Filippo Castelnuovo

Evaluation of Liver Fibrosis: Concordance Analysis between Noninvasive Scores (APRI and FIB-4) Evolution and Predictors in a Cohort of HIV-Infected Patients without Hepatitis C and B Infection

BACKGROUNDnThere is lack of data on the incidence of liver fibrosis (LF) progression in patients with human immunodeficiency virus (HIV) monoinfection and risk factors for LF.nnnMETHODSnWe performed an observational prospective study in a cohort of HIV-infected patients who had initiated highly active antiretroviral therapy (HAART). FIB-4 and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) were assessed. The concordance between the 2 scores was assessed by weighted kappa coefficient. Kaplan-Meier analysis was used to estimate the incidence of LF. Cox regression analysis was used to assess the predictors of transition.nnnRESULTSnA total of 1112 patients were observed for a mean of 2249 days of follow-up. The concordance between FIB-4 and APRI was moderate (kappa = .573). The incidence of transition to higher FIB-4 classes was 0.064 (95% confidence interval [CI], 0.056-0.072) per person-year of follow-up (PYFU), whereas the incidence of transition to higher APRI classes was 0.099 (95% CI, 0.089-0.110) per PYFU. The incidence of transition to FIB-4 >3.25 was 0.013 per PYFU (95% CI, 0.010-0.017) and 0.018 per PYFU (95% CI, 0.014-0.022) for APRI >1.5. In multivariate analyses, for transition to higher classes, HIV RNA level <500 copies/mL was found to be protective for both scores, and higher CD4+ T cell count was found to be protective for FIB-4. Additional risk factors were age ≥ 40 years, male sex, intravenous drug use as an HIV infection risk factor, higher degree of LF, higher gamma-glutamyl transpeptidase (γGT) at baseline, and use of dideoxynucleoside-analogue drugs (DDX). Consistent results for the main study outcomes were obtained for confirmed LF transition and transition to FIB-4 > 3.25 and APR I> 1.5 as study outcomes.nnnCONCLUSIONSnOverall, our results suggest a possible benefit associated with earlier HAART initiation, provided that the effectiveness of HAART is sustained and treatment with DDX is avoided.

A Randomized Controlled Trial to Evaluate Antiretroviral Salvage Therapy Guided by Rules-Based or Phenotype-Driven HIV-1 Genotypic Drug-Resistance Interpretation With or Without Concentration-Controlled Intervention: The Resistance and Dosage Adapted Regimens (RADAR) Study

BACKGROUNDnIt is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy.nnnMETHODSnIn a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study.nnnRESULTSnAmong 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response.nnnCONCLUSIONSnThe present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.

Hyperbilirubinemia during Atazanavir Treatment in 2,404 Patients in the Italian Atazanavir Expanded Access Program and MASTER Cohorts

Background:Although the mechanism of atazanavir (ATV)-related hyperbilirubinemia is well identified, its prevalence, risk factors, and association with transaminase flares have rarely been assessed in a large population from the “real life” setting.Methods:Prospectively collected data on 2,404 patients from the Italian MASTER Cohort and the Italian ATV expanded access program database were examined. Uni- and multivariable Cox proportional hazards regression models were conducted to identify risk factors for grade ≥ III hyperbilirubinemia during the administration of ATV. The risk of increased levels of serum alanine aminotranferase (ALT) was compared between patients with or without grade ≥ III hyperbilirubinemia in a Cox regression analysis stratified by hepatitis C virus (HCV) serostatus.Results:Grade III and IV hyperbilirubinemia were observed in 1,072 (44.6%) and 174 (7.2%) of the patients, respectively. Higher CD4+ T-cell counts, abnormal bilirubinemia at baseline, and ritonavir co-administration were associated with a higher risk of developing grade ≥ III hyperbilirubinemia. In contrast, female gender, clinical class C, and non-nucleoside reverse transcriptase co-administration appeared to be protective. Higher bilirubinemia at baseline and the use of ritonavir were associated with a higher risk of grade IV hyperbilirubinemia. The occurrence of grade ≥ III hyperbilirubinemia was not associated with severe hepatotoxicity (hazard ratio 1.00, 95% confidence interval 0.64–1.57; p = 0.997).Conclusions:Hyperbilrubinemia is a common side effect of an ATV pharmacotherapeutic regimen. However, grade IV increase in bilirubin was rarely found. In most cases, ATV hyperbilirubinemia appeared to be an innocent phenomenon as far as the risk of a subsequent increase in liver enzyme level is concerned.

Efficacy and safety of a switch to unboosted atazanavir in combination with nucleoside analogues in HIV-1-infected patients with virological suppression under antiretroviral therapy

BACKGROUNDnLimited data are available on the use of unboosted atazanavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-experienced HIV-infected patients.nnnMETHODSnWe conducted a multicentre, retrospective study among patients with plasma HIV-1 RNA levels <50 copies/mL under antiretroviral therapy who switched to unboosted atazanaviru200a+u200aNRTIs between January 2002 and December 2008. Virological failure during follow-up was defined as a confirmed plasma HIV-1 RNA level >50 copies/mL. Baseline risk factors for virological failure were identified using Cox proportional hazards models.nnnRESULTSnA total of 886 patients were analysed. At baseline, median age was 44 years, 71.5% were males and median CD4 cell count was 490 cells/mm(3). NRTIs used in combination with atazanavir were tenofovir, abacavir and emtricitabine/lamivudine in 36.9%, 44.1% and 94.4% of patients, respectively. Median follow-up was 21 months. The 3 year probability of virological failure was 20.1%. Only a history of virological failure under NRTIs [hazard ratio (HR) 1.63, Pu200a=u200a0.049] and under protease inhibitors (HR 2.04, Pu200a=u200a0.006) were significantly associated with the risk of virological failure. Among the 431 patients without a prior history of virological failure, the 3 year probability of virological failure was 11.3%, and only hepatitis C virus co-infection (HR 2.25, Pu200a=u200a0.026) and abacavir use (HR 0.43, Pu200a=u200a0.04) were associated with the risk of virological failure. Safety of the switch was satisfactory, with improvement of the lipid profile.nnnCONCLUSIONSnIn patients with virological suppression and no prior history of virological failure, a switch to unboosted atazanavir in combination with NRTIs is associated with a low probability of virological failure and a good safety profile.

Analysis of severe hepatic events associated with nevirapine-containing regimens: CD4+ T-cell count and gender in hepatitis C seropositive and seronegative patients.

AbstractBackground: Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of ≥250/mm3 or men with CD4+ T-cell counts of ≥400/mm3, i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients co-infected with hepatitis C virus (HCV).n Methods: Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade ≥III hepatotoxicity (i.e. ≥5 × upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients.n Results: Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade ≥III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p < 0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p = 0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome.n Conclusions: Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of ≥400/mm3 or females with CD4+ T-cell counts of ≥250/mm3.

Updated Prevalence of Genotypic Resistance Among HIV-1 Positive Patients Naïve to Antiretroviral Therapy : A Single Center Analysis

Continuous surveillance of HIV primary resistance mutations is highly important due to their potential clinical impact. All patients naïve to antiretrovirals who had ≥1 genotypic resistance testing at the Institute of Infectious Diseases (Brescia, Northern Italy) between 2001 and 2006 were analyzed. Primary resistance mutations were defined using epidemiological and clinical criteria. Mutations were interpreted using the Stanford University Algorithm. Logistic regression analysis was used to assess possible predictors of primary resistance mutations. Among 569 patients, 11% presented ≥1 mutation. Prevalence of primary resistance mutations to nucleoside reverse‐transcriptase inhibitors (NRTI), non‐nucleoside reverse‐transcriptase inhibitors (NNRTI), and protease inhibitors (PI) was 6.3%, 6%, and 1.6%, respectively. The most frequent mutations to NRTI were substitutions at position 215 (215Y in 3 patients, and 215 revertants in 16), 41L (13), 219Q (12), and 210W (10). Among mutations to NNRTI, 103N was found in 21 patients, while 181C, 188L, and 190A/S in 8, 3, and 4 patients, respectively. Fifty‐one patients (9%) had high‐to‐intermediate resistance to ≥1 antiretroviral drug before starting the treatment. Regarding the new generation drugs, nine patients had intermediate resistance to etravirine, five patients had intermediate resistance to tipranavir, while five, one, and seven patients had low resistance to etravirine, tipranavir, and darunavir. Homosexuals were more likely to harbor a virus with primary resistance mutations (OR:2.68; 95% CI:1.44–5.00; Pu2009=u20090.002) while non‐Italian nationality was protective (OR:0.38; 95% CI:0.17–0.86; Pu2009=u20090.020). Prevalence of primary resistance mutations suggests that genotypic resistance testing should be performed before starting treatment in naïve patients in Italy, particularly when NNRTI are prescribed. J. Med. Virol. 80:747–753, 2008.

Cancer incidence and mortality for all causes in HIV-infected patients over a quarter century: a multicentre cohort study

BackgroundWe aimed to assess cancer incidence and mortality for all-causes and factors related to risk of death in an Italian cohort of HIV infected unselected patients as compared to the general population.MethodsWe conducted a retrospective (1986–2012) cohort study on 16 268 HIV infected patients enrolled in the MASTER cohort. The standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using cancer incidence rates of Italian Cancer Registries and official national data for overall mortality. The risk factors for death from all causes were assessed using Poisson regression models.Results1,195 cancer cases were diagnosed from 1986 to 2012: 700 AIDS-defining-cancers (ADCs) and 495 non-AIDS-defining-cancers (NADCs). ADC incidence was much higher than the Italian population (SIRu2009=u200930.8, 95% confidence interval 27.9-34.0) whereas NADC incidence was similar to the general population (SIRu2009=u20090.9, 95% CI 0.8-1.1). The SMR for all causes was 11.6 (11.1-12.0) in the period, and it decreased over time, mainly after 1996, up to 3.53 (2.5-4.8) in 2012. Male gender, year of enrolment before 1993, older age at enrolment, intravenous drug use, low CD4 cell count, AIDS event, cancer occurrence and the absence of antiretroviral therapy were all associated independently with risk of death.ConclusionsIn HIV infected patients, ADC but not NADC incidence rates were higher than the general population. Although overall mortality in HIV infected subjects decreased over time, it is about three-fold higher than the general population at present.

Analysis of the hepatitis B virus genome and immune response in HBsAg, anti-HBs positive chronic hepatitis

Although the development of antibodies against the hepatitis B virus surface antigen generally leads to the clearance of the infecting virus, anti-HBs reactivity has been reported in patients with chronic hepatitis. In the present study we analyzed the viral genome and the antibody specificity in a series of serum samples collected from a patient who seroconverted to anti-HBs during interferon therapy without clearing HBsAg. The appearance of an anti-HBs response was accompanied by the emergence of a pre-S1 defective viral genome. However, the wild-type adw2 molecular species remained largely dominant during follow up. The patients antibody response to the surface viral antigens was directed towards the heterologous y subdeterminant and the pre-S1 fragment deleted in the variant hepatitis B virus. These results suggest that the selection of the escape viral mutant does not play a major role in viral persistence.

The prognostic role of systemic inflammatory markers on HIV-infected patients with non-Hodgkin lymphoma, a multicenter cohort study.

BackgroundThe systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. We aimed to assess the prognostic role of inflammatory markers on survival in HIV-infected patients with Non-Hodgkin Lymphoma (NHL), and to compute a prognostic score based on inflammatory biomarkers.MethodsWe evaluated data on HIV patients with NLH diagnosis between 1998 and 2012 in a HIV Italian Cohort. Using Cox proportional regression model, we assessed the prognostic role of Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). We also computed a risk score equation, assigning patients to a derivation and a validation sample. The area under the curve (AUC) was use to evaluate the predictive ability of this score.Results215 non-Hodgkin lymphoma cases (80.0% males) with a mean age of 43.2xa0years were included. Deaths were observed in 98 (45.6%) patients during a median follow up of 5xa0years. GPS, mGPS, PI and PNI were independently associated with risk of death. We also computed a mortality risk score which included PNI and occurrence of an AIDS event within six months from NHL diagnosis. The AUCs were 0.69 (95% CI 0.58 to 0.81) and 0.69 (95% CI 0.57 to 0.81) at 3 and 5xa0years of the follow-up, respectively.ConclusionsGPS, mGPS, PI and PNI are independent prognostic factors for survival of HIV patients with NHL.

Cohort Profile: Standardized Management of Antiretroviral Therapy Cohort (MASTER Cohort)

Cohort Profile: Standardized Management of Antiretroviral Therapy Cohort (MASTER Cohort) Carlo Torti, Elena Raffetti,* Francesco Donato, Francesco Castelli, Franco Maggiolo, Gioacchino Angarano, Francesco Mazzotta, Andrea Gori, Laura Sighinolfi, Angelo Pan, Roberto Cauda, Alfredo Scalzini, Eugenia Quiros-Roldan, Paola Nasta, Giampietro Gregis, Simone Benatti, Simona Digiambenedetto, Nicoletta Ladisa, Mariarosaria Giralda, Annalisa Saracino, Filippo Castelnuovo, Massimo Di Pietro, Sergio Lo Caputo, Giuseppe Lapadula, Silvia Costarelli, Silvia Lorenzotti, Nicola Mazzini, Giuseppe Paraninfo, Salvatore Casari, Emanuele Focà, Chiara Pezzoli, Massimiliano Fabbiani, Laura Monno, Piera Pierotti, Claudio Ble, Sebastiano Leone, Maria Concetta Postorino, Chiara Fornabaio, Fabio Zacchi, Alessia Zoncada and Giampiero Carosi Unità di Malattie Infettive e Tropicali, Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Grecia di Catanzaro, Catanzaro, Italia, Unità di Igiene, Epidemiologia e Sanità Pubblica, Università degli Studi di Brescia, Brescia, Italia, Divisione Universitaria di Malattie Infettive Spedali Civili di Brescia-Università degli Studi di Brescia, Brescia, Italia, Malattie Infettive Ospedale Papa Giovanni XXIII, Bergamo, Italia, Clinica di Malattie Infettive Policlinico di Bari, Bari, Italia, Malattie Infettive S.M. Annunziata, Firenze, Italia, Malattie Infettive Ospedale San Gerardo di Monza, Monza, Italia, Malattie Infettive Nuovo Polo Ospedaliero di Cona, Ferrara, Italia, Malattie Infettive Istituti Ospitalieri di Cremona, Cremona, Italia, Clinica di Malattie Infettive Policlinico A. Gemelli-Università Cattolica di Roma, Roma, Italia, Divisione Ospedaliera di Malattie Infettive Spedali Civili, Brescia, Italia and Fondazione Malattie Infettive e Salute Internazionale, Brescia, Italia