Disengagement and reengagement of HIV continuum of care in a single center cohort in northern Italy.

Background: Despite the progress in HIV care, adherence to follow up remains critical. Disengagement impairs the benefit of HIV care and the increasing number of data that associates failed retention with worse outcomes has led public health institutions to consider retention in care as a new tool to fight against HIV pandemic. Objective: The aim of this retrospective, observational study was to estimate the burden of disengagement and reengagement in care in our HIV cohort and to identify the characteristics of our LTFU and reengaged patients. Moreover, we build our cascade of care to explore how closely our center aligned with the "90-90-90" targets. Methods: From the local electronic database we extracted all HIV-infected patients with at least one contact with HIV Clinic between 2012 and 2018 excluding deceased and transferred patients. Our definition of LTFU was based on the lack of any visit during at least 1 year after the last visit. Patients re-engaged were defined as those firstly considered as LTFU patients who subsequently were newly linked to HIV care. Results: About 8% of patients were lost to follow up during the period of study, with a rate of less than 2% per year and 14.1% of them were re-engaged in care. The cascade of care shows, among HIV cases diagnosed between 2011 and 2018, 86.7% patients retained in care, 94.1% of whom were on cART and 95.6% of whom were virologically suppressed. A higher attrition was found among infections diagnosed since 2011 than before 2011, such as women, patients coming from foreign countries and those with poor virological control. Conclusions: The retention rate found in our cohort is high and is in accordance with the 90-90-90 strategy. Nevertheless, understanding disengagement and re-engagement determinants is important to strengthen retention in care in the most fragile population.

The impact of antiretroviral therapy on iron homeostasis and inflammation markers in HIV-infected patients with mild anemia.

BACKGROUND: Anemia is frequent during HIV infection and is predictive of mortality. Although cART has demonstrated to reduce its prevalence, several patients still experience unresolved anemia. We aimed to characterize iron homeostasis and inflammation in HIV-infected individuals with mild anemia in relation to cART. METHODS: In this retrospective cohort study, HIV-infected patients with mild anemia, CD4+ cells > 200/mm3 at baseline, maintaining virological response for 12 months after cART starting were selected within the Standardized Management of Antiretroviral Therapy Cohort (MASTER) cohort. Several inflammation and immune activation markers and iron homeostasis indexes were measured in stored samples, obtained at cART initiation (T0) and 12 months later (T1). Patients were grouped on the basis of hemoglobin values at T1: group A (> 13 g/dl) and B (< 13 g/dl). Wilcoxon rank sum test was used to compare biomarker values. Pearson correlation coefficients were calculated for all variables. RESULTS: cART improved CD4+ and CD8+ cell counts and their ratio, but this effect was significant only in group A. Only these patients had mild iron deficiency at T0 and showed higher transferrin and lower percentage of transferrin saturation than patients of group B, but differences disappeared with cART. cART decreased inflammation in all patients, but group B had higher levels of all markers than group A, reaching statistical significance only for IL-8 values at T1 (16 vs 2.9 pg/ml; p = 0.017). Hepcidin and IL-6 levels did not show significant differences between groups. Hemoglobin levels both at T0 and T1 did not correlate with any marker. CONCLUSIONS: Baseline mild anemia in HIV-infected patients cannot always be resolved with durable efficient cART, possibly due to residual inflammation or immune activation rather than unbalanced iron homeostasis. Further research is needed on cytokine profiling to understand the mechanisms that induce anemia in HIV with suppressive cART.

Risk of Chronic Kidney Disease among Patients Developing Mild Renal Impairment during Tenofovir-Containing Antiretroviral Treatment.

BACKGROUND: Tenofovir (TDF) can cause kidney injury through tubular dysfunction, with or without drop of estimated glomerular filtration rate (eGFR). Whether mild eGFR reductions during treatment should be considered a reason for prompt TDF discontinuation, however, remains unclear. METHODS: Patients with normal pre-TDF eGFR levels, who had developed mild renal impairment (i.e., two consecutive eGFR results between 89-60 ml/min) on TDF, were observed until onset of chronic kidney disease (CKD), defined as two eGFR<60 ml/min 3 to 6 months apart. Multivariable Poisson regression analysis was used to investigate whether outcome was associated with current and cumulative use of TDF (modeled as time-varying covariates). RESULTS: 2023 (29%) out of 6984 patients developed mild renal impairment on TDF. Among them, 191 progressed to CKD. The incidence of CKD did not significantly differ during TDF treatment (2.6 per 100 PYFU; 95%CI 2.2-3.2) or after its discontinuation (2.2 per 100 PYFU; 95%CI 1.8-2.6). However, the rate of CKD was significantly higher among patients continuing with TDF treatment compared to those who had discontinued it within 6 months of occurrence of mild renal impairment (aIRR 4, 95%CI 2.4-6.8). In contrast, among patients who had maintained TDF >6 months despite mild renal impairment, current TDF use was not associated with a significantly higher rate of CKD. Other significant predictors of CKD were older age, intravenous drug use, diabetes, hypertension, lower pre-TDF eGFR, higher eGFR drop since TDF introduction and longer exposure to TDF. CONCLUSIONS: Prompt discontinuation of TDF among patients developing mild renal impairment may prevent further progression of renal damage.

Neutrophil to Lymphocyte Ratio and Cardiovascular Disease Incidence in HIV-Infected Patients: A Population-Based Cohort Study.

Neutrophil to lymphocyte ratio (NLR) has been shown to predict occurrence of cardiovascular events in the general population. The aim of our study was to evaluate the role of NLR to predict major cardiovascular disease (CVD) events in HIV-infected subjects. We performed a retrospective cohort study of HIV-infected patients residing in the Local Health Authority (LHA) of Brescia, northern Italy, from 2000 to 2012. The incidence of CVD events in HIV-positive patients was compared with that expected in the general population living in the same area, computing standardized incidence ratios (SIRs). To evaluate the predictive role of NLR, univariate and multivariate Cox regression models were applied, computing hazard ratios (HRs). A total of 3766 HIV-infected patients (mean age 38.1 years, 71.3% males) were included (person-years 28768.6). A total of 134 CVD events occurred in 119 HIV-infected patients. A 2-fold increased risk (SIR 2.02) of CVD was found in HIV-infected patients compared to the general population. NLR levels measured at baseline and during follow-up were independently associated with CVD incidence, when also adjusting for both traditional CVD risk factors and HIV-related factors (HR 3.05 for NLR≥ 1.2). The area under the receiver operating characteristics (ROC) curve showed a modest, not statistically significant, increase, from 0.81 to 0.83, with addition of NLR to Framingham risk score model covariates. In conclusion an elevated NLR is a predictor of risk CVD in HIV-infected patients, independently from the traditional CVD risk factors.

Systemic Inflammation-Based Biomarkers and Survival in HIV-Positive Subject With Solid Cancer in an Italian Multicenter Study.

BACKGROUND: Recently, some systemic inflammation-based biomarkers have been demonstrated useful for predicting risk of death in patients with solid cancer independently of tumor characteristics. This study aimed to investigate the prognostic role of systemic inflammation-based biomarkers in HIV-infected patients with solid tumors and to propose a risk score for mortality in these subjects. METHODS: Clinical and pathological data on solid AIDS-defining cancer (ADC) and non-AIDS-defining cancer (NADC), diagnosed between 1998 and 2012 in an Italian cohort, were analyzed. To evaluate the prognostic role of systemic inflammation- and nutrition-based markers, univariate and multivariable Cox regression models were applied. To compute the risk score equation, the patients were randomly assigned to a derivation and a validation sample. RESULTS: A total of 573 patients (76.3% males) with a mean age of 46.2 years (SD = 10.3) were enrolled. 178 patients died during a median of 3.2 years of follow-up. For solid NADCs, elevated Glasgow Prognostic Score, modified Glasgow Prognostic Score, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and Prognostic Nutritional Index were independently associated with risk of death; for solid ADCs, none of these markers was associated with risk of death. For solid NADCs, we computed a mortality risk score on the basis of age at cancer diagnosis, intravenous drug use, and Prognostic Nutritional Index. The areas under the receiver operating characteristic curve were 0.67 (95% confidence interval: 0.58 to 0.75) in the derivation sample and 0.66 (95% confidence interval: 0.54 to 0.79) in the validation sample. CONCLUSIONS: Inflammatory biomarkers were associated with risk of death in HIV-infected patients with solid NADCs but not with ADCs.

Predictors of clinical progression among HIV-1-positive patients starting HAART with CD4+ T-cell counts > or =200 cells/mm3.

BACKGROUND: Baseline and follow-up predictors of new AIDS-defining events (ADE) or death among patients who started HAART with CD4+ T-cell counts > or =200 cells/mm3 have rarely been assessed simultaneously. METHODS: A prospective observational cohort study (1996-2002) is reported. HIV-infected patients initiating HAART with a CD4+ T-cell count > or =200 cells/mm3 were studied. Baseline and time-varying factors were tested for the prediction of new ADE/death using Cox regression models. RESULTS: A total of 896 subjects were studied over a median of 5.1 years. The incidence of a new ADE was 1.6 (95% confidence interval 1.3-2.1) per 100 person-years. Among baseline factors, higher CD4+ T-cell counts before HAART were associated with lower risk of ADE/death, but not after adjustment for time-varying factors. On a multivariable analysis including both baseline and time-varying covariates, longer delay from HIV diagnosis to HAART was an independent predictor of ADE/death (per year, hazard ratio [HR] 1.06; P = 0.025) and was independent of CD4+ T-cell count before treatment. Longer time spent with HIV RNA <400 copies/ml (per month, HR 0.96; P = 0.003) and higher latest CD4+ T-cell count (per log2 cells/mm3, HR 0.65; P < 0.001) were found to be protective. CONCLUSIONS: Patients with higher CD4+ T-cell counts before HAART initiation had a better prognosis. However, except for the delay in starting HAART, viroimmunological evolution outweighed the effect of baseline factors. Moreover, suppressing HIV replication for as long as possible could improve the clinical outcome. Prospective randomized clinical trials to assess the optimal timing of HAART initiation are both feasible and urgently needed.

Predictors of AIDS-defining events among advanced naïve patients after HAART.

BACKGROUND: Baseline and follow-up predictors of new AIDS-defining events or death (ADE/death) among patients who started HAART late in their disease history have rarely been assessed simultaneously. METHOD: ADE and mortality rates were assessed using Cox regression analyses. Variables were tested for prediction of ADE/death within the first 3 months of therapy and from month 3, thereafter. RESULTS: 751 HIV-infected patients with <200 CD4+/mm(3) before HAART were followed for a median of 49 months. 207 new ADE occurred (7.06 [6.16-8.10] per 100 patient-years). ADE/deaths clustered within the first 3 months of treatment (106/207, 51%). Higher CD4+ T-cell counts during the follow-up (per log(e) cells/mm(3): hazard ratio [HR] 0.51; 0.41-0.64; p < .001) and use of antiretroviral therapy (HR 0.38; 95% CI 0.21-0.69; p = .001) appeared to protect from ADE/death after month 3. Conversely, increasing follow-up with HIV RNA >400 copies/mL correlated with ADE/death (per month: HR 1.09; 95% CI 1.06-1.12; p = .001). Use of boosted protease inhibitors as first-line HAART and HCV-seropositivity were additional risk factors. Baseline CD4+ T-cell count and HIV RNA had a predominant impact in the first 3 months after HAART initiation. CONCLUSION: A careful monitoring of patients with low CD4+ is particularly necessary during the first few months of HAART. Length and extent of viral replication during the follow-up appeared to induce a significantly higher risk of HIV disease progression afterwards, implying that new drugs and new strategies aimed at ensuring long-term suppression of HIV RNA are of outstanding importance.

Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects.

Shared epidemiological risks have resulted in HIV-infected populations having a high prevalence of hepatitis B virus (HBV) co-infection. Several prospective studies have investigated the impact of HBV co-infection on HIV disease progression; most of them were negative. On the contrary, there is evidence that HIV may modify the natural history of HBV infection. HIV positive subjects have higher rates of HBV chronification, higher HBV replication, lower ALT levels and lower rates of seroconversion to anti-HBe and anti-HBs. The impact of HIV co-infection on the outcome of HBV infection is still controversial, even if some studies have shown an accelerated progression towards decompensated cirrhosis in HIV co-infected subjects. HBV co-infection is a risk factor for severe hepatotoxicity during HAART. Vaccination for HBV is mandatory in nonimmune HIV subjects, however its efficacy in immunosuppressed patients is still controversial. HIV co-infection decreases the effectiveness of Interferon in the treatment of HBV infection. Because of its activity against both HBV and HIV, lamivudine is used in HIV-HBV co-infected patients at doses of 300 mg/daily and as part of an antiretroviral regimen, but the rate of sustained response is poor and HBV strains with mutations associated with lamivudine resistance occur at a rate of 20% per year. Trials of new drugs with activity against HBV, some of them with activity also against HIV, and some of them without cross-resistance with lamivudine, are now underway. Highly Active Anti-Hepatitis B Therapy will probably soon come of age.