Giuseppe Paraninfo

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.

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). 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. 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. 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; P = 0.002) while non‐Italian nationality was protective (OR:0.38; 95% CI:0.17–0.86; P = 0.020). 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.

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

Risk Factors and Clinical Characteristics Associated with Hospitalization for Community-Acquired Bacterial Pneumonia in HIV-Positive Patients According to the Presence of Liver Cirrhosis

AbstractBackground:Community-acquired bacterial pneumonia (CABP) represents an important cause of morbidity and mortality for cirrhotic and HIV-infected patients, respectively. However, little is known on CABP in HIV-positive patients with cirrhosis. A study was performed to describe the clinical features and factors predictive of mortality and prolonged hospitalization in cirrhotic HIV-infected patients with a diagnosis of CABP.Methods:Demographic and clinical characteristics of cirrhotic HIV-positive subjects, hospitalized for CABP in our department from June 2000 to December 2006, were compared with those of non-cirrhotic HIV-infected patients with the same diagnosis hospitalized from June 2000 to November 2001. Variables with p < 0.10 in univariate analysis were tested for their predictive value for mortality and length of hospitalization with uni- and multivariate logistic regression analysis.Results:Twenty-nine cirrhotic and 73 non-cirrhotic HIV-positive patients with CABP were compared. Age and alcohol abusewere significantly higher in cirrhotics. At hospital admission, cirrhotic patients had more frequently mental status alterations (7.26 [2.21–23.82], p = 0.001) and milder symptoms and signs (temperature > 37.5 _C: 0.27 [0.10–0.75], p = 0.01; respiratory rate > 20: 0.34 [0.13–0.92], p = 0.033; systemic inflammatory response syndrome (SIRS): 0.39 [0.16–0.95], p = 0.038). Adjusting for age, cirrhosis was associated with a higher mortality (5.96 [1.05–33.57]; p = 0.043). Adjusting for age, gender, and concomitant antiretroviral treatment, cirrhosis was also associated with a prolonged hospitalization (> 7 days: 9.30 [1.84–46.82]; p = 0.007).Conclusion:The diagnosis of CABP can be difficult in cirrhotic HIV-positive patients because clinical presentation is milder. However, CABP needs to be promptly recognized because mortality is higher in these patients.

Incidence of cardiovascular events in HIV-positive patients compared to general population over the last decade: a population-based study from 2000 to 2012.

ABSTRACT Cardiovascular diseases are currently a main cause of death among people living with HIV. This population-based study aimed to investigate the incidence of cardiovascular events (CVEs) in HIV-positive people and factors associated with CVEs. We performed a retrospective cohort study of the HIV-infected patients residing in the Local Health Authority of Brescia, northern Italy, from 2000 to 2012. Incidence of CVEs events in HIV-positive patients was compared with that expected in general population living in the same area, computing standardized incidence ratios (SIRs). CVEs-associated risk factors were assessed using Cox regression analysis and competing risk model of death. About 3766 HIV-infected patients were included in the study. Over the 12-year-period, we recorded 134 CVEs: 83 (61.9%) acute myocardial infarctions (CVE type-1), and 51 (38.1%) strokes (CVE type-2). A twofold increased risk (SIR = 2.02) of CVEs was found in HIV-infected patients compared to the general population. Notably, within male patients: for CVE type-1, SIR = 1.89, for CVE type-2 SIR = 2.25; within female patients: for CVE type-1, SIR = 2.91, for CVE type-2 SIR = 2.07. Age >45 years, male gender, diabetes, and total blood cholesterol >200 mg/dl were significantly associated with CVEs incidence (for all, p < .05). These results were confirmed using the competing risk model. Our cohort study confirmed the higher incidence of CVEs in HIV-positive patients, and put emphasis on the importance of traditional cardiovascular risk factors. Overall CVE risk in HIV-positive patients was twice as high as CVE risk in general population. We found a peculiar gender distribution, with a relative risk for CVE type-1 higher in HIV-positive females, and a higher CVE type-2 risk in male patients. More studies are needed in order to support these findings and to further highlight possible gender differences in the risk of developing CVEs in HIV-positive patients.

Evolution of Antiretroviral Prescription and Response over a Period of 8 years: an Italian Multicentre Observational Prospective Cohort Study

Background:There is very less information on the use of antiretroviral (ARV) drugs and viro-immunological outcome over calendar years in Italy.Patients and Methods:We performed an analysis of a prospective observational cohort (MASTER) to assess antiretroviral drug use in first line HAART and explore whether initial treatment response changed over the years.Results:3,648 ARV-naive patients with available HIV-RNA and CD4+ T cell count at baseline who started their first HAART between 1997 and 2004 were studied. Mean age was 37.7 years; they were mostly males (72.3%) and Italians (81.4%). Prescription of non-nucleoside reverse transcriptase inhibitors and protease inhibitors boosted with ritonavir rose from 0.3% in 1997 to 58% in 2004 and from 0.3%in 1997 to 33.4% in 2004, respectively. Virological failures decreased over calendar years: from 42.9% in 1997 to 8.1%in 2004 after 6 months of HAART (p < 0.001); from 42.1%(1997) to 10.7% (2004) after 12 months (p < 0.001) and; from 39.5% (1997) to 8.2% (2004) after 18 months (p < 0.001). The same trend, but less striking, was found for immunological failure rates.Conclusions:In the general Italian population of HIV-positive patients, evolution of treatment prescription correlated with improved viro-immunological outcome.

A randomized, controlled trial of triple antiviral therapy as initial treatment of chronic hepatitis C in HIV-infected patients

Abstract Background/Aims Interferon and ribavirin combination therapy for chronic hepatitis C induces a low response rate in human immunodeficiency virus (HIV) infected patients. To assess the impact of intensification of interferon administration and of the addition of amantadine on the efficacy and safety of standard anti-hepatitis C virus (HCV) treatment in HIV-infected patients. Methods Multicentre, prospective, open-label, randomized, phase III clinical trial. Eighty co-infected patients were randomized to receive ribavirin 800–1000 mg/day in combination with, group A: interferon alpha2a 3MIU thrice weekly; group B: IFNα2a 3MIU daily, plus amantadine 200 mg/day; treatment duration was 24–48 weeks according to HCV genotype. Results Forty-one patients were randomized in group A and 39 in group B. Intention-to-treat analysis showed a sustained virological response, defined as HCV-RNA negativization, 6 months after stopping treatment in 22% of patients from group A and 13% from group B (P>0.05). The lack of a 2-log drop in HCV-RNA levels after 12 weeks of treatment showed a 100% predictive value of lack of sustained response. Conclusions Amantadine addition and interferon intensification do not improve the low efficacy of combination of interferon alfa plus ribavirin in HIV/HCV co-infected patients. Patients with no early virologic response did not have any probability of sustained response.

Effectiveness of antiretroviral regimens containing abacavir with tenofovir in treatment-experienced patients: Predictors of virological response and drug resistance evolution in a multi-cohort study

Background:In treatment-naïve patients, a combination antiretroviral therapy (cART) containing tenofovir (TDF) and abacavir (ABC) with lamivudine leads to unacceptably high virological failure rates with frequent selection of reverse transcriptase mutations M184V and K65R. We explored the efficacy of at least 16 weeks of ABC + TDF-containing cART regimens in 307 antiretroviral-experienced HIV-1-infected individuals included in observational databases.Methods:Virological failure was defined as an HIV RNA > 400 copies/ml after at least 16 weeks of treatment. Patients had received a median of three prior cART regimens. Of these, 76% concomitantly received a potent or high genetic barrier regimen (with at least one protease inhibitor [PI]) or non-nucleoside reverse transcriptase inhibitor or thymidine analogue) while a third non-thymidine nucleoside analogue was used in the remaining patients.Results:The 1-year estimated probability of virological failure was 34% in 165 patients with HIV RNA > 400 copies/ ml at ABC + TDF regimen initiation. Independent predictors of virological failure were the absence of a potent or high genetic barrier cART, the higher number of cART regimens experienced, and the use of a new drug class. In the subset of 136 patients for whom there were genotypic resistance test results prior to ABC + TDF initiation, the virological failure (1-year estimated probability 46%) was independently predicted by the higher baseline viral load, the concomitant use of boosted PI, and the presence of reverse transcriptase mutation M41L. In 142 patients starting ABC + TDF therapy with HIV RNA £ 400 copies/ml, virological failure (1-year estimated probability 17%) was associated only with the transmission category. In a small subset of subjects for whom there were an available paired baseline and follow-up genotype (n = 28), the prevalence of most nucleoside analogue reverse transcriptase inhibitor resistance mutations decreased, suggesting a possible low adherence to treatment. No selection of K65R was detected.Conclusion:The virological response to ABC + TDF-containing regimens in this moderately-to-heavily treatmentexperienced cohort was good. Higher viral load and the presence of M41L at baseline were associated with worse virological responses, while the concomitant prescription of drugs enhancing the genetic barrier of the regimen conveyed a reduced risk of virological failure. The Appendix provides the names of other members of the MASTER cohort.

The impact of gender and anchor drugs on TDF renal toxicity.

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