Management of immunosuppression and antiviral treatment before and after heart transplant for HIV-associated dilated cardiomyopathy.

Infection with HIV may lead to the development of cardiomyopathy as improved antiretroviral regimens continue to prolong patient life. However, advanced therapeutic options, such as heart transplant, have until recently been precluded to HIV-positive persons. A favorable long-term outcome has been obtained after kidney or liver transplant in HIV-positive recipients fulfilling strict virological and clinical criteria. We recently reported the first heart transplant in a HIV-infected patient carried out in our center. In this article, we detail the major challenges we faced with the management of antiretroviral and immunosuppressive treatments over the first 3 years post-transplant. The patient had developed dilated cardiomyopathy while on antiretroviral treatment with zidovudine, lamivudine and efavirenz. He was in WHO Stage 1 of HIV infection and had normal CD4+ count and persistently undetectable HIV-RNA. In spite of cardiac resynchronization therapy and maximal drug therapy, the patient progressed to end stage heart failure, requiring heart transplant. He was placed on a standard immune suppressive protocol including cyclosporine A and everolimus. Despite its potential pharmacokinetic interaction with efavirenz, everolimus was chosen to reduce the long-term risk of opportunistic neoplasia. Plasma levels of both drugs were monitored and remained within the target range, although high doses of everolimus were needed. There were no infectious, neoplastic or metabolic complications during a 3-year follow-up. In summary, our experience supports previous data showing that cardiac transplantation should not be denied to carefully selected HIV patients. Careful management of drug interactions and adverse events is mandatory.

Rapid virological response in peripheral blood mononuclear cells with an increase of hepatitis C virus-specific interferon-gamma production predisposes to sustained virological response in patients with chronic hepatitis C genotype 1 undergoing treatment with pegylated-interferon alpha 2a plus ribavirin.

OBJECTIVE: Viral load evaluation in plasma, after 1 month of treatment, represents one of the most important parameters to predict treatment response during interferon (IFN) treatment in chronic hepatitis C (CHC). It has been proven that hepatitis C virus (HCV) RNA may be present in peripheral blood mononuclear cells (PBMCs) but few studies have investigated the viral load in PBMCs during treatment. The aim of this study was to evaluate HCV RNA in PBMCs during therapy with pegylated-IFN-alpha2a plus ribavirin and whether its clearance in PBMCs may induce a treatment response. Furthermore, we also analyzed the IFN-gamma and interleukin (IL)-4 responses of PBMCs during therapy. MATERIAL AND METHODS: We studied 35 patients with CHC genotype 1 undergoing antiviral treatment with pegylated IFN-alpha2a 180 microg weekly plus ribavirin 1000 mg/daily. In these patients we evaluated HCV-RNA in plasma and PBMCs, IFN-gamma and IL-4 before treatment, after 1, 3 and 12 months of treatment and 6 months after the end of treatment. RESULTS: We found that rapid virological clearance of HCV-RNA in PBMCs with a restored and improved HCV-specific IFN-gamma response was statistically significantly higher in those with a sustained virological response (SVR). CONCLUSION: Patients having a rapid virological response in PBMCs with an improved Th1 network achieve a complete SVR, whereas those having viral clearance only in plasma without a restored Th1 network have a relapse.

IL-18 and interferon-gamma in HCV-related hepatocellular carcinoma: a model of interplay between immune status and cancer.

Hepatocellular carcinoma (HCC) is a frequent malignancy with a high rate of mortality, and the hepatitis B and C viruses are considered major etiological factors associated with the development of chronic inflammation. Today, there is increasing evidence that the inflammatory process, mediated by the complex cytokine network, is inherently associated with many cancer types, including HCC. In this study we have assayed Th1 cytokines, such as IL-18 and IFN gamma, in the sera of 23 HCC patients with HCV infection, analysing their possible association with HCC in respect to 20 patients: 12 carriers for HCV infection and 8 healthy controls. We have also evaluated the possible difference on IL-18 and IFN gamma in HCC patients with respect to the number of hepatic nodules and rate of tumor differentiation. The mean values of serum IL-18 levels were significantly higher in HCC patients than in HCV carriers (p < 0.001) while IFN gamma serum levels were similar in cases and controls. No significant correlation was present between IL-18 and IFN gamma. In addition, IL-18 was higher in HCC patients with two or more nodules in respect to HCC patients with one nodule (372+/-140 vs 109+/-73 pg /mL; p <0.001). There is no significant difference in HCC patients and no correlation between the cytokines and other evaluated variables such as HCV RNA, alpha-1 fetoprotein, genotype and demographics of HCC patients. Taken together, our data suggest that IL-18 may play a key role in the pathogenesis of HCC and its levels can be utilized as a possible marker in the diagnosis of HCC.

Safety of new DAAs for chronic HCV infection in a real life experience: role of a surveillance network based on clinician and hospital pharmacist.

BACKGROUND: Direct Antiviral Agents (DAAs) for HCV therapy represents a step ahead in the cure of chronic hepatitis C. Notwithstanding the promising results in several clinical trials, few data are available on adverse effects in real life settings. METHODS: We have evaluated 170 patients with persistent infection and on those eligible to treatment we have followed up them through a network managed by clinician and hospital pharmacist. RESULTS: According to our data we have found that 41% (32 out of 78) of enrolled patients experienced adverse reactions, of these 40% were in those under 65 years while 60% was in patients older than 65 years, SVR was achieved in 88% of the patients (including drop-out). We had 4 drop-out treatment due to major adverse reaction (heart and lung related). CONCLUSION: Even if new antiviral drugs seem to be promising, according to SVR, they require careful follow-up, possibly managed by clinician and hospital pharmacist, to avoid unrecognized side effects which may affect adherence and the real impact of these drugs on chronically infected subjects.

Acute rejection after liver transplantation: Is there a specific immunological pattern?

The aim of the study was to assess various T-cell subsets and cytokine secretion patterns both in liver tissue and in the peripheral blood of 24 liver transplant patients to assess possible specific immunological involvement in early acute rejection episodes after liver transplantation. Particularly, we studied CD4+ CD7+, CD8+ CD38+, and CD4+ CD25+ T cells by flow cytometry, as well as contemporaneously, interleukin (IL)-2 and IL-10 secretion by ELISpot to determine possible Th1-like immune responses and the immunomodulation expressed by Treg cells in acute liver rejection, respectively. As a control group we included patients transplanted without acute rejection. Early acute rejection within the first 4 weeks was proven histologically in 42% of patients. It was associated with a greater expression of CD4+ CD7+ and CD8+ CD38+ T cells in the liver than in the blood (P < .001). A contemporaneous reduced expansion of liver Treg cells was evident in patients with acute rejection (P < .001). Our data suggested that a preferential Th1-like immune mechanism operated in local fashion as characterized by a decreased presence in the liver and blood of Treg cells.

Transforming growth factor beta-1 and interferon-alpha in the AIDS dementia complex (ADC): possible relationship with cerebral viral load?

Mechanisms involved in the pathogenesis of the AIDS-dementia complex are still unclear. The dichotomy between a small number of HIV-infected cells in the brain and their marked dysfunction could be related to a cellular amplification and/or activation of cerebral viral load by several cytokines. This link between cytokines and viral load could play a role in the generation of the clinical dementia syndrome. We have studied cerebral levels of transforming growth factor-beta1 and interferon-alpha, both in the mild and severe AIDS-dementia complex and also compared these cytokines with HIV RNA load in patients with different degrees of dementia. Our data indicate that production of different cytokines characterized the expression of clinical dementia. In the mild AIDS-dementia complex, there was a significant inverse correlation between interferon-alpha and transforming growth factor-beta1 (r = - 0.743; p < 0.001), and HIV-RNA was present in inverse proportion to transforming growth factor beta1 (r = - 0.751; p < 0.001). In patients with severe AIDS-dementia, transforming growth factor-beta1 was undetectable, while interferon-alpha level were higher than in mild AIDS dementia and correlated positively to cerebral HIV-RNA. No significant difference was evident between these cytokines in the serum of ADC patients and in the control samples. Our study suggests that a relationship is possible between productive HIV infection in the cerebral nervous system and a heterogenous and different expression of the immune response via a complex interaction of cytokines with a differential modulation of the dementia phenotype.

[Anti-hepatitis B vaccination in Campania. Final observations of a 3-year vaccination campaign, with special reference to infants born to HBsAg-positive mothers]. / La vaccinazione anti-epatite B in Campania. Osservazioni consuntive di 3 anni di campagna vaccinale, con particolare riguardo ai nati da madre HBsAg positiva.

The results obtained at the end of the first three years of a hepatitis B vaccination campaign in Campania, are reported. HEVAC-B and H-B-VAX proved innocuous and efficacious in producing anti-HBs. Newborn babies and children produced anti-HBs more often and with higher titres than adults. Titre 10 mUI/ml of anti-HBs persisted, in the responders for at least 36 months on average. AVH by HBV was observed in two adult non responders. Transplacental or delivery infection was observed in 9.3% of the babies born of HBsAg positive mothers and more often among babies born of HBeAg positive mothers. Infection by HBV was observed in 6.0% of the babies, in 4.0% of the children and in 12.0% of the adults, in spite of the production of anti-HBs. HB-antigenemia, was as a rule transitory, but sometimes fluctuating or persistent. Careful observation during a prolonged follow up is necessary for these subjects.

[Acute and chronic viral hepatitis in HIV positive patients]. / Le epatiti virali acute e croniche in pazienti HIV positivi.

In this study we evaluated the spreading of HBV, HCV, HDV and HIV among drug user patients. Spreading of hepatotropic viruses resulted high (HBV 84%, HCV 87%, HDV 7%), while spreading of HIV resulted relatively low (18%). During the period considered we did not observe any favourable effect of hepatotropic viruses on the progression of HIV infection, while the chronic evolution of acute viral hepatitis HBV related was high (90%) in HIV+ patients. HIV infection did not determine different histological findings in respect to HIV- patients with chronic hepatitis, HBV or HCV related

Fosamprenavir treatment in a highly active antiretroviral therapy schedule induces a HCV-RNA decrease and a Th1 network boost in HIV/HCV-coinfected patients.

HIV/HCV co-infected naïve patients (four females and six males) were evaluated for their response to the following treatment schedule: [(AZT 300 mg + 3TC 300 mg twice daily) + (fosamprenavir 700 mg twice daily) + (RTV 100 mg)]. CD3+/CD4+ T cells, interferon-gamma (INF-gamma) and interleukin-4 (IL-4) HCV-specific response, viral loads and transaminase levels were evaluated at time 0, and after 1, 3 and 6 months of therapy (T0, T1, T3, and T6 respectively). HIV-RNA, HCV-RNA and transaminases decreased at T1 and T3 compared with T0 (Mann-Whitney p <0.001, p <0.01 and p <0.01, respectively). At all time points, CD4+ and HCV-specific INF-gamma responses were higher (p <0.001; p <0.001), and IL-4 lower (p <0.01) after treatment. At T6, HCV-RNA was only negative in four out of ten patients whereas all had normal transaminase levels. These findings indicate that HAART treatment including fosamprenavir is able to activate a Th1 network in HIV/HCV co-infected patients. Moreover, these results, to be confirmed by larger cohort follow-up studies, suggest that this protease inhibitor could have potential implications for the treatment of chronic hepatitis C in HIV-positive patients.

Hepatic and peripheral T-lymphocyte patterns in patients with chronic hepatitis C infection: what correlation with histological activity?

The immunopathological processes involved in hepatic damage during chronic hepatitis C infection are not fully understood. Several works suggest the role of T helper 1 (Th1) immune response in both injury and fibrinogenesis. in this study, we have analyzed peripheral and intrahepatic T-lymphocyte subsets in liver biopsy specimens of 13 patients with definite chronic hepatitis C (CHC) to explore the possible direct role of these patterns in the evolution of necrotic inflammation and fibrogenesis scored according to the Knodell histological activity index. in particular, we have studied CD4+/CD7+ T-lymphocytes, as phenotypic marker of Th1 immune response, CD4+/CD7- as Th2 marker, and CD8+/CD38 as activated CD8+ lymphocytes. on statistical analyses we found a significant negative correlation in liver CD8+/CD38+ T-cells grading (r= -0.607; p<0.05) and staging index (r= -0.650; p<0.05) and between CD4+/CD7+ and grading (r= -0.626; p<0.05) index. in addition, we found a positive strong correlation between CD38+/CD8+ and CD4+/CD7+ T cells (r= 0.783; p<0.05) in liver tissue and between peripheral and liver resident CD8+/CD38+ (r= 683; p<0.05). moreover, the hepatic CD4+/CD7+ T-cells showed a positive correlation with peripheral CD 8+/CD38+ T-cells (r= 0.676; p<0.05). A strong positive correlation was also observed between grading and staging index (r= 0.921; p<0.01). we found no statistical correlation between the above variables and CD4+/CD7- T cells. our data could suggest that a preferential hepatic CD4+/CD7+ OR CD8+/CD38+ T cell subset was not directly associated with hepatic damage but, on the contrary, it could have been able to block liver injury. Concerning the peripheral subsets, the only CD8+/CD 38+ T-cells result reflect the CTL activity in the liver tissue. further studies are required to better understand the possible correlation between peripheral and liver resident T-helper, subset and other hepatic resident immunocompetent cells.

[Saquinavir + Zidovudine + Lamivudine in HIV positive naive or not naive patients] / Saquinavir + Zidovudina + Lamivudina in pazienti HIV positivi naive e non.

The aim of the study was to assess the virological/immunological outcome and safety of Saquinavir (SQV), Zidovudine (AZT) and Lamivudine (3TC) therapy in HIV patients. We retrospectively evaluated the charts of 36 HIV patients (male 87% median age 31 yrs, IVDA 72%) who underwent therapy with 5QV (1800 mg/die), AZT (500 mg/die) and 3TC (300 mg/die). 26 (72%) patients were previously on antiviral therapy for at least 16 weeks. No patient ranked in the CDC group. Patients were treated for at least 48 weeks. Hematological indices, changes in CD4+ cell count and plasma HIV-RNA levels were evaluated every 30, 60, and 90 days respectively. At baseline, CD4 cell count and viral load were 230/mcl and 4.55 log respectively for patients previously on therapy and 382/ l and 4.88 log respectively for naive patients. At week 48 the mean CD4+ cell count increase was 70/ l among previously treated and 98/mcl among untreated patients. In respect to the baseline, lower mean HIV-RNA levels were observed at week 12, 24 and 48. No patient showed AIDS-defining events. No patient discontinued therapy due to suspected toxicity. Patients showed a good immunological and virological response, regardless of their previous antiviral treatment. The terapy regimen was safe and well tolerated

Vaccination against hepatitis B in preschool children with Down's syndrome.

Twenty-nine healthy HBsAg- and HBsAb-negative children with Down's syndrome who were living at home (mean age 42 months; 19 M, 10 F) were vaccinated against hepatitis B virus either with recombinant DNA or plasma-derived vaccine. Both groups of children responded well to the vaccination schedules, with HBsAb seroconversion rates close to 100%. Vaccination against hepatitis B in preschool children with Down's syndrome is effective in spite of the existing abnormalities of the immune function.