Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older.

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Higher doses of peginterferon alpha-2b administered twice weekly improve sustained virological response in difficult-to-treat patients with chronic hepatitis C: results of a pilot randomized study.

SUMMARY: Beside substantial progress in treatment of chronic hepatitis C (CHC) particular patients (genotype 1/4, high viral load, previous nonresponse, cirrhosis) remain difficult to treat. The aim of our pilot randomized study was to compare efficacy and tolerability of standard doses of Peginterferon alpha-2b + ribavirin with higher doses of Peginterferon alpha-2b administered twice weekly + ribavirin. Sixty-five outpatients with CHC were subsequently enrolled. Group A (n = 22) received recommended doses of Peginterferon alpha-2b and group B (n = 43), received high doses twice weekly. Groups were comparable for baseline characteristics. All genotype 1/4 patients had high baseline viraemia. Sustained virological response (SVR) was significantly higher in group B among naïve patients (72%vs 25%, P = 0.024). A significantly higher rate of SVR was observed in group B both considering only genotype 1/4 patients, (46%vs 13%, P = 0.03) and grouping together genotype 1/4 naive and relapsers (57%vs 11%, P = 0.039). Discontinuation rate was 32% (7 of 22) in group A and 21% (9 [corrected] of 43) in group B. Our response rates are the highest reported for genotype 1/4 with high viraemia. Our pilot study supports the need of randomized studies to evaluate both viral kinetics and efficacy of high dose and twice weekly administration of Peginterferon alpha-2b in genotype 1/4 patients with high viraemia who may need personalized treatment schedules.

Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C.

The aim of the study was to evaluate the efficacy of triple antiviral therapy with interferon, ribavirin, and amantadine in comparison with interferon and ribavirin combination treatment in patients with interferon-nonresponsive chronic hepatitis C. We performed an open-label, prospective randomized controlled trial at a secondary referral center. We used a 2:1 ratio, patients received interferon, ribavirin, and amantadine, or interferon and ribavirin for 12 months, and were followed up for an additional 6 months. Ninety-four consecutive adult interferon nonresponders with chronic hepatitis C were screened. Sixty consecutive elected patients entered the study. No patients withdrew because of adverse effects. Forty patients received interferon alfa (5 megaunits on alternate days), ribavirin (800-1,000 mg daily), and amantadine (200 mg daily) for 12 months, and 20 patients received the same treatment without amantadine. At the end of follow-up, alanine transaminase (ALT) level normalization was maintained in 23 of 40 patients (57%) after triple therapy, but in 2 of 20 patients (10%) after double therapy (P <.001, RR = 2.11, 95% CI, 1.43-3.12), whereas disappearance of serum HCV RNA persisted in 19 of 40 patients (48%) and in 1 of 20 patients (5%), respectively (P <.001, RR = 1.81, 95% CI, 1.32-2.47). The safety profile was similar in the 2 groups. In conclusion, in patients with interferon-nonresponsive chronic hepatitis C, triple antiviral therapy for 1 year results in a high rate of sustained biochemical and virologic responses.

Aberrant fragile histidine triad gene transcripts in primary hepatocellular carcinoma and liver cirrhosis.

To determine whether transcriptional alterations of the fragile histidine triad (FHIT) gene play a role in the development and progression of human hepatocellular carcinoma (HCC) we used reverse transcription-PCR to examine mRNA FHIT expression in 28 paired samples of HCC (24 in cirrhotic and 4 in noncirrhotic livers) and matched noncancerous tissue and in 10 normal livers. We also assessed loss of heterozygosity of the polymorphic D3S1300 microsatellite marker in the intron between exons 5 and 6 of the FHIT gene. Abnormal FHIT transcripts were detected in 13 cases (46.4%): 10 in the cancerous tissue only, 1 with the same pattern in both cancerous and matched noncancerous tissue, and 2 in the noncancerous tissue only. The four HCCs that arose in noncirrhotic liver all showed abnormal FHIT transcripts. No alterations were found in normal livers. Sequence analysis of abnormally sized transcripts revealed that they were generated by the fusion of exons 3 or 4 with exons 8 or 9. Among the cancerous specimens, one case showed only an abnormal sized transcript derived from the fusion of exons 4 and 9 in the absence of any normal-sized transcript, and another case showed deletion of a sequence comprised between nucleotides -35 and 399 resulting in an exon 4-9 fusion not respecting the exons' bounds. Loss of heterozygosity was found in two cases with abnormal FHIT transcripts and in only one case with normal transcript. Patients with aberrant FHIT transcripts showed a significantly higher relapse rate and shorter recurrence time (P = 0.001). This could be related to a primary genomic instability affecting particularly susceptible regions like FRA3B and could be associated with an increasing risk of recurrence without involving a causative role.

Pilot study of triple antiviral therapy for chronic hepatitis C in interferon alpha non-responders.

BACKGROUND: No effective therapy exists for interferon non-responding chronic hepatitis C patients. AIMS: Pilot study evaluating the potential efficacy and safety of triple antiviral therapy in interferon-alpha non-responders. PATIENTS AND METHODS: Twenty consecutive adult patients with chronic hepatitis C who had failed to respond to a 6-month course of interferon alpha were randomly assigned to receive a combination of interferon alpha + oral ribavirin (double therapy), or the same combination + oral amantadine (triple therapy), for 6 months. RESULTS: By the end of therapy, normal alanine transaminase (biochemical response) was obtained in 2 out of 10 patients on double therapy but in 7 out of 10 on triple therapy (p < 0.05), and negative serum hepatitis C virus (HCV) RNA (virological response) occurred in 1 out of 10 patients on double therapy but in 7 out of 10 patients on triple therapy (p < 0.01). Six months after therapy, biochemical response was sustained in 1 (double therapy) and 4 patients (triple therapy), respectively, and the virological response was sustained in no patient on double therapy but in 3 patients on triple therapy. CONCLUSIONS: Triple antiviral therapy seems to be able to induce biochemical and virological responses in interferon alpha non-responders with chronic hepatitis C.

Analysis of clinical and virological factors associated with response to alpha interferon therapy in chronic hepatitis C.

Interferon alpha (IFN-alpha) therapy is currently the treatment of choice for chronic hepatitis C (HCV) infection, but it fails to achieve a sustained response in approximately 75% of those treated. The factors which determine whether or not an individual will respond to IFN-alpha are uncertain, although a number of potentially predictive factors have been proposed. In this study a wide range of clinical, demographic, and virological parameters were evaluated in relation to therapeutic outcome in a group of 30 Italian patients with chronic hepatitis C. All patients received 3 MU leukocyte-derived IFN-alpha three times a week for 6 months and were then followed prospectively for at least 12 months. 53% of patients responded initially, but a sustained response was observed in only 17%. Responders were found to be significantly younger than nonresponders (45.6 +/- 3.1 vs. 55.4 +/- 2.7), and less frequently cirrhotic (2/16 vs. 7/14). Sustained responders had a mean pretreatment HCV-RNA titer approximately tenfold lower than that of those who did not have a sustained response, but the difference was not statistically significant. HCV genotype was found to be significantly associated with both initial and sustained response. Patients infected with HCV-2a were more likely to respond (89%) than those who were infected with HCV-1b (37%), and they were also more likely to sustain that response (33% vs. 6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Combination antiviral therapy with ribavirin and interferon alfa in interferon alfa relapsers and non-responders: Italian experience.

BACKGROUND/AIMS: A sustained biochemical and virologic response to standard interferon therapy for chronic hepatitis C is seen in no more than 25% of patients, and the efficacy of re-treatment or of higher doses in non-responders and relapsers has not been established. A more effective therapy for interferon alfa-resistant hepatitis C is needed. METHODS: A study of ribavirin plus interferon alfa combination therapy was conducted in 30 patients with chronic hepatitis C resistant to a previous standard course of interferon alfa (14 interferon non-responders, 16 interferon relapsers). Patients were randomly assigned to receive either ribavirin, 800 mg daily, and interferon alfa, 3 MU thrice weekly (n = 15), or interferon alfa alone, 3 MU thrice weekly (n = 15), for 6 months. RESULTS: At the end of treatment, normal alanine aminotransferase levels were observed in eight patients in the combination therapy group: one (14%) interferon non-responder and seven (87%) interferon relapsers (p = 0.01). Six months post-therapy, sustained normalization of alanine aminotransferase was achieved in seven (87%) interferon alfa relapsers, but not in any of the interferon alfa non-responders (p = 0.001). In the group of patients treated with interferon alfa alone, sustained normalization of alanine aminotransferase was observed in one interferon relapser only. Serum HCV RNA became negative in eight patients receiving combination therapy--two (28%) interferon non-responders and six (75%) interferon relapsers. Six months later, circulating HCV RNA remained negative in seven patients: one (14%) interferon non-responder and six (75%) interferon relapsers (p = 0.04). Sustained clearance of HCV RNA was not observed in patients re-treated with interferon alone. The sustained response to combination therapy was accompanied by reduced hepatic necroinflammatory activity on liver biopsy. Hepatitis C virus genotype was not significantly associated with response to combination therapy. Side effects were mild and well tolerated. CONCLUSIONS: Our experience indicates that combination therapy of ribavirin plus interferon alfa induces sustained biochemical, virologic, and histologic responses in most patients who are interferon relapsers.

A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C.

BACKGROUND/AIMS: In chronic hepatitis C, interferon alfa (IFN-alpha) therapy fails to achieve a sustained response in approximately 75% of patients. Similarly, ribavirin induces only a transient response. The aim of this study was to evaluate whether ribavirin and IFN-alpha in combination could be effective in IFN-alpha-resistant chronic hepatitis C. METHODS: Twenty patients with chronic hepatitis C resistant to a previous course of IFN-alpha were randomly assigned to receive either ribavirin combined with IFN-alpha or IFN-alpha alone for 6 months. RESULTS: Serum alanine aminotransferase levels decreased significantly during therapy in both treatment groups, but after therapy, the levels remained significantly decreased only in the combination therapy group. Nine months after treatment, sustained normalization of aminotransferase levels, associated with sustained loss of serum hepatitis C virus RNA, was observed in 40% of the patients in the combination therapy group but in none of the patients treated with IFN-alpha alone (P < 0.05). The sustained response was accompanied by reduced hepatic necroinflammatory activity on biopsy. CONCLUSIONS: These findings suggest that ribavirin plus IFN-alpha combination therapy is able to induce a sustained biochemical and virological response in a significant proportion of patients with IFN-alpha-resistant chronic hepatitis C.

Serum pepsinogen I and II concentrations and IgG antibody to Helicobacter pylori in dyspeptic patients.

AIMS: To investigate the association between histologically confirmed gastritis, carriage of Helicobacter pylori and pepsinogen (PG) I and PG II concentrations. METHODS: Prospective study of 81 dyspeptic patients undergoing upper gastrointestinal endoscopy was made. The extent of gastric mucosal inflammation and the presence of H pylori was determined, and serology to evaluate PG I and II concentrations and IgG titres to H pylori was carried out. RESULTS: The presence of H pylori was strongly correlated with high IgG antibody titres to H pylori and gastritis. Patients who were H pylori positive had significantly higher PG I and PG II concentrations and a significantly lower PG I:PG II ratio than patients who were negative for H pylori. In 13 patients with duodenal ulcer and H pylori positive gastritis serum PG I concentrations were significantly higher than in H pylori positive patients without duodenal ulcer. Significant correlations were found between the age of patients and serum PG II, the PG I:PG II ratio, IgG antibodies to H pylori, the severity of body gastritis and H pylori infection, and between the degree of gastritis in the body of the stomach and the PG II concentration. CONCLUSIONS: Serum PG I and II concentrations, together with a fall in the PG I:PG II ratio, could be used as predictors of H pylori infection as well as serum IgG antibody response to H pylori.

Persistent hepatitis C viraemia without liver disease.

In viral infections persistence of the virus is not always associated with virus-induced disease. To find out if active hepatitis C virus (HCV) infection can persist without liver disease we selected four symptom-free individuals with antibodies to HCV but normal aminotransferase levels. They were followed up for 3 years by monthly serology and a liver biopsy was done. At presentation, all four had both antibodies to HCV and circulating HCV RNA. During follow-up their sera remained persistently positive for all HCV antibodies and RNA yet aminotransferase levels did not increase and liver biopsy was normal. These findings indicate that persistent hepatitis C viraemia is not invariably associated with liver damage.

Serum IgM antibodies to hepatitis C virus in acute and chronic hepatitis C.

A standardized commercially available immunoassay is not available for detection of IgM antibodies against hepatitis C virus antigens (IgM anti-HCV). Therefore, different "in-house" enzyme immunoassays have been assessed. These assays vary greatly in sensitivity, but specificity seems satisfactory in all of them. A typical IgM antibody response to HCV antigens is usually found in nearly all patients with acute hepatitis C. This antibody response rarely precedes the appearance of IgG anti-HCV, and it persists for a few months at high titer. Low titers of IgM anti-HCV are detectable in 50-80% of cases with chronic hepatitis C. IgM anti-HCV reactivity is typically found during acute exacerbation of chronic hepatitis C. Furthermore, many patients with chronic active hepatitis C without acute exacerbation also have IgM anti-HCV. In these patients a correlation exists between the titer of IgM anti-HCV and the biochemical parameters of liver disease. When alpha interferon therapy induces a sustained remission of liver disease activity, positivity for IgM anti-HCV disappears in more than 70% of cases. In contrast, patients who do not respond to therapy rarely loose IgM anti-HCV. In conclusion, serum IgM antibodies to HCV antigens are reliable markers of active HCV-induced liver disease both in acute and in chronic HCV infection.

Hepatitis C viraemia rebound after "successful" interferon therapy in patients with chronic non-A, non-B hepatitis.

A quantitative polymerase chain reaction (PCR) assay for hepatitis C viral RNA (HCV-RNA) was used to monitor viraemia levels in six patients at multiple time points before, during, and after interferon therapy for chronic non-A, non-B hepatitis (NANBH). Prior to therapy, serum HCV-RNA was detected in all patients at approximately 10(4)-10(5) HCV genomes/ml. HCV viraemia became undetectable within 1 month of commencing interferon in three of the five patients whose alanine aminotransferase (ALT) levels decreased to normal on therapy. In the remaining two responder patients, viraemia levels declined more slowly, becoming undetectable after a period of several months. Recurrence of viraemia during therapy was observed in two cases. The one patient whose serum ALT levels remained elevated throughout therapy showed no decline in viraemia. On stopping interferon after a 6 months course, HCV genome titres climbed rapidly in all patients, reaching higher levels than had been observed prior to therapy. Biochemical relapse occurred within 7 months of ending interferon treatment in all but one of the patients who demonstrated this viraemia "rebound" phenomenon.

Significance of IgM antibody to hepatitis C virus in patients with chronic hepatitis C.

We assessed the correlation between the positivity for serum IgM antibody to hepatitis C virus and the activity of liver disease in patients with chronic hepatitis C virus infection. Serum samples were taken from 10 antibody to hepatitis C virus-positive asymptomatic patients with normal serum ALT levels, from 14 untreated patients with clinically and histologically proven chronic hepatitis C and from 26 patients with clinically and histologically proven chronic hepatitis C assigned to receive recombinant interferon alpha-2a (6 million IU three times a week for 6 mo). Each serum specimen was tested for IgM antibody to hepatitis C virus-associated C100-3 antigen by enzyme-linked immunosorbent assay. Patients were observed for at least 12 mo. All 10 patients with normal ALT values tested negative for IgM antibody to hepatitis C virus. In contrast, 33 of 40 (82%) patients with chronic hepatitis C had IgM antibody to hepatitis C virus, and a positive correlation was seen between the ALT level and the level of IgM antibody to hepatitis C virus (r = 0.803, p less than 0.001). During interferon treatment, ALT levels declined into the normal range in 18 of 26 treated patients (69%) and remained normal after stopping treatment in 8 patients (31%). In untreated patients, in treated patients who did not respond to interferon treatment and in responder patients who relapsed, no significant changes in IgM antibody to hepatitis C virus levels were seen during the study period. In contrast, IgM antibody to hepatitis C virus became undetectable by the end of interferon treatment in seven of eight patients with a sustained response.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversibility of gastrointestinal motor abnormalities in chronic intestinal pseudo-obstruction.

A 43-year-old man with chronic intestinal pseudo-obstruction is presented. He had undergone two laparotomies in an attempt to eliminate the cause of repeated episodes suggestive of obstruction. Gastrointestinal manometry showed severe abnormalities compatible with the diagnosis of chronic intestinal pseudo-obstruction. Laboratory tests indicated the presence of intestinal malabsorption and villous atrophy. A gluten-free diet accompanied by 10 days of treatment with tetracycline and 2 short periods of treatment with cisapride led to gradual, but apparently complete, resolution of the pseudo-obstructive syndrome. Repeated manometric studies showed progressive normalization of both the fasting and postprandial upper gastrointestinal motor pattern.

HCV infection and chronic active hepatitis in alcoholics.

Histological signs of chronic active hepatitis were found in 11/41 (27%) patients with chronic alcoholic liver disease. All these 11 patients tested positive for antibodies to HCV and no other causes of chronic hepatitis were found.

Serological and histological aspects of hepatitis C virus infection in alcoholic patients.

The recent cloning of the genome of hepatitis C virus (HCV) has allowed the detection of antibodies to HCV (anti-HCV) in human serum. The presence of serum antibodies to HCV often indicates active infection with HCV. We have assessed the serological and histological features in a group of alcoholic patients with chronic liver disease and have evaluated the possible etiologic role of HCV infection in the development of liver damage. Serum samples and liver biopsy specimens were obtained from 41 consecutive patients, all having a definite history of alcohol abuse and evidence of chronic hypertransaminasemia. Fifteen patients (37%) were positive for anti-HCV by ELISA, and 13 (86.6%) of them were also positive by RIBA. Eleven of these patients had histologic features of chronic active hepatitis (CAH), a lesion which is not known to be induced by excessive alcohol intake. No other possible causes of CAH were found, and CAH was not present in any of the anti-HCV negative patients. In patients with CAH, mean AST to ALT ratio was less than 1 (0.6), a finding which is characteristic of viral rather than alcoholic chronic liver disease. In conclusion, our study suggests that sporadic hepatitis C virus infection plays an etiologic role in the development of chronic active liver disease in a subgroup of alcoholic patients.

Effect of alpha-interferon therapy on hepatitis C viraemia in community-acquired chronic non-A, non-B hepatitis: a quantitative polymerase chain reaction study.

Sera from 30 patients with community-acquired, biopsy-proven chronic non-a,non-B hepatitis (NANBH) were tested for antibodies to the C100 protein of hepatitis C virus (HCV). The 20 patients who showed reactivity in this assay were followed prospectively for 6 months, during which time seven were treated with recombinant alpha-interferon. HCV RNA was detected by "nested" polymerase chain reaction (PCR) in 19 of the 20 anti-C100-positive sera taken at the onset of the study and also in five of the ten anti-C100-negative sera. Pretreatment viraemia levels ranged from 2 x 10(3) to 2 x 10(8) HCV genomes/ml. After 6 months of interferon, elevated serum alanine aminotransferase (ALT) levels had fallen to normal in four of the seven treated patients. In each case the response to interferon was accompanied by either a disappearance of or a decline (1 log to 8 log reduction) in viraemia. HCV genome titres in the three nonresponders and in the 13 untreated anti-C100-positive patients did not change significantly over this 6 month period. These findings confirm the aetiological role of HCV in community-acquired NANBH and suggest that quantitative PCR will become a valuable technique for monitoring the antiviral effect of interferon and other experimental treatments.

Rectal cell proliferation and colon cancer risk in ulcerative colitis.

Cell proliferation kinetics of 30 patients affected by extensive ulcerative colitis in remission have been studied with autoradiography of rectal biopsies incubated with tritiated thymidine. The results have been compared with those of 20 control subjects without evidence of colonic diseases, and of 16 patients with multiple nonfamilial colonic adenomas. The labeling index was similar in the three groups (P = NS). On the contrary, the labeling frequency (SEM) in the upper 40% of the crypt (phi h value) was 0.04 +/- 0.01 in controls, 0.16 +/- 0.02 in ulcerative colitis, and 0.10 +/- 0.01 in adenoma patients (P less than 0.001 ulcerative colitis versus controls, P less than 0.01 adenomas versus controls, P = NS ulcerative colitis versus adenomas). The distribution of phi h values in ulcerative colitis showed a bimodal trend with 22 patients having mean phi h values similar to adenoma patients (0.10 +/- 0.01) and 8 with higher values (0.30 +/- 0.02). No relationship was found between phi h values and duration of colitis, age of patients, or age at onset of symptoms. These data show that cell kinetics studies can detect patients at particularly high risk of colon cancer, and that additional factors should determine colon cancer risk level in ulcerative colitis.