Treatment with direct-acting antiviral agents of hepatitis C virus infection in injecting drug users: A prospective study.

In this prospective study, we evaluated the effectiveness and tolerability of novel therapies against hepatitis C virus (HCV) in a cohort of PWID enrolled at our centre from April 2015 to July 2016. In this analysis, a total of 174 patients were included: eleven (6.3%) were treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) containing regimens, 163 (93.7%) with IFN-free treatments. RBV has been used in 70 patients (40.2%); 59 (33.9%) patients were in opioid substitution therapy (OST) with methadone or buprenorphine. Overall, sustained virological response (SVR) has been observed in 162 subject (93.1%), breakthrough (BT) in three (1.7%), relapse in one (0.6%) and dropout in eight (4.6%). Treatment was interrupted for clinical conditions in seven patients: six (3.4%) had hepatic decompensation and one died for hepatocellular carcinoma (HCC). In multivariate analysis, predictive factors of treatment failure were as follows: albumin level below 3 g/dL (OR=7.190; 95% IC=1.236-41.837; P<.001), MELD score >10 (OR=5.886; 95% IC=1.411-35.994; P<.001) and years of HCV infection >20 (OR=1.286; 95% IC=0.556-9.455; P=.016). In conclusion, treatment with DAAs was effective and well tolerated in PWID; cirrhotic subjects with MELD > 10 and albumin low level showed a higher risk of developing serious adverse events and treatment failure.

Role of CYP27B1+2838 promoter polymorphism in the treatment of chronic hepatitis B HBeAg negative with PEG-interferon.

In HBV-infected patients, the vitamin D deficiency has been related to chronic liver diseases, progression of hepatic fibrosis and poor response to the treatment. The CYP27B1 gene, which encodes the 1-α-hidroxylase and involved in the 1,25-dihydroxyvitamin D synthesis, was recently associated to type-1 diabetes, autoimmune disorders and treatment response in HCV. Then, we aimed to investigate the role of CYP27B1 polymorphisms in HBV treatment with PEG-IFN. We retrospectively enrolled 190 patients with chronic hepatitis B HBeAg negative treated for 48 weeks with PEG-IFN α-2a. We examined the role of rs4646536 CYP27B1 SNP (CYP27B1+2838) according to virological and serological response. Our results showed that the TT genotype of CYP27B1+2838 was significantly prevalent in patients with end-of-therapy virological response (37.6%) vs CT/CC (9.4%) (P < 0.001). Virological relapse was prevalent in patients with CT/CC genotype (12.6%) vs TT genotype (2.1%) (P < 0.001). TT genotype was also related to HBsAg loss (P = 0.004) and anti-HBs appearance (P = 0.002). In the multivariate analysis, the TT genotype resulted to be a good positive predictor of sustained virological response (OR = 5.632, IC = 1.938-16.368, P = 0.001) and serological response (OR = 6.161, IC = 1.856-20.457, P = 0.003). The CYP27B1+2838 polymorphism may be useful as pretreatment factor to selection of patients with higher probability of response to therapy.

Significant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir.

The new standard of care for treatment for infection with genotype 1a/b of HCV now is the combination of telaprevir (TLV) with ribavirin (RBV) and pegylated interferon (Peg-IFN). Although this new therapy gives a higher response rate than the Peg-IFNα plus RBV treatment, a greatly higher rate of anaemia onset has been reported in all clinical trials. Because haemolysis is a typical concentration-dependent side effect of RBV, modulated by ITPA gene polymorphisms, we aimed to compare the early RBV plasma exposure of nine patients after 2 weeks of treatment with triple therapy with RBV concentrations of 187 patients treated with RBV and Peg-IFNα over the same time scale; this comparison was performed also stratifying patients according to ITPA polymorphism genotype and anaemia onset after 1 month of treatment. All TLV-treated patients had unfavourable ITPA genetic profile and developed anaemia. Moreover, both the rate of anaemia onset and the haemoglobin loss at 1 month were significantly higher in patients treated with TLV. This observation has been confirmed also in patients with the same ITPA genetic profile in double therapy. Strikingly, also early RBV plasma concentrations were significantly higher in patients treated with TLV. These unbiased results confirm the observations recently reported and suggest that the high rate of anaemia onset could be mainly due to the increased RBV exposure, probably caused by a 'boosting effect' by TLV. These data highlight the great importance of early therapeutic drug monitoring of RBV in the management of anaemia in the triple therapy.

Sequential therapy with entecavir and PEG-INF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes.

Complete eradication of hepatitis B virus (HBV) is rarely achieved. Treatment options include currently available nucleos(t)ide analogues and pegylated interferon. The aim of our exploratory study was to assess the effectiveness of sequential therapy for chronic hepatitis B (CHB) vs the current standard of care. We evaluated an association with entecavir and pegylated interferon alfa-2a (PEG-IFN) in 20 patients with hepatitis B, high HBV viremia and genotypes A, B, C and E. Patients received entecavir alone for 12 weeks, then entecavir and PEG-IFN for 12 weeks, lastly PEG-IFN alone for 36 weeks. The results were compared with 20 patients (control group) treated in the past with 48 weeks of PEG-IFN monotherapy. Our results show that complete sustained virological response (SVR) and partial SVR were, respectively, 60% and 80% in the study group and 10% and 30% in the control group; anti-HBe seroconversion rate were 76.9% vs 15%, and anti-HBs seroconversion were 20% vs 0%, respectively. We found a correlation among different genotypes and virological and serological outcomes - genotype C has a better virological response, while genotype A had a better serological response, and E genotype had a poor response. These results show that a sequential approach is a promising strategy of treatment in patients with CHB and high viremia in comparison with PEG-IFN monotherapy. The E genotype seems to have the worse rate of response and requires other treatment strategies.

The use of trough ribavirin concentration to predict sustained virological response and haematological toxicity in HIV/HCV-co-infected patients treated with ribavirin and pegylated interferon.

OBJECTIVES: To study the association between trough ribavirin concentration (C(trough)) with sustained virological response (SVR) and haemoglobin (Hb) decrease in HIV/hepatitis C virus (HCV)-co-infected (HIV+/HCV+) patients treated with anti-HCV therapy. METHODS: HIV+/HCV+ patients treated with ribavirin and pegylated interferon were prospectively evaluated. Qualitative and quantitative HCV-RNA, Hb levels and ribavirin C(trough) were measured at baseline and weeks 2, 4, 12, 24, 36 and 48 during therapy. HCV-RNA was also measured at 24 weeks after the end of therapy. Efficacy analysis was performed on patients with a definitive virological outcome (SVR, relapser and non-responder), whereas for toxicity analysis, dropouts were considered until the last available observation. RESULTS: Fifty-two patients (54.7% with genotype 1 or 4) were included. Overall, no correlation between ribavirin C(trough) and early virological response (EVR) nor SVR was found. However, in patients with genotype 1 or 4, ribavirin C(trough) was independently associated with EVR (P = 0.036) and SVR (P = 0.046). A ribavirin C(trough) cut-off of 1600 ng/mL was found to be associated with both EVR (chi(2) = 5.69, P = 0.028) and SVR (chi(2)=4.2, P = 0.04). Higher ribavirin C(trough) correlated with Hb decrease (R = -0.361, P = 0.009) and was independently associated with an Hb decrease of >4 g/dL (P = 0.009). Receiver operating characteristic (ROC) analysis indicated that a ribavirin C(trough) of >2300 ng/mL was associated with an Hb decrease of >4 g/dL (chi(2) = 8.08, P = 0.01). CONCLUSIONS: Our study confirmed a relationship between ribavirin exposure and both efficacy and toxicity. Moreover, we found ribavirin C(trough) cut-offs for both SVR in genotypes 1 and 4 and overall haematological toxicity. These findings deserve further clinical evaluation.

Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.

BACKGROUND: The epidemiology of acute hepatitis C has changed during the past decade in Western countries. Acute HCV infection has a high rate of chronicity, but it is unclear when patients with acute infection should be treated. METHODS: To evaluate current sources of hepatitis C virus (HCV) transmission in Italy and to assess the rate of and factors associated with chronic infection, we enrolled 214 consecutive patients with newly acquired hepatitis C during 1999-2004. The patients were from 12 health care centers throughout the country, and they were followed up for a mean (+/- SD) period of 14+/-15.8 months. Biochemical liver tests were performed, and HCV RNA levels were monitored. RESULTS: A total of 146 patients (68%) had symptomatic disease. The most common risk factors for acquiring hepatitis C that were reported were intravenous drug use and medical procedures. The proportion of subjects with spontaneous resolution of infection was 36%. The average timespan from disease onset to HCV RNA clearance was 71 days (range, 27-173 days). In fact, 58 (80%) of 73 patients with self-limiting hepatitis experienced HCV RNA clearance within 3 months of disease onset. Multiple logistic regression analyses showed that none of the variables considered (including asymptomatic disease) were associated with increased risk of developing chronic hepatitis C. CONCLUSIONS: These findings underscore the importance of medical procedures as risk factors in the current spread of HCV infection in Italy. Because nearly all patients with acute, self-limiting hepatitis C--both symptomatic and asymptomatic--have spontaneous viral clearance within 3 months of disease onset, it seems reasonable to start treatment after this time period ends to avoid costly and useless treatment.

A randomized trial of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin.

BACKGROUND: There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin. AIM: To evaluate efficacy and safety of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in such patients. METHODS: 161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily and amantadine 200 mg/daily for 12 months. RESULTS: At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure. CONCLUSIONS: The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).

Relationship between the early boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy.

In a prospective cohort of 18 patients treated with boceprevir, we examined the role of boceprevir plasma concentration at the onset of breakthrough during the treatment. Nine patients experienced breakthrough during therapy. The resistance patterns were as follows: S122S/R, I132V, T54A/I132V, V156S/I170A, V36M/T54S/R155K, V36M/R155K and T54/R155K. Boceprevir-S isomer (SCH 534128) median concentration in patients with breakthrough was 48.3 ng/mL (interquartile range 43-58 ng/mL); in others, it was significantly (p 0.019) higher: 151 ng/mL. Low boceprevir plasma concentration can lead to virologic resistance; therapeutic drug monitoring should be used to prevent the onset of viral breakthrough during triple-regimen therapy with boceprevir.

Altered adrenocorticotropin and cortisol response to corticotropin-releasing hormone in HIV-1 infection.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are common in HIV infection. To characterize further the site of these derangements and their possible causes, eight male drug addicts with symptomatic HIV infection (stage IV C2) underwent the following investigations: repeated baseline determinations of cortisol, adrenocorticotropin (ACTH), interleukin 1 beta (IL-1 beta), IL-6 and interferon alpha (IFN-alpha); and ovine corticotropin-releasing hormone (CRH) test (100 micrograms IV) for ACTH and cortisol determinations. Baseline cortisol levels were either normal or elevated in all patients. A significant linear correlation was found between baseline levels of cortisol and both IL-6 (r = 0.955; p < 0.001) and IL-1 beta (r = 0.863; p < 0.005), but not between cortisol and ACTH or between ACTH and circulating cytokines. Both ACTH and cortisol responses to CRH were nearly absent in six out of eight patients, and delayed in the others. The areas under the curves of both ACTH and cortisol after CRH were significantly lower in HIV patients than in a group of eight healthy control subjects (p = 0.0157 for ACTH and p = 0.046 for cortisol). Out data suggest the possibility of an inappropriate stimulation of the HPA axis in symptomatic HIV infection by HIV-induced release of cytokines, with a blunted pituitary and adrenal response to CRH.

Pulmonary sarcoidosis associated with Leydig cell testicular neoplasm.

The first case of association between Leydig cell testicular tumor and sarcoidosis is reported. From a review of the literature, this is the ninth case of association between a testicular tumor and Besnier's disease. Lung biopsy should always be performed in patients with testicular cancer when retroperitoneal lymph node involvement cannot be demonstrated in order to avoid unnecessary antineoplastic chemotherapy.

Treatment with interferon-alpha2b of naive non-cirrhotic patients with chronic hepatitis C according to viraemia and genotype. Results of a randomized multicentre study. The North West Italian Hepatological Group.

OBJECTIVE: To establish whether tailoring the dosage of interferon (IFN)-alpha2b in non-cirrhotic naive patients with chronic hepatitis C according to hepatitis C virus (HCV) genotype and viraemic level improves the rate of sustained response (normal alanine aminotransferase values and HCV-RNA negativity 6 months after the end of therapy). PATIENTS: A total of 538 consecutively collected HCV-positive patients with non-cirrhotic chronic hepatitis who had not been previously treated. METHODS: Quantitative viraemia and genotype were determined in each patient by a core laboratory. The patients were randomized to: Group 1, 86 patients with genotype non-1 and viraemia < 1,000,000 HCV genome equivalents/ml (GenEq/ml) treated with 3 Million Units (MU) IFN three times weekly (t.i.w.) for 1 year; Group 2, 42 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 3 MU IFN t.i.w. for 1 year; Group 3, 46 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 5 MU IFN t.i.w. for 1 year; Group 4, 85 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 5, 88 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN t.i.w. for 1 year; Group 6, 94 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 7, 97 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN daily for 2 months followed by 5 MU t.i.w. for a further 10 months. RESULTS: According to an intention-to-treat analysis, a sustained virological response (negative HCV-RNA by polymerase chain reaction 6 months after the end of therapy) was observed in 42% of Group 1 patients, in 21% of Group 2 patients versus 24% of Group 3 patients [P = not significant (NS)], in 28% of Group 4 patients versus 35% of Group 5 patients (P = NS), and in 8.5% of Group 6 patients versus 12% of Group 7 patients (P = NS). CONCLUSIONS: Even though a trend towards a therapeutic improvement is observed, the adoption of more aggressive IFN protocols, such as induction therapy, does not appear to significantly improve the rate of sustained response in patients with chronic hepatitis C associated with HCV genotype 1 and highly viraemic levels compared with standard therapy. Moreover, patients with only one unfavourable predictive factor (genotype 1 or high viraemia) do not gain major therapeutic benefits when treated with high doses of IFN.

Is a 3-month course of treatment with Peg-interferon effective in acute HCV hepatitis?

From February 2002, all the consecutive patients referring to the Department of Infectious Diseases, University of Turin, who were diagnosed as having acute HCV hepatitis were included in a prospective cohort study to evaluate if a 3-month course of Peg-Interferon alpha-2b (1.5 microg/kg once weekly) is effective to decrease the risk of progression to chronic disease. ALT and HCV-RNA measurements were scheduled at week 4 and 12 during treatment, and 24 weeks after the end of therapy. As of April 2003, ten patients were enrolled in the study. As to HCV genotype, seven patients had type 1 and 3 type non-1. At entry, median HCV-RNA level was 129500 (range: 3000-3100000 copies/mL) and six patients were symptomatic. Treatment was given within 20 days (range: 8-30) of the ALT peak. All patients completing 4 weeks (n = 9) and 12 weeks of treatment (n = 7) had undetectable HCV-RNA. Five patients who completed the 24-week follow-up after the end of treatment had a sustained viral response with ALT levels within normal range. Therapy was well tolerated in all patients. Even if our data are not definitive, our results show that once-weekly administration of Peg-interferon alfa-2b in patients with acute HCV infection may be an effective and convenient regimen.

[Atypical hepatitis]. / L'epatite atipica.

Acute viral hepatitis has a rather homogeneous clinical pattern, excepting a few features which are related to the specific viral agent. However, a few cases may be defined "atypical", as fas as clinical features, transmission pattern, serology are concerned. These include cholestatic hepatitis syndrome, fulminant HEV hepatitis during pregnancy, neonatal hepatitis. Non-typical aspects may be observed when extrahepatic manifestations are present (cryoglobulinemia, bone marrow aplasia, guillain-Barré syndrome, peripheral neuropathy, skin involvement, etc.). Finally, viral hepatitis may be "atypical" when associated with other infections (malaria, typhoid fever, etc.), mostly in patients from tropical Countries.

[Viral infections and neoplasms of the uterine cervix]. / Infezioni virali e neoplasia della cervice uterina.

Since the last century, epidemiological studies of cervical carcinoma have shown a close link with sexual activity and in particular with promiscuity starting at an early age. Aetiological research has therefore concentrated on identifying sexually transmitted pathogens. In recent years studies have focused on the apparently significant role of HSV and particularly HPV in the aetiopathogenesis of this tumour. After the first cytohistological findings the HPV-cervical cancer link has been confirmed by electron microscopy, immunohistochemical studies and hybridisation of viral DNA. The identification of different HPV types presenting varying degrees of oncogenic risk offers the prospect of reaching a reliable prognosis on the basis of the particular virus identified in the lesion. The hypothesis that the virus has a decisive influence on the biology of th tumour is also intriguing: findings on the incidence and course of cervical cancer in the youngest women seems to suggest tha HPV may be a fundamental tumour growth factor.

[Use of topical methisoprinol (Viruxan) in female genital condylomatosis]. / Utilizzazione del metisoprinolo (Viruxan) per via topica nella condilomatosi genitale femminile.

Medical therapy of genital condylomatosis seems to be the most rational strategy, since this pathology is characterised by highly frequent recurrences after destructive physical therapy alone. Successful therapy of female genital condylomatosis with methisoprinol (Viruxan), administered as ointment and/or vaginal ovules is reported. The drug proved to be efficient both in curing this viral infection and preventing its recurrences.

Cryoglobulinemia-related vasculitis during effective anti-HCV treatment with PEG-interferon alfa-2b.

HCV infection may be related to many extrahepatic manifestations including mixed cryoglobulinemia (MC). Clinical manifestations commonly associated to MC include arthralgia, purpura, vasculitis, peripheral neuropathy and renal function abnormalities. Treatment with interferon often leads to remission, especially in virological responders, or to disappearance of MC-related clinical manifestations. We report on a patient with chronic hepatitis C, deficit of G6P-DH, type II MC, who developed a cryoglobulinemic vasculitis with purpura, renal impairment and arterial hypertension, during treatment with PEG-interferon a-2b plus amantadine. The occurrence of purpuric lesions and MC-related nephropathy with increased cryocrit despite negative viremia, in a patient previously asymptomatic, during interferon treatment, is unusual.

Antiretroviral activity of pegylated interferon alfa-2a in patients co-infected with HIV/hepatitis C virus.

OBJECTIVES: To evaluate the early anti-HIV activity of pegylated interferon (PEG-IFN) alfa-2a and ribavirin in HIV/hepatitis C virus (HCV) co-infected patients not receiving antiretroviral therapy. PATIENTS AND METHODS: In 19 patients with baseline plasma HIV load (HIV-RNA) >1000 copies/mL treated with PEG-IFN alfa-2a and ribavirin, HIV-RNA and T-cell subsets were measured at baseline and 2, 4 and 12 weeks after initiation of anti-HCV therapy. RESULTS: We observed a significant HIV-RNA decrease (>1 log(10) copies/mL) through week 12 of anti-HCV treatment. The magnitude of HIV-RNA decline was associated with baseline HIV-RNA, CD4 count and PEG-IFN weight-adjusted dose. CONCLUSIONS: A significant early anti-HIV activity of PEG-IFN alfa-2a was observed. Such an effect warrants further clinical evaluation in the management of co-infected patients.

A short course of pegylated interferon-alpha in acute HCV hepatitis.

Acute hepatitis C virus (HCV) infection evolves to chronicity in 50-84% cases. Treatment with interferon-alpha (IFN-alpha) was repeatedly found to provide sustained cure rates higher than that in chronic HCV infection, but the optimal treatment strategy has not yet been defined. In a multicentre open-label study, we investigated the therapeutic performance of a short course of pegylated (peg) IFN-alpha in patients with acute HCV hepatitis. Peg IFN-alpha2b, 1.0-1.5 micro g/kg weekly, was administered for 12 weeks. Forty-six patients were enrolled; 26 of them were intravenous drug users. Eleven patients had jaundice. Treatment was started within 1-90 days from the peak alanine aminotransferase. Treatment was well tolerated with a single dropout (2%). Thirty-three of 46 patients (72%) had a sustained virological response (SVR) after a 6 months post-treatment follow-up, 8 (17%) relapsed after treatment and 4 were nonresponders (9%). A lower peak viraemia, receiving at least 1.2 micro g/kg of peg IFN-alpha, and a negative HCV-RNA at week 4 and week 12 were predictors of SVR. Thus, in patients with early (week 4) viral response, a short course of peg IFN-alpha at a weekly dose >1.2 micro g/kg, may be a valuable option for the treatment of acute HCV hepatitis.

Circulating acid-labile interferon in chronic versus acute, HBV-related liver disease. A marker of immune-mediated hepatocellular damage?

An acid-labile Interferon was detected in the circulation of 76.1% of patients with chronic active type B hepatitis, in 30% of patients with acute type B hepatitis, studied within 15 days from starting of symptoms, and in 25% of patients with acute type B hepatitis studied 4 to 6 weeks after the admission. Patients in the third group showing evidence of circulating Interferon had also a delayed recovery and tardive HBsAg clearance. Circulating immune complexes were detected in 85.7% of patients of the first group, in 63.3% of patients of the second group, and in 25% of patients of the third group. We suggest that an acid-labile circulating Interferon could be related to immune-mediated hepatocellular damage (evidenced by circulating immune complexes) in hepatitis B virus infection, gradually disappearing during recovery from acute hepatitis or persisting indefinitely in chronic active hepatitis.