Gaetano Scotto

Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48‐week treatment. Patients (n = 696) received peginterferon alfa‐2a, 180 mg/week, or peginterferon alfa‐2b, 1.5 mg/kg/week, plus ribavirin, 1000‐1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV‐RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8‐51.4] of the patients in the standard group and in 48.8% (CI 44.2‐53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (HEPATOLOGY 2007.)

Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial

BACKGROUND/AIMS To evaluate the therapeutic efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. METHODS One hundred and fifty-one patients were randomly assigned to receive either recombinant interferon alpha-2b (nine million units three times per week) and lamivudine (100 mg/daily per os) for 24 weeks or lamivudine alone (100 mg/daily per os) for 52 weeks. Patients were followed up for a further 48 weeks. RESULTS Sustained HBeAg seroconversion with undetectable serum levels of HBV DNA was observed in 25 of 76 patients (33%) treated with the combination therapy and in 11 of 75 patients (15%) treated with monotherapy (P=0.014). Histological improvement defined as a reduction of at least two points in the inflammation score as compared with pretreatment score was observed in 35 of 76 patients (46%) treated with combination therapy and in 20 of 75 patients (27%) treated with monotherapy (P=0.021). Both therapeutic regimens were well tolerated. CONCLUSIONS Six-month treatment with interferon alpha-2b and lamivudine in combination appeared to increase the rate of sustained HBeAg seroconversion compared to 1-year lamivudine monotherapy. However, the potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Determinants of relapse after a short (12 weeks) course of antiviral therapy and re‐treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection

In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24‐week course of therapy. RVR patients received pegylated interferon (Peg‐IFN) alfa‐2b (1.5 μg/kg) and ribavirin (1000‐1200 mg/day) for 12 weeks; those who relapsed were re‐treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1‐85.8) attained SVR, and 67 (14.1%, CI 10.4‐16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm3 [odds ratio, 2.51; confidence interval (CI), 1.49‐4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03‐2.70) were independently associated with relapse. Forty‐three of 67 patients with relapse agreed to be re‐treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI. (HEPATOLOGY 2008.)

Interferon alpha-2b and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial

PURPOSE To assess the efficacy of interferon alpha-2b and ribavirin in combination in the treatment of patients with chronic hepatitis C who had either failed to respond to therapy with interferon alpha (nonresponders), or who had relapsed after interferon therapy (relapsers). SUBJECTS AND METHODS Four hundred patients with chronic hepatitis C (200 nonresponders and 200 relapsers) were randomly assigned in equal numbers to receive either subcutaneous administration of recombinant interferon alpha-2b (3 million units three times per week) and ribavirin (1,000 to 1,200 mg/daily orally) or interferon alpha-2b alone (6 million units three times per week). Both ribavirin and interferon alpha-2b were given for 24 weeks. The patients were then followed for an additional 24 weeks. RESULTS At the end of the treatment period, normalization of serum alanine aminotransferase levels and absence of hepatitis C virus RNA were seen in 21% of nonresponders and in 39% of relapsers who were treated with interferon alpha-2b and ribavirin, compared with 5% of nonresponders (P = 0.001) and 9% of relapsers treated with interferon alpha-2b alone (P <0.001). At the end of follow-up, 14% of nonresponders and 30% of relapsers treated with the combination therapy had a sustained response, compared with 1% of nonresponders (P = 0.001) and 5% of relapsers treated with interferon alpha alone (P <0.001). CONCLUSIONS A 24-week course of treatment with interferon alpha-2b and ribavirin offers a chance of sustained response, whereas retreatment with interferon alpha-2b alone does not give satisfactory results. The role of long-term therapy in inducing prolonged remission remains to be explored.

Prevalence of Plasmodium spp. in malaria asymptomatic African migrants assessed by nucleic acid sequence based amplification

BackgroundMalaria is one of the most important infectious diseases in the world. Although most cases are found distributed in the tropical regions of Africa, Asia, Central and South Americas, there is in Europe a significant increase in the number of imported cases in non-endemic countries, in particular due to the higher mobility in todays society.MethodsThe prevalence of a possible asymptomatic infection with Plasmodium species was assessed using Nucleic Acid Sequence Based Amplification (NASBA) assays on clinical samples collected from 195 study cases with no clinical signs related to malaria and coming from sub-Saharan African regions to Southern Italy. In addition, base-line demographic, clinical and socio-economic information was collected from study participants who also underwent a full clinical examination.ResultsSixty-two study subjects (31.8%) were found positive for Plasmodium using a pan Plasmodium specific NASBA which can detect all four Plasmodium species causing human disease, based on the small subunit 18S rRNA gene (18S NASBA). Twenty-four samples (38%) of the 62 18S NASBA positive study cases were found positive with a Pfs25 mRNA NASBA, which is specific for the detection of gametocytes of Plasmodium falciparum. A statistically significant association was observed between 18S NASBA positivity and splenomegaly, hepatomegaly and leukopaenia and country of origin.ConclusionThis study showed that a substantial proportion of people originating from malaria endemic countries harbor malaria parasites in their blood. If transmission conditions are available, they could potentially be a reservoir. Thefore, health authorities should pay special attention to the health of this potential risk group and aim to improve their health conditions.

Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3

BACKGROUND & AIMS The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established. METHODS Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration. RESULTS At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25). CONCLUSIONS HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks.

Prevalence of HBV-genotypes in immigrants affected by HBV-related chronic active hepatitis

BACKGROUND The genetic heterogeneity of the HBV genome has been established and eight genotypes can be classified according to the criterion of >8% differences in the complete nucleotide sequence of the viral genome. AIMS To evaluate the prevalence of HBV-infection in a population of immigrants and to determine in patients with detectable serum HBV-DNA the HBV-genotypes. METHODS Between January 2005 and December 2005 a total of 556 immigrants were tested for HBsAg. In HBsAg positive patients the biochemical and virological activity of infection and the possible presence of co-infections (HCV, HDV, HIV) were evaluated. In patients with detectable serum HBV DNA, the HBV-genotype was determined by INNOLiPA. RESULTS Among the 556 subjects tested, 60 (10.7%) resulted HBsAg positive. All were men, and 42 (70%) come from Africa, 10 (16.6%) from Asia and 9 (14.4%) from East-Europe. 28/60 (46.6%) patients presented normal ALT levels (<40 IU/L) and undetectable serum HBV DNA (<100 copies/mL in real-time PCR), while 32 (53.4%) patients had ALT levels above laboratory normal values and detectable serum HBV DNA. Genotype distribution was as follow: genotype E, 16 (50%), genotype D, 9 (28.1%), genotype A, 7 (21.9%). CONCLUSION Our study evidences a moderate prevalence of HBV-infection in immigrants, particularly in sub-Saharan African people, and the potentiality of migratory flow in the introduction of genotype non-D hepatitis B virus, potentially characterized by a different natural history and, possibly, a different response to antiviral treatment.

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 years

BACKGROUND & AIMS In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. METHODS One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. RESULTS One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. CONCLUSIONS In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

Epidemiological and clinical features of HEV infection: a survey in the district of Foggia (Apulia, Southern Italy)

In this study we assessed the seroprevalence of hepatitis E virus (HEV) infection in both the Italian population and immigrants from developing countries in Foggia (Apulia, Southern Italy). The seroprevalence of HEV was determined in 1217 subjects [412 (34%) immigrants and 805 Italian subjects (blood donors, general population, HIV-positive, haemodialysis patients)]. Serum samples were tested for anti-HEV and confirmed by Western blot assay; in positive patients HEV RNA and genotype were also determined. There were 8·8% of patients that were positive to anti-HEV, confirmed by Western blot. The prevalence in immigrants was 19·7%, and in Italians 3·9% (blood donors 1·3%, general population 2·7%, HIV-positive patients 2·0%, haemodialysis patients 9·6%). Anti-HEV IgM was found in 38/107 (35·5%) of the anti-HEV-positive serum samples (34 immigrants, four Italians). This study indicates a higher circulation of HEV in immigrants and Italian haemodialysis patients, whereas a low prevalence of HEV antibodies was seen in the remaining Italian population.

Early and Sustained Virological Response in Non-Responders with Chronic Hepatitis C

AbstractObjectives: The purpose of this randomized open-label study was to assess the efficacy of treatment with pegylated interferon-α-2a versus pegylated interferon-α-2b, both plus ribavirin, in inducing early and sustained virological response (EVR and SVR) in chronic hepatitis C non-responders. Patients and methods: A total of 108 patients with chronic hepatitis C who were non-responders to previous combined therapy (standard interferon-α plus ribavirin for ≥3 months) were enrolled and equally randomized into two groups in this intention-to-treat analysis. The patients exhibited similar baseline features. One group received subcutaneous pegylated interferon-α-2a 180 μg once weekly, while the other was treated with subcutaneous pegylated interferon-α-2b 1.5 μg/ kg once weekly. Ribavirin 15 mg/kg/day was included in both protocols. Treatment duration for EVR was 12 weeks. Patients who demonstrated non-detectable hepatitis C virus (HCV) RNA or a ≥2 log10 reduction in viral load at week 12 continued therapy up to 48 weeks, with assessments every 3 months during a follow-up of 24 weeks. Results: All patients in both groups completed the EVR study, then seven patients receiving pegylated interferon-α-2a and seven patients receiving pegylated interferon-α2b discontinued treatment as a result of severe adverse effects. After 12 weeks of treatment, viral load reduction was >2 log10 with both pegylated interferon-α-2a (−2.53) and pegylated interferon-α-2b (−2.48) with no significant difference. At the end of week 48, HCV RNA was undetectable in 14 of 54 patients (25.9%) receiving pegylated interferon-α-2a and in 15 of 54 patients (27.7%) receiving pegylated interferon-α-2b. When terminating follow-up, an SVR was observed in 11 of 54 patients (20.4%) who received pegylated interferon-α-2a and 10 of 54 patients (18.4%) receiving pegylated interferon-α-2b. The incidence and severity of adverse events was similar in both groups. Conclusions: Our results seem to show that in chronic hepatitis C patients who are non-responsive to previous therapy, EVR to the two pegylated interferons did not significantly differ with a similar therapeutic efficacy defined as SVR.