Paola Nasta

Insulin resistance impairs rapid virologic response in HIV/hepatitis C virus coinfected patients on peginterferon-alfa-2a.

Objectives:To investigate the association between insulin resistance and rapid virologic response. Design:All consecutive HIV/hepatitis C virus coinfected patients who started peg-interferon alpha-2a (180 μg/week) and ribavirin 1000–1200 mg/day were analysed. Methods:Insulin resistance was defined according to the homeostasis model of assessment-insulin resistance calculated as fasting insulin (mIU/l) × fasting glucose (mmol/l)/22.5. Rapid virologic response was defined as testing negative for hepatitis C virus-RNA after 4 weeks of therapy. Fasting levels of insulin and glucose in plasma were measured in all patients on the first day of treatment. Hepatitis C virus-RNA was determined by quantitative PCR assay (version 3.0). Hepatitis C virus-RNA was measured by qualitative PCR assay (COBAS 2.0) after 4 weeks of treatment. Results:Seventy-four HIV/hepatitis C virus coinfected patients were enrolled [mean age 41.7 years (SD 5.3), 61 men, 54.1% with advanced fibrosis (F3-4 according to METAVIR classification), 52.4% with infection by hepatitis C virus genotype 1 or 4]. Rapid virologic response was reached by 30 subjects. In the multivariate analysis the independent predictors of rapid virologic response were: genotype 1 or 4 [adjusted odds ratio 0.18 (0.06–0.55)], hepatitis C virus-RNA < 400.000 UI/ml [adjusted odds ratio 0.229 (0.09–0.92)] and homeostasis model of assessment-insulin resistance more than 3.00 [adjusted odds ratio 0.1 (0.05–0.6)]. Conclusion:The homeostasis model of assessment-insulin resistance score should be evaluated and possibly corrected before starting anti-hepatitis C virus therapy.

HIV-related liver disease: ARV drugs coinfection and other risk factors.

Highly-active antiretroviral therapy (HAART) has proven remarkably effective for prolonging the life of patients with human immunodeficiency virus (HIV). However, while most HAART agents are safe, many have the potential to cause liver toxicity. Physicians must therefore consider the possibility of drug-induced liver injury in the management of HIV-infected patients, especially those with certain risk factors such as coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), female gender, alcohol abuse, older age, or obesity. Understanding how, when, and why drug-related liver damage occurs is key to managing these patients safely and effectively. Knowledge of HAART-related liver effects will help ensure that patients receive the most benefit with the least toxicity from any given drug regimen. As more information about the mechanisms of drug related liver injury is known, clinicians will be better able to tailor therapies to suit individual situations, resulting in greater patient safety and outcomes.

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure*

The prevalence and factors associated with an increased risk of renal dysfunction in HIV‐infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings.

Circulating sCD14 Is Associated with Virological Response to Pegylated-Interferon-Alpha/Ribavirin Treatment in HIV/HCV Co-Infected Patients

Objectives Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients. Methods 98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log10 reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearsons correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR. Results 71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1–4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2–3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031–0.688, p = 0.015). SVR was associated only with HCV genotypes 2–3 (AOR 0.022 for genotypes 1–4 vs 2–3, 95%CI 0.001–0.469, p = 0.014). Conclusions In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.

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

BACKGROUND Limited data are available on the use of unboosted atazanavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-experienced HIV-infected patients. METHODS We conducted a multicentre, retrospective study among patients with plasma HIV-1 RNA levels <50 copies/mL under antiretroviral therapy who switched to unboosted atazanavir + NRTIs 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. RESULTS A 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, P = 0.049] and under protease inhibitors (HR 2.04, P = 0.006) 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, P = 0.026) and abacavir use (HR 0.43, P = 0.04) were associated with the risk of virological failure. Safety of the switch was satisfactory, with improvement of the lipid profile. CONCLUSIONS In 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.

Hepatitis B Virus and HIV Coinfection in Low-Income Countries: Unmet Needs

Approximately 350 million people (5%-7% of the worlds population) are chronically infected with the hepatitis B virus (HBV) and 600000 (0.2%) die each year of HBV-related disease and hepatocellular carcinoma. Sub-Saharan Africa and the Far East have high HBV endemicity (population prevalence 18%); Eastern and Southern Europe South America and the rest of Africa and Asia have intermediate endemicity (population prevalence 2%-8%); northern Europe North America and Australia have low endemicity (population prevalence !2%). It is estimated that worldwide 40 million people live with HIV infection and that 3 million (7.5%) of them die of HIV-related tumors and opportunistic infections. This striking difference in mortality between those with HIV infection and those with chronic HBV infection can explain why treatment of HIV infection has a priority over HBV treatment to reduce mortality both in the general population and in the single coinfected patient. In low-endemicity areas most HBV infections occur in adolescents and young adults and the majority of infections are acquired sexually or through percutaneous exposure. Thus HBV and HIV share common transmission pathways in these areas and the prevalence of hepatitis B surface antigen (HBsAg) reactivity in HIV-coinfected patients is 5%-10% 2.5-10 times the population prevalence. (excerpt)

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

Unboosted fosamprenavir is associated with low drug exposure in HIV-infected patients with mild–moderate liver impairment resulting from HCV-related cirrhosis

OBJECTIVES The aim of this study was to compare amprenavir pharmacokinetics in HIV/hepatitis C virus (HCV)-co-infected cirrhotic patients receiving non-boosted fosamprenavir 700 mg twice daily with HCV/HIV-co-infected non-cirrhotic subjects and HIV-mono-infected subjects receiving fosamprenavir/ritonavir 700/100 mg twice daily. Liver stiffness at baseline and alanine aminotransferase levels at baseline and during follow-up were measured in order to find a correlation between drug levels and liver fibrosis or hepatotoxicity. METHODS Amprenavir plasma concentration was determined by HPLC. Liver stiffness was measured by transient elastometry. Liver function tests were determined every 1-3 months during follow-up. RESULTS Nineteen HIV-infected patients were included. Eight had chronic HCV hepatitis (group NC), five had HCV-related liver cirrhosis (group C) and six were HIV-mono-infected (group M). In group C patients, amprenavir C(trough), AUC(0-12) and half-life were 86%/83%, 64%/55% and 58%/59% lower when compared with controls and co-infected subjects without cirrhosis, respectively; conversely, drug clearance in cirrhotics was 181%/124% higher. In 3/5 cirrhotic patients (60%) and in 2/14 non-cirrhotic patients (14%), C(trough) was below the minimum target concentration of 400 ng/mL; nonetheless, in all these patients, HIV viral load was undetectable. No correlation was found between amprenavir pharmacokinetics and liver stiffness or hepatotoxicity at follow-up. CONCLUSIONS On the basis of these data, it seems reasonable to boost fosamprenavir with ritonavir even in cirrhotic patients; amprenavir pharmacokinetics could not be predicted by liver stiffness and seem not to predict hepatotoxicity at follow-up.

Adherence to HIV treatment: results from a 1‐year follow‐up study

Summary We evaluated adherence to HIV treatments every 4 months during one year in 63 HIV‐infected subjects using combination therapies including a protease inhibitor. A total of 18 subjects reported a high level of adherence, 14 in two evaluations, and eight a low level of adherence in all the three evaluations. The remaining 23 subjects (36.5%) reported different levels of adherence to treatment in the three evaluations. These findings suggest that the level of adherence to treatment changes markedly for each patient over time.

Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients

Background:The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. Methods:Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. Results:A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab–positive and HCV-RNA–positive patients, respectively. Among HCV-Ab–negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab–positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA–positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab–positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. Conclusions:Occurrence of hepatotoxicity was a rare finding among HCV-Ab–negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.