype did not influence the risk of non-LRD or LRD. CONCLUSIONS: HCV seropositive HIV patients had a 9-fold increased risk of LRD compared to patients who were HCV seronegative. Risk of death from any cause or LRD was not influenced by level of HCV viremia or HCV genotype.

Real world efficacy of dolutegravir plus lamivudine in people living with HIV with undetectable viral load after previous failures.

BACKGROUND: Dolutegravir (DTG) +lamivudine (3TC) combination has been found to be as effective as triple therapies, and has been extensively prescribed in clinical practice as a maintenance therapy. We aimed to investigate the effect of previous virological failures (VFs) on virological efficacy. METHODS: The analysis included data of people living with HIV (PLWH) with HIV-RNA ≤50 copies/mL enrolled in an Italian retrospective multicohort study who were switching to DTG+3TC. Primary endpoint was viral rebound (VR; confirmed HIV-RNA ≥50 copies/mL or single HIV-RNA ≥50 copies/mL followed by change of antiretroviral therapies [ART]). Kaplan-Meier curves were used to estimate probabilities of VR based upon histories of previous VFs (single HIV-RNA ≥1000 copies/mL or confirmed HIV-RNA ≥50 copies/mL). A weighted Cox regression model was fitted to estimate the causal hazard ratio (HR) of history of failure on the risk of VR. RESULTS: A total of 966 PLWH were included; 20.1% had a history of previous VF. VR was detected in 23 PLWH. The one-year probability was 1.2% (95% confidence interval [CI], 0.2%-2.2%) in PLWH without previous VF and 3.3% (95% CI, 0.4%-6.2%) in those with ≥1 VF (log-rank P = 0.042). By multivariate analysis adjusted for CD4+ cell count at nadir, duration of virological suppression, and mode of HIV transmission, PLWH with ≥1 previous VF had a higher risk of virological rebound than those without previous VF (adjusted hazard ratio 3.06 [95% CI, 1.00-9.44], P = 0.051). CONCLUSION: Despite the low absolute one-year risk in both groups, real-world data confirmed that PLWH with a previous failure have an increased risk of viral rebound.

Hepatitis delta coinfection in persons with HIV: misdiagnosis and disease burden in Italy.

Hepatitis Delta virus (HDV) causes severe liver disease. Due to similarities in transmission routes, persons living with HIV (PLWH) are at risk of HDV infection. This analysis investigates the prevalence and the long-term clinical outcome of people with HDV in a large cohort of PLWH. We retrieved HBsAg ± anti-HDV positive PLWH enrolled from 1997 to 2015 in the multicentre, prospective ICONA study. The primary endpoint was a composite clinical outcome (CCO = having experienced ≥1 of the following: Fib4 score >3.25; diagnosis of cirrhosis; decompensation; hepatocellular carcinoma or liver-related death). Kaplan-Meier curves and unweighted and weighted Cox regression models were used for data analysis. Less than half of HBsAg positive patients had been tested for anti-HDV in clinical practice. After testing stored sera, among 617 HBV/HIV cases, 115 (19%) were anti-HDV positive; 405 (65%) HBV monoinfected; 99 (16%) undeterminate. The prevalence declined over the observation period. HDV patients were more often males, intravenous drug users, HCV coinfected. After a median of 26 months, 55/115 (48%) developed CCO among HDV+; 98/403 (24%) among HBV monoinfected; 18/99 (18%) in HDV unknown (p < 0.001). After controlling for geographical region, alcohol consumption, CD4 count, anti-HCV status and IFN-based therapies, the association with HDV retained statistical significance [HR = 1.67 (1.15, 2.95; p = 0.025)]. HDV infection among PLWH is underdiagnosed, although HDV entails an high risk of liver disease progression. Because effective drugs to treat HDV are now available, it is even more crucial to identify PLWH at an early stage of liver disease.