Roberto Tambini

Acyclovir for treatment of infectious mononucleosis: a meta-analysis.

A meta-analysis of 5 randomized controlled trials (RCT), involving 339 patients with acute infectious mononucleosis (IM) treated with acyclovir (ACV) was performed. ACV was given intravenously in 2 RCTs, which included patients with more severe disease, and orally in the remaining 3 RCTs, which included patients with mild to moderate IM. Both clinical and virological endpoint data available from RCT were evaluated in this study. There was a trend towards clinical effectiveness of ACV treatment, but no statistically significant results were achieved. In contrast, a significant reduction in the rate of oropharyngeal EBV shedding was observed at the end of the therapy (overall OR: 6.62; 95% CI: 3.56-12.29; p < 0.00001). However, no difference in EBV shedding was observed 3 weeks later. There was no significant difference on adverse events in the groups of patients treated with ACV or placebo. In conclusion, clinical data do not support use of ACV for the treatment of acute IM, despite good virological activity of this drug. There is a need for more effective treatment of EBV infection.

Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria

ABSTRACT The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-γ), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-γ, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 ± 2.8 pg/ml; controls, 3.2 ± 0.7 pg/ml) and IFN-γ (39.2 ± 67.6 pg/ml; controls, 8.4 ± 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 ± 2.6 pg/ml), whereas IFN-γ levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 ± 200.4 pg/ml and 56.6 ± 38.4 pg/ml, respectively; controls, 17.4 ± 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 ± 1.2 pg/ml; controls, 2.4 ± 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 ± 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-γ levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-γ may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.

Evolution of coinfection with human immunodeficiency virus and hepatitis C virus in patients treated with highly active antiretroviral therapy

A retrospective analysis of data from a cohort of patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were treated with highly active antiretroviral therapy (HAART) at 3 infectious diseases units in northern Italy was performed. While the patients were receiving HAART, CD4(+) cell counts significantly increased and HIV RNA serum levels decreased. However, no significant overall changes in alanine aminotransferase (ALT) levels and HCV RNA serum levels were observed. Fifteen (4.6%) of 323 patients died within 3 years of follow-up; death was related to cirrhosis in 5 patients (1.6%). No significant difference was observed between cirrhosis-related mortality and mortality related to other causes. Patients with ALT levels >4 times the normal values at initiation of HAART showed a significant decrease in ALT levels, whereas patients with normal ALT levels at initiation of HAART showed a significant increase over time, suggesting that HAART may have long-term beneficial or detrimental effects, depending on patient characteristics.

Antiretroviral drug resistance testing in patients with HIV-1 infection: a meta-analysis study.

Abstract BACKGROUND: HIV-1 resistance tests, both phenotype and genotype, have been entering clinical practice during the last years, but limited prospective studies have been reported in antiretroviral-treated patients with virological failure. PURPOSE: A meta-analysis of randomized controlled trials (RCTs) published or presented at the most important international conferences until February 2001 was performed to estimate the impact of resistance-guided antiretroviral therapy on virological outcome. METHOD: A search for RCTs was performed by using a MEDLINE database, Internet sources, and international conference presentations and was updated September 2001. All RCTs available, including four RCTs on genotype resistance testing, one RCT on phenotype resistance testing, and one RCT on genotypic and phenotypic testing, were analyzed. The rate of patients with undetectable viremia at 3 months was reported in all RCTs and the rate at 6 months was reported in 4 of 6 RCTs. RESULTS: The rate of patients with undetectable viral load after 3 months was 42.6% in patients who were treated based on genotype results and was 33.2% in patients who were treated based on standard of care (SOC; odds ratio [OR] 1.7; 95% CI: 1.3-2.2). At 6 months, undetectable viremia was observed in 38.8% and 28.7% of the patients, respectively (OR: 1.6; 95% CI: 1.2-2.2). In 142 patients, expert advice was provided to optimize clinical use of genotypic data. The higher rate of viral suppression was achieved in this subgroup of patients (50.7% vs. SOC 35.8%; OR 2.4; 95% CI 1.5-3.7). In contrast, undetectable viremia was achieved in 37.5% patients who were treated based on phenotype results versus 33.8% patients who were treated based on SOC (OR 1.1; 95% CI 0.8-1.6). CONCLUSION: These results support the use of a genotypic test in patients experiencing virological failure during antiretroviral treatment. Expert interpretation of the test may increase the probability of virological response.

Cerebrospinal Fluid Levels of IL-6 in Patients with Acute Infections of the Central Nervous System

Interleukin-6 (IL-6) activity was measured in the cerebrospinal fluid (CSF) of patients with acute bacterial or viral meningitis and in AIDS patients with various cerebral disorders. Increased levels of IL-6 were detected in the CSF of patients with bacterial meningitis. On the contrary, most of the samples from patients with viral meningitis (predominantly caused by mumps virus) had no detectable IL-6 activity in CSF. A moderate increase of IL-6 levels was detected in the CSF of AIDS patients with AIDS dementia complex (ADC), progressive multifocal leukoencephalopathy and cerebral toxoplasmosis. Moreover, higher levels of IL-6 were detected in the CSF of patients with cryptococcal meningitis. We conclude that the initial events of CSF inflammation in patients with acute viral meningitis are different from those in patients with acute bacterial meningitis, and the role of IL-6 is less critical to the process.

Anti-inflammatory response of IL-4, IL-10 and TGF-beta in patients with systemic inflammatory response syndrome.

The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a large number of clinical infective and non-infective conditions. The aim of this study was to investigate the role of anti-inflammatory cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Serum levels of IL-4, IL-10 and TGF-beta were determined in 45 patients with SIRS: 38 patients had SIRS of infectious origin, whereas seven patients had non-infectious SIRS. Twenty healthy subjects were used as controls. Serum levels of IL-4, IL-10 and TGF-beta were determined by an immunoenzyme assay. A significant increase of IL-4 was observed in these patients at the time of diagnosis and 5 days later. In contrast, serum levels of IL-10 were not increased at the time of diagnosis, but a slight decrease was noted after 5 days. Serum levels of TGF-beta were not increased at time of diagnosis, and a slight increase was observed after 5 days. Serum levels of IL-4 were significantly higher in patients with infectious SIRS at the time of diagnosis, whereas no significant difference between infectious and non-infectious SIRS was noted for serum levels of IL-10 and TGF-beta at the time of diagnosis and 5 days later. During SIRS, serum levels of IL-4 were significantly increased with a significant correlation between IL-4 and mortality, and only levels of IL-4 were significantly increased in the SIRS caused by infectious stimuli.

Nevirapine or Efavirenz Combined with Two Nucleoside Reverse Transcriptase Inhibitors Compared to HAART: A Meta-Analysis of Randomized Clinical Trials

Abstract Purpose: A meta-analysis of randomized controlled trials (RCTs) was performed to evaluate effectiveness and tolerability of triple antiretroviral therapy regimens in HIV-infected patients. Method: RCTs including the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP) or efavirenz (EFV) compared to two nucleoside reverse transcriptase inhibitor (NRTI) regimens and to three-drug regimens based on two NRTIs and one protease inhibitor (PI; highly active antiretroviral therapy [HAART]) were analyzed by Peto’s method. Results: A significant virological response was observed in patients treated with NNRTIs (odds ratio [OR] 3.6; 95% CI, 2.2-6.0), particularly in naïve patients (OR 7.4; 95% CI, 4.1-13.5). A fair reduction of HIV disease progression was also observed in patients treated with NNRTIs (OR 0.8; 95% CI, 0.6-1.0). Moreover, a significantly lower rate of HIV progression was observed in patients with a CD4 + lymphocyte count below 100/mm3. Five RCTs comparing two NRTIs and one NNRTI to HAART were subsequently evaluated. A slightly higher rate of virological response was observed with NNRTIs (OR 1.6; 95% CI, 1.1-2.1), whereas no difference was observed concerning progression of HIV disease. Conclusion: Antiretroviral therapy including NVP or EFV was more effective in reducing viral load than therapy with only two NRTIs and was slightly more effective than HAART. Effectiveness in delaying HIV disease progression was less evident, even though lower rate of progression was observed in patients with advanced HIV infection compared to two NRTIs alone.

Circulating levels of FAS/APO-1 in patients with the systemic inflammatory response syndrome

Resolution of inflammation/infection involves removal of neutrophils and other inflammatory cells by the induction of apoptosis. Fas/Apo-1 is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form. In this study we investigated the role of circulating Fas/Apo-1 in patients with systemic inflammatory response syndrome (SIRS). We evaluated 57 critically ill patients, 34 with infectious SIRS (sepsis and septic shock), and 23 patients with noninfectious SIRS. Circulating Fas/Apo-1 was determined by a commercially available immunoassay. Our results clearly show that levels of Fas/Apo-1 were significantly elevated in patients with infectious and noninfectious SIRS (10.4 +/- 8.1 pg/mL, controls: 5.0 +/- 0.7 pg/mL; p < 0.0001). In addition, Fas/Apo-1 levels were not able in predicting in predicting poor outcome of patients with SIRS. In conclusion, these results show that increased levels of Fas/Apo-1 from patients with SIRS is a mechanism which contribute to inflammatory response through accumulation of neutrophils at sites of inflammation/infection.

Circulating levels of granulocyte macrophage colony-stimulating factor in patients with the systemic inflammatory response syndrome.

OBJECTIVES Granulocyte-macrophage colony stimulating factor (GM-CSF) is a key regulator cytokine that modulates the proliferation and maturation of polymorphonuclear and mononuclear progenitors. This study was designed to investigate and clarify the role of GM-CSF in 52 critically ill patients with systemic inflammatory response syndrome (SIRS). METHODS Serum levels of GM-CSF were detected by an immunoenzyme assay. RESULTS Our results clearly show that the serum concentrations of GM-CSF were significantly elevated in patients with infectious and noninfectious SIRS (33.2+/-45.7pg/ml, controls: 17.2+/-9.8pg/ml; p=0.0303). In addition, GM-CSF levels significantly decreased in patients with SIRS, particularly in patients with infectious SIRS, 5 and 7 days later. There was a clear tendency toward higher levels of GM-CSF in patients with poor, as compared with those having a good outcome of the disease. CONCLUSION These results show that GM-CSF may play an important role in patients with infectious and noninfectious SIRS, and that GM-CSF levels progressively and significantly decrease in patients with infectious SIRS.

A retrospective study on the efficacy and safety of amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients

To evaluate the efficacy and safety of Amphotericin B dissolved in dextrose (Amb) or in a lipid emulsion (Intralipid, Amb-IL) in AIDS patients with cryptococcal meningitis, we conducted a retrospective study in 30 AIDS patients with cryptococcal meningitis. A clinical complete resolution was obtained in 11 patients (55%) treated with Amb, and in six patients (60%) treated with Amb-IL. Intralipid did not decrease the infusion-related adverse effects, in particular nephrotoxicity and anaemia. Our results indicate that Amb-IL formulation is useful in the treatment of cryptococcal meningitis in AIDS patients, but it does not reduce the infusion-related adverse events.