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Biomedical subjects

Paolo Sacchi

Publications and source records attributed to Paolo Sacchi.

At least 19 recordsLinked to original sources
PubMed2005

Hepatotoxicity and nelfinavir: a meta-analysis.

BACKGROUND & AIMS: The inclusion of protease inhibitors in 3-drug highly active antiretroviral regimens for treating patients who are infected with human immunodeficiency virus-1 has had a significant impact in increasing survival and decreasing morbidity. However, the effectiveness of this class of drugs may be compromised by the occurrence of drug-related hepatotoxicity, which is problematic especially in individuals co-infected with hepatitis viruses. Based on its clinical and pharmacologic profile, especially its unique pattern of resistance, nelfinavir has been used frequently as a first-line protease-inhibitor therapy for human immunodeficiency virus-1-infected patients. The aim of this study was to identify the relative potential for developing hepatotoxicity for nelfinavir vs other protease inhibitors. METHODS: An exploratory meta-analysis of liver enzyme level increases was conducted in a combined total of 4268 patients derived from 3 large recently conducted prospective and retrospective clinical trials and a prospective cohort study. RESULTS: The results indicate that among 4 commercially available protease inhibitors and a 2-protease inhibitor combination, nelfinavir and indinavir are associated with the lowest rates of occurrence of severe hepatotoxicity (ie, combined estimates of liver enzyme level increases of 2.9% and 3.1%, respectively). The low rate of occurrence of severe hepatotoxicity for nelfinavir was shown even among patients co-infected with hepatitis viruses. CONCLUSIONS: In conclusion, these data provide support for the conclusion that differences in the potential for hepatotoxicity do exist among the commercially available protease inhibitors.

Chemical and Drug Induced Liver Injury↗
PubMed2005

Area-under-the-curve for peginterferon alpha-2a and peginterferon alpha-2b is not related to body weight in treatment-naive patients with chronic hepatitis C.

One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response. This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently: peginterferon alpha-2a is flat-dosed at 180 microg regardless of body weight, whereas peginterferon alpha-2b is dosed by body weight at 0.5-1.5 microg/kg. Bodyweight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response. To test this hypothesis, we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported pharmacokinetics study. In total, 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks. Patients were randomly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12). Ribavirin was dosed by body weight at 1000 mg/day (< or = 75kg) or 1200 mg/day (> 75 kg). We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b. Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [coefficient of variation (CV): 37.5%] and, despite dosing by body weight, for peginterferon alpha-2b (CV: 36.8%). Thus, there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a, and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b.

Antiviral Agents↗
PubMed2004

Host factors affecting the outcome of treatment of hepatitis C.

The development of peginterferon and ribavirin combination therapy has significantly improved the sustained virologic response (SVR) rates in patients with chronic hepatitis C. However, poor patient adherence to therapy negatively influences drug levels and drug exposure, often preventing the development of an inhibitory drug level. To optimize patient adherence, the clinician must recognize factors predicting low adherence and negotiate a treatment plan that the patient understands and to which he or she commits. If adverse effects become intolerable, continuing patients on a reduced dose rather than withdrawing treatment seems to confer considerable advantage in preserving the chance for attaining an SVR. Results of a head-to-head comparison have demonstrated the possibility that, in cases of dose reduction, levels of peginterferon alfa-2a could remain above the limit of detection, whereas those of peginterferon alfa-2b might not.

Antiviral Agents↗
PubMed2004

Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis c: a randomized, controlled study.

The two available pegylated interferon formulations, peginterferon alpha-2a and peginterferon alpha-2b, have different pharmacokinetic profiles; as a result they may have differing abilities to suppress the hepatitis C virus. A recently reported study by Formann and colleagues assessing early viral kinetics among 20 patients receiving peginterferon alpha-2b either once or twice weekly suggests that once-weekly administration of peginterferon alpha-2b is not sufficient for continuous exposure to interferon over 160 h. Twice-weekly administration is recommended to avoid increases in viral load as interferon levels decline prior to the end of the one-week dosing period. The objective of this study was to compare viral dynamics and pharmacokinetics between peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive chronic hepatitis C patients. Patients were randomized to receive peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12) once weekly. Serum peginterferon concentrations were measured at baseline, 24, 48, 120 and 168h. Hepatitis C virus (HCV) RNA was measured at baseline, 24, 48, 120 and 168 h during week 1 and then at 4 and 12 weeks. Peginterferon alpha-2b achieved maximal serum levels at 24 h, and then decreased rapidly. Of the 12 patients who received peginterferon alpha-2b, no drug was detectable in seven (58%) patients at 120 h and in 11 (92%) at 168 h. In contrast, peginterferon alpha-2a concentrations increased continuously over time, reaching maximal serum levels from 48 to 168 h. Drug was detectable in all 10 patients at 168 h. At weeks 1 and 4 no significant difference was observed in mean HCV RNA between the groups. However, at week 12, mean HCV RNA was significantly lower in the peginterferon alpha-2a group versus the peginterferon alpha-2b group (2.8126 vs 3.8726; P<0.01). The differences in mean HCV RNA values at 12 weeks may be related to the different absorption and distribution profiles of the two drugs. In conclusion, once-weekly administration of peginterferon alpha-2b (1.0 microg/kg/wk) may be insufficient for continuous interferon exposure; twice-weekly administration may help avoid increases in viral replication as interferon levels decline. Larger-scale studies assessing both viral kinetics and sustained virological responses are needed to confirm these observations.

Administration, Cutaneous↗
PubMed2003

Overview on the incidence and the characteristics of HIV-related opportunistic infections and neoplasms of the heart: impact of highly active antiretroviral therapy.

The manifestation of cardiac involvement in the course of HIV infection has been significantly changed since the introduction of highly active antiretroviral therapy. While in the pre-highly active antiretroviral therapy era the predominant cardiac pathology was represented by localization of opportunistic infection, now new forms of heart involvement are described. Among infectious agents, viruses and bacteria caused the majority of infections. The 'classic' opportunistic agents, such as Toxoplasma, non-tuberculous mycobacteria, cytomegalovirus and Cryptococcus, have virtually disappeared. Endocarditis is still the most frequent infectious disease of the heart in HIV-infected patients, occurring mainly in drug users, and with the improvement in prognosis, the need for cardiac surgery is increasing. Tuberculosis, the incidence of which is still high in poor resources settings where antiretroviral drugs are not available, is a frequent cause of pericarditis, frequently evolving into cardiac tamponade. Recent studies suggest the direct role of HIV as the cause of myocarditis and heart vessel pathology. This finding points out the need of improving our knowledge about the pathogenesis, diagnosis and treatment of this kind of complication.

AIDS-Related Opportunistic Infections↗
PubMed2003

Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome.

OBJECTIVES: Metabolic syndrome is a cluster of risk factors, such as central obesity, dyslipidemia, glucose intolerance, hypertension, related to insulin resistance. In HIV patients insulin resistance and several metabolic abnormalities of the metabolic syndrome have been described, but few and conflicting studies have investigated the behaviour of blood pressure. The aims of the present study were to evaluate the prevalence of hypertension in a large group of HIV-patients on highly active antiretroviral therapy (HAART) and to investigate the relationship between hypertension, metabolic syndrome and insulin resistance. DESIGN: Case control study. METHODS: We enrolled 287 HIV-positive patients on HAART (mean age 41.1 +/- 7.5 years) and 287 age- and sex-matched controls. Insulin resistance was estimated by the homeostasis model insulin resistance assessment (HOMA) index. Metabolic syndrome was defined according to the European Group for the Study of Insulin Resistance. RESULTS: HIV patients showed a prevalence of subjects with hypertension (34.2 versus 11.9%; P < 0.0001) and metabolic syndrome (33.1 versus 2.4%; P < 0.0001) higher than controls. HOMA was higher in HIV-patients than controls (3.3 +/- 1.2 versus 2.0 +/- 0.9; P < 0.0001). HOMA (3.7 +/- 1.0 versus 3.1 +/- 1.2; P < 0.001) and the prevalence of subjects with the metabolic syndrome (64.3 versus 16.9%; P < 0.0001) were greater in HIV-patients with than in those without hypertension. Multiple logistic regression analysis showed that family history of hypertension (odds ratio [(OR): 8.73; 95% confidence interval (CI): 4.31-17.70; P < 0.0001], metabolic syndrome (OR: 6.79; 95% CI: 3.27-14.10; P < 0.0001), lipodystrophy (OR: 4.80; 95% CI: 2.43-9.85; P < 0.0001) and HOMA (OR: 4.13; 95% CI: 1.14-14.91; P < 0.05) were predictors of hypertension in HIV-patients. CONCLUSIONS: The present study shows that hypertension is frequent in HIV patients on HAART and that hypertension appears to be linked to insulin resistance; in particular, hypertension seems to be a part of the metabolic syndrome.

Adult↗
PubMed2002

Fast relapse and high drop out rate of 48 weeks daily interferon monotherapy in HIV-infected patients with chronic hepatitis C.

BACKGROUND: The standard of care for HCV Hepatitis is the combination of interferon (IFN) plus Ribavirin. In HIV patients the use of this combination therapy may induce drug interactions, and reduces the adherence to HAART. The aim of this study is to evaluate safety and efficacy of a 48 weeks daily dose IFN schedule. METHODS: We evaluated 50 coinfected patients; alpha IFN 2a was administered at a dose of 3 MU daily. The baseline values were the following : CD4+ 515 cells/mmc (mean); HIV-RNA <50 copies/ml in all patients; HCV-RNA 28, 3 x 106 copies/ml. RESULTS: At 48 weeks, 10 patients (20%) achieved a biochemical and virological response according to an intention to treat analysis.Twenty four patients (48%) underwent a drop-out mainly by side effects related to overlapping toxicity of interferon and antiretroviral therapy. All the patients, who responded to the treatment, showed a fast relapse one month after the end of treatment. CONCLUSION: Although our results demonstrated a very poor outcome and a bad tolerance to interferon monotherapy, this approach should not be dropped out, mainly in patients at high risk for side effects and in those with cirrhosis who do not tolerate or are at increased risk for the use of ribavirin.

Antiviral Agents↗
PubMed2002

HCV chronic hepatitis in patients with HIV: clinical management issues.

HIV-hepatitis C virus (HCV) coinfection is common and affects more than one-third of all HIV infected persons worldwide. Prevalence among risk categories varies according to shared risk factors for transmission, mainly intravenous drug use (IDU) and hemophiliacs. Chronic HCV infection seems to accelerate the course of HIV disease, resulting in a worsened clinical and immunological progression. At the same time, several studies suggest that HIV disease modifies the natural history of HCV infection, leading to a faster course of progression from active hepatitis to cirrhosis, to end stage liver disease and death. HCV infection mimics opportunistic diseases because its natural history is significantly accelerated in HIV patients. Since highly active antiretroviral therapy (HAART) has slowed the progression of HIV disease and decreased the rate of HIV associated mortality, the prognosis of HIV disease has been modified, and the need to treat HCV coinfection become a significant issue. Because of the poor response rate obtained by either interferon alone or interferon thrice weekly plus ribavirin, the combination of pegylated interferon and ribavirin will probably become the standard of care, although the clinicians should be aware of the overlapping toxicity of nucleoside analogues and ribavirin. Many selected categories of patients pose particular challenges to physicians treating HCV infection: nonresponders to interferon, cirrhotic patients, and patients infected with both HCV and HBV. Liver transplantation in HIV patients is currently under evaluation, but should become the rescue therapy for HIV patients with end stage liver disease.

Anti-HIV Agents↗
PubMed2002

Distinct mutational drug resistance profiles of HIV-1 RNA in plasma and culture isolates of patients receiving antiretroviral therapy.

The differences in profiles of HIV mutational drug resistance between paired plasma samples and culture isolates were analyzed in treated and untreated HIV-infected patients. The DNA sequence of the entire protease gene and codons 1-320 of the reverse transcriptase gene was analyzed from the paired plasma samples and viral isolates. Differences in the distribution of resistance mutations from the two sources were detected in 13 of 14 patients receiving antiretroviral therapy. Some excess mutations, observed in plasma samples but not in culture isolates, are reportedly associated with resistance to antiretroviral drugs. These results emphasize the need for standardization and clinical laboratory use of phenotypic assays that avoid extensive cocultivation.

Antiretroviral Therapy, Highly Active↗