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.

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.

A Multicenter Phase 2 Randomized Controlled Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients with COVID-19 Pneumonia.

INTRODUCTION: Acute lung injury and acute respiratory distress syndrome are common complications in patients with coronavirus disease 2019 (COVID-19). Poor outcomes in patients with COVID-19 are associated with cytokine release syndrome. Binding of interleukin-8 (CXCL8/IL-8) to its chemokine receptors, CXCR1/2, may mediate this inflammatory process. The aim of this clinical trial was to determine if CXCR1/2 blockade with reparixin can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. The dose and safety of reparixin have been investigated in clinical trials of patients with metastatic breast cancer. METHODS: This was a phase 2, open-label, multicenter, randomized study in hospitalized adult patients with severe COVID-19 pneumonia from May 5, 2020 until November 27, 2020. Patients were randomized 2:1 to receive 1200 mg reparixin orally three times daily or standard of care (SOC) for up to 21 days. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensive care unit admission, and/or use of rescue medication. RESULTS: Fifty-five patients were enrolled between reparixin (n = 36) and SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared with the SOC group (16.7% [95% CI 6.4-32.8%] vs. 42.1% [95% CI 20.3-66.5%], P = 0.02). The sensitivity analysis based on the Cox regression model provided an adjusted hazard ratio of 0.33 with statistical significance lower than 0.05 (95% CI 0.11-0.99; P = 0.047). Reparixin treatment appeared to be well tolerated. CONCLUSION: In patients with severe COVID-19, reparixin led to an improvement in clinical outcomes when compared with the SOC. A larger phase 3 clinical study is needed to confirm these results. TRIAL REGISTRATION: EudraCT identifier, 2020-001645-40; registered May 6, 2020 (retrospectively registered), and clinicaltrials.gov (NCT04794803) on March 8, 2021.

Female gender is associated with long COVID syndrome: a prospective cohort study.

OBJECTIVE: We explored the association between female gender and long COVID syndrome, defined as persistence of physical and/or psychological symptoms for more than 4 weeks after recovery from acute COVID-19 disease. The secondary aim was to identify predictors of long COVID syndrome by multivariable logistic regression analysis. METHODS: This was a single-centre prospective cohort study conducted at San Paolo Hospital in Milan, Italy. We enrolled adult patients who were evaluated at the post-COVID outpatient service of our Infectious Diseases Unit between 15 April 2020 and 15 December 2020. Participants were individuals who had clinically recovered from COVID-19 and in whom virological clearance had occurred. Previous infection by SARS-CoV-2 was microbiologically documented by positivity using a reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab. All enrolled patients underwent blood tests and a comprehensive medical examination at follow-up. Individuals were interviewed about resolved and persisting symptoms and were asked to fill in two questionnaires to allow assessment of the Hospital Anxiety and Depression symptoms (HADS) score and of the Impact of Event Scale-Revised (IES-R) score. RESULTS: A total of 377 patients were enrolled in the study. The median time from symtpom onset to virological clerance was 44 (37-53) days. A diagnosis of long COVID syndrome was made in 260/377 (69%) patients. The most common reported symptoms were fatigue (149/377, 39.5%), exertional dyspnoea (109/377, 28.9%), musculoskeletal pain (80/377, 21.2%) and "brain fog" (76/377, 20.2%). Anxiety symptoms were ascertained in 71/377 (18.8%) individuals, whereas 40/377 (10.6%) patients presented symptoms of depression. Post-traumatic stress disorder (defined by a pathological IES-R score) was diagnosed in one-third of patients (85/275, 31%). Female gender was independently associated with long COVID syndrome at multivariable analysis (AOR 3.3 vs. males, 95% CI 1.8-6.2, p < 0.0001). Advanced age (adjusted (A)OR 1.03 for 10 years older, 95% CI 1.01-1.05, p 0.01) and active smoking (AOR 0.19 for former smokers vs. active smokers, 95% CI 0.06-0.62, p 0.002) were also associated with a higher risk of long COVID, while no association was found between severity of disease and long COVID (AOR 0.67 for continuous positive airway pressure (CPAP)/non-invasive mechanical ventilation (NIMV)/orotracheal intubation (OTI) vs. no 02 therapy, 95% CI 0.29-1.55, p 0.85). DISCUSSION: Factors that were found to be associated with a higher risk of developing "long COVID" syndrome were female gender, older age and active smoking, but not severity of the acute disease. Individuals affected by SARS-CoV-2 infection with the aforementioned features should be early identified and involved in follow-up programmes.

Predictors of low ovarian reserve in cART-treated women living with HIV.

ABSTRACT: Ovarian dysfunction and lower circulating anti-Müllerian hormone (AMH) feature women living with HIV (WLWH). Because treated human immunodeficiency virus (HIV) infection is characterized by a pro-inflammatory/oxidative phenotype resulting in residual comorbidity, we sought to investigate possible associations between plasma AMH and markers of inflammation, immune activation/senescence/exhaustion, oxidative stress as well as comorbidities in a cohort of combined anti-retroviral therapy (cART)-treated WLWH versus age-matched HIV-uninfected, healthy women.Eighty WLWH on effective cART aged 25 to 50 years and 66 age-matched healthy women were enrolled. We measured: plasma AMH, IL-6, reactive oxygen species modulator 1 (ROMO1) (ELISA); plasma tumor necrosis factor α, IL-10, soluble vascular cell adhesion molecule 1, osteopontin (Luminex); CD4/CD8 activation (CD38/CD69), apoptosis (CD95), exhaustion (PD1), maturation (CD45RA/CD45R0/CD127/CCR7), recent thymic emigrants (CD31/CD103) (flow cytometry). Mann Whitney and chi-squared tests were used. Univariate and multivariate logistic regression analyses were used to assess factors associated with low AMH (≤1 ng/mL).Compared to healthy women, WLWH were more frequently non-Caucasian, drug/alcohol abusers, with history of late menarche, lower hormonal contraceptive use, with higher gravidity and lower parity. WLWH showed significantly lower AMH (P = .004) as well as higher ROMO1 (P = .0003) and tumor necrosis factor α (P < .0001). The multivariate analyses revealed ROMO1 (adjusted odds ratio [AOR]: 1.42, P = .03) and HIV infection (AOR: 8.1, P = .0001) as independently associated with low AMH. The logistic regression model with both HIV status and ROMO1 (a marker of oxidative stress) confirmed HIV as the only predictor of low AMH (AOR: 17, P = .0003).Despite effective cART, WLWH showed lower AMH compared to age-matched peers, indicating pre-mature ovarian ageing. Both HIV and oxidative stress are independently associated with low AMH, emphasizing the impact of HIV-associated oxidative stress on reproductive aging.

Decrease in Incidence Rate of Hospitalizations Due to AIDS-Defining Conditions but Not to Non-AIDS Conditions in PLWHIV on cART in 2008-2018 in Italy.

BACKGROUND: We aimed to describe the change in the incidence and causes of hospitalization between 2008 and 2018 among persons living with HIV (PLWHIV) who started antiretroviral therapy (ART) from 2008 onwards in Italy. METHODS: We included participants in the ICONA (Italian Cohort Naïve Antiretrovirals) cohort who started ART in 2008. All the hospitalizations occurring during the first 30 days from the start of ART were excluded. Hospitalizations were classified as due to: AIDS-defining conditions (ADC), non-ADC infections and non-infections/non-ADC (i.e., cardiovascular, pulmonary, renal-genitourinary, cancers, gastrointestinal-liver, psychiatric and other diseases). Comparisons of rates across time were assessed using Poisson regression. The Poisson multivariable model evaluated risk factors for hospitalizations, including both demographic and clinical characteristics. RESULTS: A total of 9524 PLWHIV were included; 6.8% were drug users, 48.9% men-who-have sex with men (MSM), 39.6% heterosexual contacts; 80.8% were males, 42.3% smokers, 16.6% coinfected with HCV and 6.8% with HBV (HBsAg-positive). During 36,157 person-years of follow-up (PYFU), there were 1058 hospitalizations in 747 (7.8%) persons; they had HIV-RNA >50 copies mL in 34.9% and CD4 < 200/mmc in 27%. Causes of hospitalization were 23% ADC, 22% non-ADC infections, 55% non-infections/non-ADC (11% cancers; 9% gastrointestinal-liver; 6% cardiovascular; 5% renal-genitourinary; 5% psychiatric; 4% pulmonary; 15% other). Over the study period, the incidence rate (IR) decreased significantly (from 5.8 per 100 PYFU in 2008-2011 to 2.21 per 100 PYFU in 2016-2018). Age > 50 years, intravenous drug use (IDU), family history of cardiovascular disease, HIV-RNA > 50, CD4 < 200, were associated with a higher hospitalization risk. CONCLUSIONS: In our population of PLWHIV, the rate of hospitalization decreased over time.

Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium.

OBJECTIVES: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. METHODS: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/µL. RESULTS: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04). CONCLUSION: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Serious clinical events in HIV-positive persons with chronic kidney disease.

OBJECTIVES: Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited. DESIGN: Prospective cohort study. METHODS: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 ml/min per 1.73 m or 25% eGFR decrease when eGFR ≤ 60 ml/min per 1.73 m) were followed to incident serious clinical events (SCE); end stage renal and liver disease (ESRL and ESLD), cardiovascular disease (CVD), AIDS-defining and non-AIDS-defining malignancies (NADM), other AIDS or death, 6 months after last visit or 1 February 2016. Poisson regression models considered associations between SCE and modifiable risk factors. RESULTS: During 2.7 (IQR 1.1-5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE [incidence rate 68.9/1000 PYFU (95% confidence interval 63.4-74.4)] with 8.3% (6.9-9.0) estimated to experience any SCE at 1 year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD [65.9 (43.8-100.9)] and death [4.8 (4.3-5.3)]. Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, whereas dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR less than 30 ml/min per 1.73 m predicted CVD and death and low BMI predicted other AIDS and death. CONCLUSION: In an era where many HIV-positive persons require less monitoring because of efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

Differences in Virological and Immunological Risk Factors for Non-Hodgkin and Hodgkin Lymphoma.

Background: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk. Methods: Data from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided. Results: Among 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs > 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs < 50 copies/mL = 1.97, 95% CI = 1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI = 1.92 to 4.41) were associated with NHL only. Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL. Conclusions: CD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk.

High-density lipoprotein-cholesterol levels and risk of cancer in HIV-infected subjects: Data from the ICONA Foundation Cohort.

Investigation of the relationship between high-density lipoprotein-cholesterol (HDL-c) and the risk of developing cancer in a prospective cohort of human immunodeficiency virus (HIV)-infected patients.The Italian Cohort of Antiretroviral-naïve Patients Foundation Cohort is an Italian multicenter observational study recruiting HIV-positive patients while still antiretroviral treatment-naïve, regardless of the reason since 1997.Patients with at least 1 HDL-c value per year since enrollment and one such value before antiretroviral treatment initiation were included. HDL-c values were categorized as either low (<39 mg/dL in males or <49 mg/dL in females) or normal. Cancer diagnoses were classified as AIDS-defining malignancies (ADMs) or non-AIDS-defining malignancies (NADMs). Kaplan-Meier curves and Cox proportional-hazards regression models were used.Among 4897 patients (13,440 person-years of follow-up [PYFU]), 104 diagnoses of cancer were observed (56 ADMs, 48 NADMs) for an overall incidence rate of 7.7 (95% confidence interval [CI] 6.3-9.2) per 1000 PYFU.Low HDL-c values at enrollment were associated with higher risk both of cancer (crude hazard ratio [HR] 1.72, 95% CI 1.16-2.56, P = 0.007) and of NADM (crude HR 2.50, 95% CI 1.35-4.76, P = 0.003). Multivariate analysis showed that the risk of cancer diagnosis was higher in patients with low HDL-c values (adjusted HR [AHR] 1.87, 95% CI 1.18-2.95, P = 0.007) in older patients, those patients more recently enrolled, and in those with low current cluster of differentiation 4+ levels, and/or high current HIV-ribonucleic acid.The multivariate model confirmed an association between HDL-c (AHR 2.61, 95% CI 1.40-4.89, P = 0.003) and risk of NADM.Low HDL-c is an independent predictor of cancer in HIV-1-infected subjects.

Is nelfinavir exposure associated with cancer incidence in HIV-positive individuals?

OBJECTIVE: Nelfinavir exhibits potent anticancer properties against a range of tumours. However, in 2006/2007, nelfinavir supplies were accidently contaminated with a carcinogen. This analysis investigated the association between nelfinavir use and cancer risk in HIV-positive persons. DESIGN: Observational cohort study. METHODS: D:A:D study data was analysed using Poisson regression models to examine associations between cancer incidence and cumulative nelfinavir exposure, current nelfinavir exposure, and exposure to nelfinavir between 1 July 2006-30 June 2007. RESULTS: A total of 42 006 individuals (50% white, 73% male) contributed 303 005 person-years of follow-up between 1 January 2004 and 1 February 2014. At study enrolment, median age was 40 [interquartile range (IQR) 33-46] years and 8305 individuals had a history of nelfinavir use [median duration 1.7 (IQR 0.7-3.4) years]. During follow-up, nelfinavir was used by 2476 individuals for a median of 1.7 (IQR 0.7-3.8) years; 1063 were exposed to nelfinavir between 1 July 2006 and 30 June 2007. Overall, 2279 cancers were diagnosed at a rate of 0.75 [95% confidence interval (95% CI) 0.72-0.78] per 100 person-years. Neither greater cumulative exposure to nelfinavir [adjusted risk ratio (aRR) 0.93 for every additional 5 years, 95% CI 0.82-1.06, P = 0.26] nor current use of nelfinavir (aRR 0.98 vs other protease inhibitor use, 95% CI 0.68-1.41, P = 0.92) were associated with cancer risk. The adjusted risk of cancer for participants exposed to nelfinavir between 1 July 2006 and 30 June 2007 compared to those receiving other treatment over this period was 1.07 (95% CI 0.78-1.46, P = 0.68). CONCLUSION: Nelfinavir use was not associated with a lower cancer incidence than other protease inhibitor regimens. As of February 2014, exposure to the 2006/2007 contamination of nelfinavir does not appear to be associated with increased cancer incidence.

Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons.

OBJECTIVES: Although several antiretroviral drugs, including the d-drugs stavudine (d4T) and didanosine (ddI), may cause biomarker-defined hepatotoxicity, their association with clinically defined end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) remains unknown. DESIGN: Prospective cohort study. METHODS: Data collection on adverse events of anti-HIV drugs study (D:A:D) participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or α-fetoprotein along with imaging), death, 6 months after last visit or 1 February 2014. Associations between ESLD/HCC and cumulative use of individual antiretrovirals were investigated using Poisson regression adjusting for potential confounders. RESULTS: During a median follow-up of 8.4 years, 319 ESLD/HCC cases occurred [incidence 1.01/1000 person-years (95% confidence interval 0.90-1.12)] with a 1-year mortality rate of 62.6%. After adjustment, cumulative (per 5 years) exposure to d4T [relative rate 1.46 (95% confidence interval 1.20-1.77)], ddI [1.32 (1.07-1.63)], tenofovir [TDF, 1.46 (1.11-1.93)] and (fos)amprenavir [APV; 1.47 (1.01-2.15)] was associated with increased ESLD/HCC rates. Longer exposure to emtricitabine [0.51 (0.32-0.83)] and nevirapine [0.76 (0.58-0.98)] were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation. CONCLUSION: Cumulative use of d4T, ddI, TDF and APV were independently associated with increased ESLD/HCC rates, and intensified monitoring of liver function should hence be considered among all individuals exposed for longer time periods. The use of d-drugs should furthermore be avoided, where there are alternatives available, and focus should be put on those with longer-term d-drugs exposure who remain at increased ESLD/HCC risk. The unexpected, and viral hepatitis-independent, TDF association calls for further investigations.

An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: The Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study.

BACKGROUND: With the aging of the population living with HIV, the absolute risk of cardiovascular disease (CVD) is increasing. There is a need to further facilitate the identification of persons at elevated risk in routine practice. METHODS AND RESULTS: Prospective information was collected on 32,663 HIV-positive persons from 20 countries in Europe and Australia, who were free of CVD at entry into the Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Cox regression models (full and reduced) were developed that predict the risk of a global CVD endpoint. The predictive performance of the D:A:D models were compared with a recent CVD prediction model from the Framingham study, which was assessed recalibrated to the D:A:D dataset. A total of 1010 CVD events occurred during 186,364.5 person-years. The full D:A:D CVD prediction model included age, gender, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, high-density lipoprotein, CD4 lymphocyte count, cumulative exposure to protease- and nucleoside reverse transcriptase-inhibitors, and current use of abacavir. A reduced model omitted antiretroviral therapies. The D:A:D models statistically significantly predicted risk more accurately than the recalibrated Framingham model (Harrell's c-statistic of 0.791, 0.783 and 0.766 for the D:A:D full, D:A:D reduced, and Framingham models respectively; p < 0.001). The D:A:D models also more accurately predicted five-year CVD-risk for key prognostic subgroups. CONCLUSIONS: An updated, easily recalibrated, global CVD-risk equation tailored to HIV-positive persons was developed using routinely collected CVD risk parameters and incorporating markers on immune function (CD4 lymphocyte count), and exposure to antiretroviral therapies. The estimated CVD risk can be used to quantify risk and to guide preventive care.

CD4 cell count and the risk of infective and non-infective serious non-AIDS events in HIV-positive persons seen for care in Italy.

INTRODUCTION: Serious non-AIDS events (SNAE) are frequent in HIV patients receiving cART. Current CD4 count was shown to be more strongly associated with infective compared to not-infective SNAE and unable to predict cardiovascular events. We investigated the relationship between baseline and current CD4 count and the risk of both infective and non-infective SNAE in HIV-positive patients according to current ART use. METHODS: We included all HIV-positive persons enrolled in the ICONA Foundation Study cohort who had at least one follow-up visit. SNAE were grouped in infective (pneumonia, sepsis, endocarditis and meningitis) and non-infective (malignancies, chronic kidney disease, cardiovascular events, hepatic events and pancreatitis) aetiology. Incidence of these event groups were calculated overall and according to baseline and current CD4 count (grouped as 0-200, 201-350, 351-500, 501-750, and >750 cells/mm(3)). Participants' follow-up accrued from the date of enrolment (baseline) to a diagnosis of SNAE or their last visit. An event was defined the first time one of the considered SNAE occurred so that each person contributed a single event. A Poisson regression model for each of the two endpoints was used. RESULTS: A total of 10,822 patients were included (25.3% females, 38.2% heterosexuals) and 26.6% had hepatitis co-infections. Median age was 36 (IQR 31-42) years. Overall, 423 not-infective and 385 infective SNAE were included. The most frequent non-infective SNAE were malignancies (n=202) and the most frequent infective SNAE were pneumonia (n=289). Crude rates of non-infective SNAE were 0.78, 1.08 and 0.80/100 PYFU, and those of infective SNAE were 1.00, 0.51 and 0.66/100 PYFU in ART naive, currently off and currently on ART patients, respectively. Higher current CD4 count was associated with reduced risk of both infective and non-infective SNAE in naives and in patients on ART (Table 1). The association was less strong in the group which suspended ART (for non-infective SNAE the p value for interaction between current log-CD4 and ART-status, p=0.004). Conversely, we found no association between baseline CD4 count and risk of non-infective SNAE in people treated with ART (p value for interaction = 0.0001). When CVD were considered separately, there was no association with CD4 count (not shown). CONCLUSIONS: Our findings show that, differently from ART naive, in ART-treated patients, non-infective SNAE are predicted by current but not by baseline CD4, suggesting that immune restoration is crucial to prevent these events.

Increased incidence of sexually transmitted diseases in the recent years: data from the ICONA cohort.

INTRODUCTION: Sexually transmitted diseases (STDs) data collected in HIV+ patients could be used as indicator of risky sexual behaviour possibly linked to HIV transmission. We described the STDs incidence over time and identified higher incidence factors. METHODOLOGY: All patients in the ICONA Foundation Study enrolled after 1998 were included. STDs considered: any-stage syphilis, human papilloma virus (HPV) diseases, gonococcal and non-gonococcal urethritis, herpes simplex virus (HSV) genital ulcers, vaginitis and acute hepatitis B virus (HBV), hepatitis A virus (HAV), and hepatitis C virus (HCV) infections (only for non-IVDU (intravenous drug user) patients). STDs incidence rate (IR): number of STDs divided by person years of follow-up (PYFU). Calendar periods: 1998-2002, 2003-2007 and 2008-2012. Predictors of STDs occurrence were identified using Poisson regression and sandwich estimates for the standard errors were used for multiple STD events. RESULTS: Data of 9,168 patients were analyzed (median age 37.3 (SD=9.3), 74% male, 30% MSM). Over 46,736 PYFU, 996 episodes of STDs were observed (crude IR 17.3/1,000 PYFU). Median (IQR) CD4/mmc and HIV-RNA/mL at STD: 433 (251-600) and 10,900 (200-63,000). Highest crude IRs were observed for any-stage syphilis (3.95, 95% CI 3.59-4.35), HPV diseases (1.96, 1.71-2.24) and acute hepatitis (1.72, 1.49-1.99). At multivariable analysis (variables of adjustment shown in Figure 1), age (IRR 0.82 per 10 years younger, 95% CI 0.77-0.89), MSM contacts (IRR 3.03, 95% CI 2.52-3.64 vs heterosexual) and calendar period (IRR 1.67, 95% CI 1.42-1.96, comparing 2008-2012 with 1998-2002) significantly increased the risk of acquiring STDs. Moreover, having a HIV-RNA >50 c/mL (IRR 1.44, 95% CI 1.19-1.74 vs HIV-RNA <50 c/mL) and current CD4+ cell count <100/mmc (IRR 4.66, 95% CI 3.69-5.89, p<0.001 vs CD4+ cell count >500) showed an increased risk of STDs. Being on ARV treatment significantly reduced the risk of developing an STD (IRR 0.37, 95% CI 0.32-0.43) compared to ART-naïve people, even in the situation of temporary interruption of treatment (IRR 0.51, 95% CI 0.39-0.43) (see Figure 1). CONCLUSIONS: The overall incidence of STDs has been increasing in the recent years. Interventions to prevent STDs and potential further spread of HIV infection should target the recently HIV diagnosed, the young population and MSM. Being on ARV treatment (potentially an indicator of whether a person is regularly seen for care) seems to reduce the risk of acquiring STDs independently of its viro-immunological effect.

Factors associated with HPV-DNA clearance in a cohort of HIV-positive patients: role of cART and gender.

INTRODUCTION: We aimed to assess any factors associated with dysplasia regression and with HPV clearance in a cohort of HIV+ patients, with particular focus on cART and gender. METHODS: Asymptomatic HIV+ patients of the San Paolo Infectious Disease (SPID) cohort who underwent anoscopy/gynaecological evaluation were enrolled. Anal/cervical brushing were analyzed for: HPV-PCR detection/genotyping (HR-HPV), cytologic abnormalities (Bethesda System 2001: LSIL-HSIL). Demographics and HIV-related parameters were evaluated at baseline. Activated CD8+/CD38+ lymphocytes were measured (flow citometry). Patients were examined at baseline (T0) and at 12-18 months visit (T1). HPV clearance was defined as negativisation of HPV at T1; SIL regression (SIL-R) and progression (SIL-P) were defined as change from HSIL/LSIL to a lower-grade/absence of dysplasia and as change from absence of HSIL/LSIL to a higher-grade dysplasia at T1, respectively. Mann Whitney test, Chi-square test and multivariate logistic regression were used. RESULTS: A total of 189 patients were examined, 60 (32%) were women. One hundred fifty patients (79%) were HPV+, 113 (75%) harboured HR-HPV; 103 (68%) showed LSIL/HSIL at T0 (32% of women and 65% of men) (all were HPV-positive). No differences in demographics and HIV-related markers were found between patients with SIL-P (33, 41%) and patients with SIL-R (47, 59%). HPV+ patients who cleared HPV (28, 18%) were found to be more frequently female, heterosexual infected, more frequently on cART and with lower Log10 HIV-RNA and lower levels of CD8+/CD38+ % compared with HPV persistence group (Table 1). CONCLUSIONS: Close follow-up of HPV and SIL should be promoted particularly in men and in untreated individuals. We cannot exclude behavioural variables linked to risky sex and reinfection.

Determinants of use of the fixed dose combination emtricitabine/rilpivirine/tenofovir (Eviplera) in HIV-infected persons receiving care in Italy.

INTRODUCTION: Emtricitabine/rilpivirine/tenofovir (EVP) is a fixed-dose combination of antiretrovirals (ARV) approved by the European Medicines Agency in November 2011 and introduced in Italy in February 2013. It is a once-a-day single tablet and is licensed in Europe for use only in ARV-naïve patients with a viral load (VL) ≤100,000 copies/mL. OBJECTIVE: To identify factors that may be associated with the use of EVP as first-line regimen in HIV-infected individuals starting cART from ARV-naïve in Italy. METHODS: Clinical sites in ICONA Foundation Study in which ≥1 person had started EVP were selected for this analysis. From these we included all patients who started an EVP-based cART regimen as well as those starting other cART regimens after the date of introduction of EVP at the site (after February 2013 in any case) and with a VL ≤100,000 copies/mL from ARV-naïve. Characteristics at the time of starting cART were compared using chi-square test and unadjusted and adjusted logistic regression analysis. Factors investigated included: gender, mode of HIV transmission, time from HIV diagnosis, CD4 count, nation of birth, AIDS, HCV-status, age, CD8 count, VL, diabetes, smoking, total and HDL cholesterol, eGFR, blood glucose, level of education and employment and site location. Factors showing unadjusted associations with a p-value of 10% or smaller, were retained in the multivariable model. RESULTS: We identified 183 patients starting EVP and 173 starting the control regimen from 23 sites. The number of patients starting EVP included at each site ranged from 1 to 12 and the number of those starting the control regimen was similar. The most frequently used drugs in the concurrent group were: TDF (75%), FTC (74%), DRV (39%), ATV/r (26%), LPV/r (9%), EFV (13%) and RAL (14%). In univariable analysis, there were differences in median CD4 count (390 cells/mm(3) in EVP versus 348 in controls, p=0.002), time from HIV diagnosis to starting cART (11 versus 3 months, p=0.001) and prevalence of students (6% versus 3%, p=0.07). No differences were observed for all other factors examined. The table shows estimates of the odds ratios (OR) for factors included in the multivariable model. CONCLUSIONS: CD4 count was higher in EVP-treated patients compared to controls. Guidelines suggest avoiding initiation of EVP in presence of high VL, possibly explaining this residual difference in CD4. There was also a tendency to prescribe EVP to people with perceived lower adherence or hesitant to start or perhaps with a slow progressing disease.