Long-term maintenance of virologic suppression in native and migrant HIV-1 naïve patients: an Italian cohort study.

Little is known about long-term maintenance of virologic suppression in HIV migrants in Italy. The study aims to compare virologic failure rates and associated factors among antiretroviral therapy (ART)-naïve migrants and natives enrolled in the ARCA database since 2007 who achieved virologic suppression within 18 months from the beginning of the ART. Kaplan-Meier method assessed the probability of virologic suppression and failure. Cox regression model was used for multivariate analysis. Of 2515 patients, 2020 (80.3%) were Italian, 286 (10.6%) migrants from low-income countries, of whom 201 (75.0%) from Africa, and 227 (9.0%) from high-income-countries. The median follow-up was 4.5 years (IQR 2.5-7). No difference was observed in the time of achievement of virological suppression in the three groups (log-rank: p = 0.5687). Higher probability of virologic failure was observed in Africans compared to Italians, to patients from high-income-countries and from low-income-countries other than Africans (Log-rank = p < 0.001). In the adjusted analysis, a higher virologic failure risk was found in Africans only compared to Italians. [HR 4.01; 95% CI 2.44-6.56, p < 0.001]. In Italy, African migrants are less likely to maintain virologic suppression compared to natives and other migrants. Targeted interventions could be needed for foreigners, especially for Africans.

A rare hepatic mass in an Italian resident.

BACKGROUND: Amebiasis is a rare condition in developed countries but epidemiologically growing. Clinical manifestation may range from asymptomatic to invasive disease, amoebic liver abscess being the most common manifestation. We report a peculiar case of left hepatic amoebic liver abscess in a patient without a well-known source of infection and presenting with left portal vein thrombosis. CASE PRESENTATION: Patient, working as longshoreman, presented with complaints of remittent-intermittent fever lasting from 2 weeks. Physical examination was normal. Blood tests showed mild anemia, neutrophilic leukocytosis and elevated inflammation markers. Chest x-rays was normal. Abdominal ultrasound showed multiple hypoechoic liver masses. CT-scan of abdomen showed enlarged left liver lobe due to the presence of large abscess cavity along with thrombosis of left portal vein. The indirect hemagglutination test for the detection of antibodies to Entamoeba histolytica (Eh) was positive. Ultrasound-guided percutaneous drainage revealed "anchovy sauce" pus. Metronidazole and a follow up imaging at 3 months showed resolution of abscess cavity. CONCLUSION: This case shows that amoebic liver abscess is possible even in first world country patients without travel history. Left sided abscess and portal vein thrombosis are rare and hence reported.

The Ligurian HIV Network: How Medical Informatics Standards Can Help Clinical Research.

Integrating evidence from systematic research in daily clinical practice is one of the pillars of evidence-based medicine. Electronic data capture tools simplify data collection from different centers and supports the management of multicenter clinical trials. The Ligurian HIV Network (LHN) is one such tool, originating from a regional effort to integrate clinical trial capabilities for HIV and other chronic infectious diseases. In order to manually collect a complete report of all clinical tests on patients enrolled in a trial, a strenuous human effort and the allocation of great resources would be necessary. Moreover, the risk of error in a manual system is very high. The proposed system automatically extracts clinical data from the EHR of three hospitals of the LHN in a standardized way, and enhance their re-use in clinical trials. Through dedicated questionnaires, physicians reported a strongly positive feedback about the efficacy of the platform in supporting clinical research.

Predictors of retention in care in HIV-infected patients in a large hospital cohort in Italy.

Retention in care is a key feature of the cascade of continuum of care, playing an important role in achieving therapeutic success and being crucial for reduction of HIV transmission. The aim of this study was to evaluate the rate of retention in care in a large referral centre in the North of Italy and to identify predictors associated with failed retention. All new HIV-infected subjects were consecutive enrolled from 1 January 2008 to 31 December 2014. Demographics, immune-virological status, hepatitis co-infection and timing of initiation of combined antiretroviral therapy (cART) data were collected at baseline and at the time of last observation. Failed retention in care was defined as lack of laboratory data, clinical visits and drug dispensation for more than 6 months from the last visit. Cox regression analysis was used. Multivariate analysis of variables with P<0.05 in univariate analysis was performed. We enrolled 269 patients (mean age 46.1 years). Males were 197 (73%), Italian 219 (81%) with mean length of disease of 5.1 years. cART was prescribed for 257 patients (95%). The rate of retention in care was 78.4% and the rate of virological suppression was 75%. Predictors of being loss to follow-up were foreign origin (P = 0.048), CD4+ count <200/mmc (P = 0.001) and not being treated for HIV infection (P = 0.0004). Predictors of cART efficacy were shorter duration of HIV infection and baseline HIV-RNA <100 000 copies/ml. These findings underline the necessity to improve retention in care by identifying groups at increased risk of being loss to follow-up. Retention in care of vulnerable population is crucial to reach 90-90-90 UNAIDS endpoint.

Genetic polymorphisms of IL28b gene as predictors of response to dual therapy in genotypes 1 and 4-HCV and HIV/HCV-infected patients.

We describe the genotypes and allele distribution of interleukin 28B (IL28B) rs12979860 and rs8099917 single nucleotide polymorphisms (SNPs) in hepatitis C virus (HCV) G1-4 infected patients, to assess predictive ability and to determine whether the combined determination of two IL28B SNPs might improve sustained virologic response (SVR) prediction of both in HCV mono- and HIV/HCV co-infected patients. IL28B SNPs were genotyped in 269 patients, 181 mono- and 88 co-infected, treated with pegylated interferon and ribavirin. Data stratified by HCV mono- and HCV/HIV co-infected patients showed that 58% and 31% of the rs12979860CC carriers and 49% and 21% of the rs8099917TT carriers had SVR. IL28B SNPs, HCV mono-infection and HCV RNA load were associated with SVR as independent predictors in the two study groups as a whole. ROC curve analyses in the two populations separately, based on gender, age, baseline HCV RNA load and rs12979860/rs8099917 revealed similar receiver operating characteristics (ROC) areas under the curve values. Combining the determination of IL28B SNPs, rs8099917 genotyping improved the response prediction in rs12979860CT carriers only in mono-infected patients. In the era of direct-acting antiviral agents, adopting SVR baseline predictors to orientate naïve-patient management represents an important issue. A model involving IL28B SNPs appears able to predict SVR in both populations.

IANUA: a regional project for the determination of costs in HIV-infected patients.

HIV treatment is based on combined antiretroviral therapy (cART) which has substantially improved survival, thus resulting in an increase in patient life expectancy as well as in the cost of HIV-related medical care. Therefore, several cost effectiveness studies were implemented worldwide, with one specifically in the Liguria region (Italy), to compare the annual economic expense in this area for HIV services, and the related improvement in patients' health. The IANUA project is intended to implement both cost-effectiveness and cost-utility analysis, therefore data related to clinical indicators and perceived health status were collected, the latter using a questionnaire based on the EQ-5D-3L. Information about the antiretroviral drugs and the relative quantity that a patient withdraws from the hospital pharmacy every month were extracted from the regional "F-file". All data gathered were stored in the Ligurian HIV Network, a web platform developed by the DIBRIS - Medinfo laboratory. More than eight hundred questionnaires were collected, and data will be elaborated by economists and psychologists. The first statistical elaborations showed that, as expected, costs increased as the number of therapeutic lines increased. Moreover, the average annual costs for patients whose last CD4 values were below 200 cells/mmc corresponded to the maximum expense recorded, however, the cost for patients with final CD4 counts above 500 cells/mmc was not, as expected, the lowest found. This can be explained by the fact that stabilized patients, who had CD4 values below 500 cells/mmc, did not need very expensive care, while patients with CD4 counts above 500 cells/mmc improved their health status thanks to cART.

Immunomodulation due to plasma or plasma-platelet apheresis donation: Events occurring during donation procedures.

BACKGROUND: It has been recently shown that during therapeutic apheresis procedure, a large amount of soluble HLA class I molecules settles onto plastic apheresis circuits, inducing sustained TGFß1 pre/post-transcriptional modulation in activated patients' leukocytes. Reportedly, donors' leukocytes may be exposed to similar immunosuppressing activities during donor apheresis procedures. On this basis, it could be hypothesized that such events can cause immune modulation. It is uncertain which blood cell population is most impacted by these events. This study is focused on the effects on the T lymphocytes. STUDY DESIGN AND METHODS: To assess if such events occur, lymphocytes from 20 apheresis donors collected before and after three closely timed plasma and platelet donation procedures were analyzed for sHLA-I mediated immunomodulation. RESULTS: The results confirmed that sHLA-I molecules bind to the apheresis circuit surfaces. Circuits can also transiently activate donors' CD8(+) T lymphocytes, to which sHLA-I molecules can bind, thus modulating short-lasting immune effects, such as transcriptional and post-transcriptional TGFß1 modulation and soluble Fas ligand release. However, no significant change in relative proportions, absolute number and cell viability of lymphocyte subpopulations was found and no ex vivo immune effect was detectable longer than 14 days after procedure in any cell type in all donors. CONCLUSION: Short-lived sHLA-I mediated immunomodulation was demonstrable in lymphocytes from every donor as a consequence of apheresis procedures, but no enrolled subject experienced any adverse reaction or showed any sign of immunosuppression during 24 months of follow-up after the donations.

Quality of life of people living with HIV, preliminary results from IANUA (Investigation on Antiretroviral Therapy) study.

INTRODUCTION: The introduction of combined antiretroviral treatment (cART) has reduced HIV-associated morbidity and mortality, and changed the patients' perspective of life. As a result, Health Related Quality of Life (HRQOL) has become a crucial clinical issue. OBJECTIVE: Assessment of HRQOL in a sample of Italian patients from IANUA study. Investigate correlation between CD4 cell counts, viral load and changes in HRQOL. MATERIALS AND METHODS: EQ-5D-3L self-reported questionnaire has been used in the evaluation of HRQOL. It assesses five dimensions: "mobility," "self care," "usual activities," "pain/discomfort" and "anxiety/depression." Each dimension has three levels: no problems, some problems and extreme problems. In addition, it includes a Visual Analogue Scale (VAS) where one's own health "today" is rated from 0 "worst imaginable health" to 100 "best imaginable health." The respondents provide information on marital status, education, employment/unemployment, other treatments used in addition to HAART (1,2,3,4,5 or more) and number of hospitalizations due to HIV/AIDS. RESULTS: 684 patients completed the questionnaire: 231 females and 453 males. The mean age of the sample was 51 years (range 21-78). The mean VAS score was 69.9. 558 patients (81.5%) reported no problems in mobility. 642 patients (93.5%) had no problems in self care. 423 patients (61.8%) had no pain/discomfort while 219 had some problems. 326 patients (46.1%) had some problems in anxiety/depression. CONCLUSIONS: The analysis of self-reported questionnaires indicates that HRQOL in our sample group is not deeply affected by HIV/AIDS. The dimensions that are affected in the least are "mobility" and "self care" while the major problem is "anxiety/depression" with half of the sample reporting moderate or high level.

A comparison of inpatient admissions in 2012 from two European countries.

INTRODUCTION: This study compares the trends of HIV inpatient admissions between a London tertiary HIV centre (United Kingdom) and four infectious disease wards in Italy (IT) to recognize common patterns across Europe. METHODS: Data regarding HIV inpatient admissions was collected by using discharge diagnostic codes from 1 January to 31 December 2012, including patient demographics, combined antiretroviral therapy (cART) history, CD4, viral load (VL) and mortality rates. Discharge diagnoses were categorized according to the International Classification of Disease (ICD) 9 and 10 system. All ICD categories that reach a 3% threshold of total admissions were analyzed. RESULTS: A total of 731 admissions (257 in Italy and 474 in the United Kingdom) for 521 patients (1.5 mean admission per patient). Female admissions were higher in Italy at 22.6% (n=58) compared to 14.9% (n=47) in the United Kingdom. Median age of patients was 47 years old. There was an undetectable VL in 65.8% (n=169) of admissions in Italy and 67.1% (n=319) in the United Kingdom (p=0.385); 86.4% (n=222) and 82.4% (n=389) of admissions were on cART, respectively. Mean CD4 was 302 in Italy compared to 368 in the United Kingdom (p=0.003). Average length of admission was 16 days with a 10.2% (n=21) mortality rate in Italy compared to 8 days with 2.8% (n=9) mortality in the United Kingdom (p<0.001). HCV co-infection was present in 64.6% (n=166) in Italy and 13.5% (n=64) in the United Kingdom and commonest mode of transmission was needle use in Italy (67.3%, n=173) and men who have sex with men in the UK cohort (59.9%, n=284). The cause of inpatient admissions according to ICD codes can be seen in following Figure 1. CONCLUSIONS: Significant differences in the duration of inpatient admission and mortality rates can be observed between these two cohorts which is secondary to the impact of Hepatitis C co-infection in Italy. However increases in the number of Hepatitis C co-infection patients amongst MSM in London has been reported [1] and route of transmission in Italy is shifting towards MSM [2], therefore it is important to learn how HIV is developing and managed in a global context to help plan future for services. The UK cohort demonstrates a wider range of conditions necessitating admission, and with an ageing HIV population, this is expected to increase in the future, requiring general and specialist HIV physicians to work closely together. The HIV-RNA threshold is 400 copies/mL to account for blips according to British HIV Association (BHIVA) Guidelines 2012 [3].

Blood transfusions with high levels of contaminating soluble HLA-I correlate with levels of soluble CD8 in recipients' plasma; a new control factor in soluble HLA-I-mediated transfusion-modulated immunomodulation?

BACKGROUND: The cause of transfusion-related immunomodulation (TRIM) has proved tantalisingly elusive. An ever-growing body of evidence indicates that the infusion of large amounts of soluble and cell-associated antigens into a recipient can somehow induce TRIM. One soluble molecule that has been implicated in TRIM is soluble human leucocyte antigen I (sHLA-I). However, patients infused with large amounts of sHLA-I do not always and unambiguously experience TRIM. As soluble CD8 (sCD8) molecules have been shown to capable of binding membrane and soluble HLA-I molecules, we focused on sCD8 as a possible modulator of sHLA-I-mediated TRIM. MATERIAL AND METHODS: To this aim we compared the up-regulation of circulating sCD8 in plasma from patients suffering from the same pathology, but chronically transfused with two different blood derivatives: pre- and post-storage leucodepleted red blood cells which contain low and high levels of contaminating sHLA-I, respectively. RESULTS: Significantly larger amounts of sCD8 circulating molecules were detectable in the plasma of patients transfused with post-storage leucodepleted red blood cells whose supernatants contained significantly larger amounts of sHLA-I contaminating molecules. CONCLUSION: With the limitation of indirect evidence, this report introduces a new facet of the bioactivity of sCD8 as a possible modulator of sHLA-I-mediated TRIM.

Virological and immunological response to antiretroviral regimens containing maraviroc in HIV type 1-infected patients in clinical practice: role of different tropism testing results and of concomitant treatments.

We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatment-experienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA <50 copies/ml and immunological response as time to a CD4 cell count increase of ≥ 100/µl from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log10 higher: HR 1.29, 95% CI 1.05-1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96-4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.

Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation.

Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8(+)cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2-4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-activating pathway, may result in lack of killing of uninfected CD4(+)NKp44Ligand(+) cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4(+) depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A-CD57(+)killer cell Ig-like receptor(+)CD85j(+)) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients.

A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer.

BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 µg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.

Phase 4 randomized trial of intradermal low-antigen-content inactivated influenza vaccine versus standard-dose intramuscular vaccine in HIV-1-infected adults.

This study evaluated safety, tolerability and immunogenicity of intradermal (ID) trivalent inactivated split influenza vaccine, with a lower antigen content (9 mcg HA per strain) than the conventional intramuscular one (15 mcg), in HIV-1-infected adults younger than 60 years. A total of 54 HIV-1-positive participants were enrolled and randomly assigned to receive a single dose of either ID-administered low-antigen-content split inactivated vaccine or intramuscularly-administered (IM) standard-dose inactivated split vaccine. Subjects were provided with a diary to monitor any local and/or systemic reactions to the vaccine for 7 days following vaccination. Serum samples were collected before, 28 days and 90 days after immunization. The plasma HIV-RNA and CD4+ T-lymphocyte count were checked at day 0 and day 90. Serum hemagglutination-inhibition (HI) activity for the three influenza strains included in the vaccine composition was measured to assess the antibody response at one month and 3 months after vaccination. Both vaccines showed optimal safety and tolerability profiles. All the three Committee for Medicinal Products for Human Use immunogenicity criteria for vaccine approval in adults younger than 60 were met by both vaccines against A(H1N1) and A(H3N2) viruses. Both vaccines met mean-fold-increase and seroprotection criteria but failed seroconversion criteria against B virus. No difference in terms of post-vaccination geometric mean titers, mean fold increase, seroprotection and seroconversion rates were found comparing ID and IM vaccines. In conclusion, the recently available low-antigen-content ID vaccine is safe, well-tolerated and as immunogenic as IM standard-dose influenza vaccine.