Gaetano Filice

Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients

Objective:To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment. Methods:The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points. Results:Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9–28.9] due to toxicity and 7.6% (95% CI, 4.9–10.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32–0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10–3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09–7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80–0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74–5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06–0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04–1.26 versus hard-gell saquinavir). Conclusions:If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.

Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: A pilot study

Real‐time shear wave elastography (SWE) is a novel, noninvasive method to assess liver fibrosis by measuring liver stiffness. This single‐center study was conducted to assess the accuracy of SWE in patients with chronic hepatitis C (CHC), in comparison with transient elastography (TE), by using liver biopsy (LB) as the reference standard. Consecutive patients with CHC scheduled for LB by referring physicians were studied. One hundred and twenty‐one patients met inclusion criteria. On the same day, real‐time SWE using the ultrasound (US) system, Aixplorer (SuperSonic Imagine S.A., Aix‐en‐Provence, France), TE using FibroScan (Echosens, Paris, France), and US‐assisted LB were consecutively performed. Fibrosis was staged according to the METAVIR scoring system. Analyses of receiver operating characteristic (ROC) curve were performed to calculate optimal area under the ROC curve (AUROC) for F0‐F1 versus F2‐F4, F0‐ F2 versus F3‐F4, and F0‐F3 versus F4 for both real‐time SWE and TE. Liver stiffness values increased in parallel with degree of liver fibrosis, both with SWE and TE. AUROCs were 0.92 (95% confidence interval [CI]: 0.85‐0.96) for SWE and 0.84 (95% CI: 0.76‐0.90) for TE (P = 0.002), 0.98 (95% CI: 0.94‐1.00) for SWE and 0.96 (95% CI: 0.90‐0.99) for TE (P = 0.14), and 0.98 (95% CI: 0.93‐1.00) for SWE and 0.96 (95% CI: 0.91‐0.99) for TE (P = 0.48), when comparing F0‐F1 versus F2‐ F4, F0‐ F2 versus F3‐F4, and F0 ‐F3 versus F4, respectively. Conclusion: The results of this study show that real‐time SWE is more accurate than TE in assessing significant fibrosis (≥F2). With respect to TE, SWE has the advantage of imaging liver stiffness in real time while guided by a B‐mode image. Thus, the region of measurement can be guided with both anatomical and tissue stiffness information. (HEPATOLOGY 2012;56:2125–2133)

Hepatocellular Mitochondrial Alterations in Patients With Chronic Hepatitis C: Ultrastructural and Biochemical Findings

OBJECTIVE:Hepatitis C virus (HCV) infection is associated with increased lipoperoxidation, which may lead to interference with mitochondrial function with possible depletion of mitochondrial DNA (mtDNA). We correlated the ultrastructural findings of liver biopsy specimens with the lipoperoxidation markers and contents of mtDNA in chronic hepatitis C (CHC) patients with a different HCV genotype.METHODS:Liver biopsy samples obtained from 75 CHC patients were processed for histological and electron microscopic examination. Twenty-two subjects without known liver disease served as controls. Hepatic glutathione in its reduced (H-GSH) and oxidized (H-GSSG) forms were determined from biopsy specimens by high-performance liquid chromatography. Plasmatic and lymphocytic GSH and erythrocytic malonyldialdehyde (MDA) were also determined, along with the ratio between mtDNA and nuclear DNA (nDNA).RESULTS:Ultrastructural alterations of the mitochondria were documented in 23 patients with genotype 1b, compared with 15 patients with genotype 2a/2c (p= 0.020) and seven patients with genotype 3a (p < 0.001). A significant depletion of H-GSH and lymphocytic GSH, an increase of H-GSSG and MDA, and a reduction of the mtDNA/nDNA ratio were documented in patients with genotype 1b, compared with patients with genotype 2a/2c and 3a and with controls.CONCLUSIONS:In patients with genotype 1b frequent ultrastructural alterations of the mitochondria may be observed, and the depletion of mtDNA in these patients may represent the expression of a greater impairment of the process of oxidative phosphorylation. An increased production of free radicals in patients with genotype 1b may influence the evolution of the liver disease by enhancement of the cytopathic effect of HCV.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Point shear wave elastography method for assessing liver stiffness

AIM To estimate the validity of the point shear-wave elastography method by evaluating its reproducibility and accuracy for assessing liver stiffness. METHODS This was a single-center, cross-sectional study. Consecutive patients with chronic viral hepatitis scheduled for liver biopsy (LB) (Group 1) and healthy volunteers (Group 2) were studied. In each subject 10 consecutive point shear-wave elastography (PSWE) measurements were performed using the iU22 ultrasound system (Philips Medical Systems, Bothell, WA, United States). Patients in Group 1 underwent PSWE, transient elastography (TE) using FibroScan (Echosens, Paris, France) and ultrasound-assisted LB. For the assessment of PSWE reproducibility two expert raters (rater 1 and rater 2) independently performed the examinations. The performance of PSWE was compared to that of TE using LB as a reference standard. Fibrosis was staged according to the METAVIR scoring system. Receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating characteristic curve (AUC) for F ≥ 2, F ≥ 3 and F = 4. The intraobserver and interobserver reproducibility of PSWE were assessed by calculating Lins concordance correlation coefficient. RESULTS To assess the performance of PSWE, 134 consecutive patients in Group 1 were studied. The median values of PSWE and TE (in kilopascals) were 4.7 (IQR = 3.8-5.4) and 5.5 (IQR = 4.7-6.5), respectively, in patients at the F0-F1 stage and 3.5 (IQR = 3.2-4.0) and 4.4 (IQR = 3.5-4.9), respectively, in the healthy volunteers in Group 2 (P < 10(-5)). In the univariate analysis, the PSWE and TE values showed a high correlation with the fibrosis stage; low correlations with the degree of necroinflammation, aspartate aminotransferase and gamma-glutamyl transferase (GGT); and a moderate negative correlation with the platelet count. A multiple regression analysis confirmed the correlations of both PSWE and TE with fibrosis stage and GGT but not with any other variables. The following AUC values were found: 0.80 (0.71-0.87) for PSWE and 0.82 (0.73-0.89) for TE (P = 0.42); 0.88 (0.80-0.94) for PSWE and 0.95 (0.88-0.98) for TE (P = 0.06); and 0.95 (0.89-0.99) for PSWE and 0.92 (0.85-0.97) for TE (P = 0.30) for F ≥ 2, F ≥ 3 and F = 4, respectively. To assess PSWE reproducibility, 116 subjects were studied, including 47 consecutive patients scheduled for LB (Group 1) and 69 consecutive healthy volunteers (Group 2). The intraobserver agreement ranged from 0.83 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 1 and from 0.84 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 2. The interobserver agreement yielded values from 0.83 (95%CI: 0.78-0.88) to 0.93 (95%CI: 0.91-0.95). CONCLUSION PSWE is a reproducible method for assessing liver stiffness, and it compares with TE. Compared with patients with nonsignificant fibrosis, healthy volunteers showed significantly lower values.

The pavia consensus statement

The intersection of cardiovascular disease and HIV infection is common and complex, yet inadequately understood. Considering and managing actual or potential cardiovascular illness in patients with HIV infection are important aspects of HIV care. As the diagnosis and management of cardiovascular disease is itself complex, specialists in this area of medicine may need to be consulted. They, in turn, need to be aware of the complex manifestations of HIV infection and the cardiovascular implications of HIV therapy. The bilateral nature of these interactions is an important issue considered in the present report.

Comparison of the Plasma Pharmacokinetics of Lamivudine During Twice and Once Daily Administration in Patients with HIV

ObjectiveTo compare the plasma pharmacokinetics of lamivudine 150mg twice daily and 300mg once daily in patients with HIV-1 infection.DesignNonblind, sequential, pharmacokinetic study.Participants13 patients with HIV-1 infection (median age 36 years).MethodsPatients were tested during twice daily and then once daily regimens of lamivudine. In both regimens, the total daily dose of lamivudine was identical (300 mg/day). Blood samples for pharmacokinetic analysis were taken over a 12-hour period after ≥7 days of twice daily administration, and again over a 24-hour period after 7 days of once daily administration,.Results12 patients completed the study. Lamivudine pharmacokinetic parameters (mean ± SD) after administration of 150mg twice daily were: peak plasma concentration (Cmax) 2077 ± 816 μg/L; trough plasma concentration (Cmin) 332 ±219 μg/L; elimination half-life (t½β) 6.1 ± 1.9h; time to Cmax (tmax) 1.6 ± 0.7h; average concentration over the dosage interval (Cav) 711 ± 269 μg/L; and area under the concentration-time curve (AUC) over 2 dosage intervals (24h) 17 085 ± 6464 μg □h/L. Corresponding values after administration of 300mg once daily were: Cmax3461 ± 854 μg/L; Cmin 146 ± 87 μg/L; t½β 7.9 ± 3.4h; tmax2.2 ± 1.3h; Cav 705 ± 177 μg/L; and AUC over 1 dosage interval (24h) 16 644 ± 4150 μg □ h/L. Statistical analysis showed a significant difference (p < 0.05) between the 2 schedules for Cmax and Cmin values, whereas no significant differences emerged for the other parameters.ConclusionsOnce daily lamivudine leads to a similar exposure in plasma as twice daily administration of the same total daily dose. Since once daily administration may result in improved compliance, these results provide the pharmacokinetic basis for using lamivudine in a once daily regimen. Randomised clinical studies are needed to confirm this pharmacokinetic finding.

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.

Performance of Real-Time Strain Elastography, Transient Elastography, and Aspartate-to-Platelet Ratio Index in the Assessment of Fibrosis in Chronic Hepatitis C

OBJECTIVE The purpose of this article is to evaluate the diagnostic performance of transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index in assessing fibrosis in patients with chronic hepatitis C by using histologic Metavir scores as reference standard. SUBJECTS AND METHODS Consecutive patients with chronic hepatitis C scheduled for liver biopsy were enrolled. Liver biopsy was performed on the same day as transient elastography and real-time strain elastography. Transient elastography and real-time strain elastography were performed in the same patient encounter by a single investigator using a medical device based on elastometry and an ultrasound machine, respectively. Diagnostic performance was assessed by using receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) analysis. RESULTS One hundred thirty patients (91 men and 39 women) were analyzed. The cutoff values for transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index were 6.9 kPa, 1.82, and 0.37, respectively, for fibrosis score of 2 or higher; 7.3 kPa, 1.86, and 0.70, respectively, for fibrosis score of 3 or higher; and 9.3 kPa, 2.33, and 0.70, respectively, for fibrosis score of 4. AUC values of transient elastography, real-time strain elastography, aspartate-to-platelet ratio index were 0.88, 0.74, and 0.86, respectively, for fibrosis score of 2 or higher; 0.95, 0.80, and 0.89, respectively, for fibrosis score of 3 or higher; and 0.97, 0.80, and 0.84, respectively, for fibrosis score of 4. A combination of the three methods, when two of three were in agreement, showed AUC curves of 0.93, 0.95, and 0.95 for fibrosis scores of 2 or higher, 3 or higher, and 4, respectively. CONCLUSION Transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index values were correlated with histologic stages of fibrosis. Transient elastography offered excellent diagnostic performance in assessing severe fibrosis and cirrhosis. Real-time elastography does not yet have the potential to substitute for transient elastography in the assessment of liver fibrosis.

Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort

BackgroundThe risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed.MethodsRetrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade ≥III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity.ResultsIncidence of grade ≥III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade ≥III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome.ConclusionUse of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.