Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children.

BACKGROUND: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2-12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children. METHODS: An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. RESULTS: 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported. CONCLUSION: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

Real-World Analysis of Survival and Clinical Events in a Cohort of Italian Perinatally HIV-1 Infected Children From 2001 to 2018.

Background: Combined antiretroviral therapy (cART) has been associated with a steep decrease in mortality and morbidity in HIV-1 infected children. New antiretroviral molecules and drug classes have been developed and the management of HIV-infected children has improved, but recent data on survival are limited. Methods: An observational retrospective study investigating changes in mortality and morbidity was conducted on 1,091 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results: Three hundred and fifty-four (32%) AIDS events and 26 (2%) deaths occurred overtime. Mortality rates decreased from 0.4/100 person-years in 2001-2006 to 0.27/100 person-years in 2007-2012 and 0.07/100 person-years in 2013-2018. Notably, 92% of the dead children were born in Italy, but only 50% were followed-up since birth or within three months of age. Seventy three percent of children had started cART at age ≥6 months; 23% were treated for <30 days before death. B and C clinical events progressively decreased (P < 0.0001). Opportunistic infections significantly decreased over time, but still were the most common events in all the periods (6.76/100 person-years in 2013-2018). In the last period, severe bacterial infections were the most common ones. Cancer rates were 0.07/100; 0.17/100; 0.07/100 person-years in the three periods, respectively. Conclusions: Progressive reductions both in mortality and in rates of class B and C clinical events and OIs have been observed during the cART era. However, deaths were still registered; more than half of dead children were enrolled after birth and had belatedly started cART.

Patients with chronic hepatitis C receiving treatment with direct acting antivirals: How is this population changing?

BACKGROUND AND AIMS: Direct acting antiviral agents (DAAs) have revolutionized the landscape of chronic hepatitis C (CHC) enabling treatment of all those infected. It remains to be determined how the characteristics of those receiving treatment are changing. MATERIALS AND METHODS: We retrospectively analysed all the patients with CHC who received treatment with DAAs in a large referral centre since 01/01/2015. We stratified their demographic, clinical and virological characteristics at baseline and the sustained virological response (SVR) rates according to the year of treatment. RESULTS: In the study were included 2565 patients. During the study period, the yearly proportion of men and cirrhotic patients decreased (p<0.001) whereas mean age increased from 59.8 to 62.2 years old (p=0.04). An increasing trend was observed in the foreign-born patients from 4.3% to 7.9%, without reaching statistical significance. The prevalence of comorbidities had also increased during the study period (p<0.001). Instead, the yearly number of experienced patients decreased significantly (p<0.001) as well as the mean MELD score of cirrhotic patients from 9 to 7.6 (p<0.001). SVR rates increased significantly, from 93.4% in 2015 to 97.1% in 2018 (P<0.05). CONCLUSIONS: The population of patients with CHC receiving DAAs is becoming older and with more comorbidities. Nevertheless, this did not impact SVR rates.

Epi-aortic lesions, pathologic FMD, endothelial activation and inflammatory markers in advanced naïve HIV-infected patients starting ART therapy.

INTRODUCTION: PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV-infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART). PATIENTS AND METHODS: All consecutive naïve patients with CD4 cell count<200/mL starting any PI/r-based or NNRTI-based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi-aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM-1 and VCAM-1) and inflammatory markers (IL-6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co-infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ(2) nonparametric method. RESULTS: In Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200. CONCLUSIONS: Our data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow-up epi-aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM-1 significantly worsens during the period of observation; also VCAM-1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D-dimers and high sensitivity C-reactive protein (hsCRP). IL-6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve-month follow-up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non-specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima-media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.

Performance of liver stiffness measurements by transient elastography in chronic hepatitis.

AIM: To compare results of liver stiffness measurements by transient elastography (TE) obtained in our patients population with that used in a recently published meta-analysis. METHODS: This was a single center cross-sectional study. Consecutive patients with chronic viral hepatitis scheduled for liver biopsy at the outpatient ward of our Infectious Diseases Department were enrolled. TE was carried out by using FibroScan™ (Echosens, Paris, France). Liver biopsy was performed on the same day as TE, as day case procedure. Fibrosis was staged according to the Metavir scoring system. The diagnostic performance of TE was assessed by using receiver operating characteristic (ROC) curves and the area under the ROC curve analysis. RESULTS: Two hundred and fifty-two patients met the inclusion criteria. Six (2%) patients were excluded due to unreliable TE measurements. Thus, 246 (171 men and 75 women) patients were analyzed. One hundred and ninety-five (79.3%) patients had chronic hepatitis C, 41 (16.7%) had chronic hepatitis B, and 10 (4.0%) were coinfected with human immunodeficiency virus. ROC curve analysis identified optimal cut-off value of TE as high as 6.9 kPa for F ≥ 2; 7.9 kPa for F ≥ 3; 9.6 kPa for F = 4 in all patients (n = 246), and as high as 6.9 kPa for F ≥ 2; 7.3 kPa for F ≥ 3; 9.3 kPa for F = 4 in patients with hepatitis C (n = 195). Cut-off values of TE obtained by maximizing only the specificity were as high as 6.9 kPa for F ≥ 2; 9.6 kPa for F ≥ 3; 12.2 kPa for F = 4 in all patients (n = 246), and as high as 7.0 kPa for F ≥ 2; 9.3 kPa for F ≥ 3; 12.3 kPa for F = 4 in patients with hepatitis C (n = 195). CONCLUSION: The cut-off values of TE obtained in this single center study are comparable to that obtained in a recently published meta-analysis that included up to 40 studies.

Emtricitabine/tenofovir in the treatment of HIV infection: current PK/PD evaluation.

INTRODUCTION: Emtricitabine/tenofovir disoproxil fumarate fixed-dose combination (FTC/TDF FDC) is the co-formulation of a nucleoside and a nucleotide, respectively. After oral administration, both drugs exhibit plasma and intracellular half-lives suitable for once-daily dosing. Within the host cells, active metabolites FTC-TP and TFV-DP act as chain terminators to the newly synthesized proviral DNA, showing synergy at enzymatic level (viral reverse transcriptase). When given in HAART combinations, FTC/TDF FDC has a remarkable effectiveness in controlling HIV replication and securing a significant CD4(+) cell recovery. If patients treated with FTC/TDF FDC fail, a lower incidence of TDF-associated K65R resistance mutation seems to develop. Furthermore, cytidine analog-associated M184V is less likely to appear with FTC than with lamivudine when both are given with TDF. FTC and TFV are not metabolized by CYP450 enzymes and are eliminated by the renal route. TFV may accumulate in tubular cells and cause a decrease in GFR and a loss of phosphates. As a onsequence, patients treated with FTC/TDF FCD may experience varied degrees of renal impairment and osteopenia/osteoporosis. AREAS COVERED: This paper has focused on the PK/PD features of FTC and TDF, when given as single agent or when administered as FDC. The interpretation of efficacy/toxicity was guided by PK/PD features. The review of the available literature included also conference presentations and recent guidelines (as of May 2012). EXPERT OPINION: FTC/TDF FDC is a potent and reliable component of most HAART combinations due to its maintained activity across time, as demonstrated in many trials and studies. Toxicity issues (kidney, bone) are still to be entirely elucidated and the drug-induced component well separated from patient- and HIV-related ones. However, the clinical gain associated with the use of FTC/TDF FDC is fully acknowledged by its leading position in most current treatment guidelines.

Churg-Strauss syndrome: a diagnosis not to be forgotten.

Churg-Strauss syndrome (CSS) is a peculiar form of vasculitis with involvement of small- and medium-size arteries, histologically characterized by necrotizing granulomas in vessel walls and in perivascular tissues. The Authors report a case of CSS occurred in a young man being treated with corticosteroids for a diagnosis of asthma. The patient was hospitalized because of fever, diarrhoea and abdominal pain; the first assessment showed leucocytosis and eosinophilia,increase in flogosis indexes and anti-pANCA antibodies positive. A few days later an acute peritonitis with multiple intestinal perforations occurred and a partial resection of small bowel was performed,followed by another resection of an ileal segment because of a new double perforation close to the previous intestinal anastomosis. In the bowel resection pieces necrotizing vasculitis and granulomatous infiltrates involving lymphocytes and eosino- phils were observed. Although the severe intestinal involvement and especially the symptoms necessitating iterative surgery were significant factors of poor prognosis the patient was successfully treated firstly with metylprednisolone only and then with monthly administration of immunosuppressive drugs combined with lower daily dose of steroids. The CSS diagnosis is not to be forgotten althoughits early clinical features can be frequently mistaken for an allergic disease; an early diagnosis can allow to perform the best treatment, to reach the disease remission and to improve the quality of life of the patients.