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A Bi-Monthly Publication of the Hepatitis Support Project

December 10, 2007
Volume 4, Issue 22

Liz Highleyman

To download pdf version click here

In This Issue:

Hepatitis C

• Safety and Efficacy of CPG 10101

• Psychiatric Conditions

• HCV Clearance in Children

• Fibrosis Progression in Coinfected Patients

Safety and Efficacy of CPG 10101
Data from a Phase 1b study of the toll-like receptor 9 (TLR-9) agonist CPG 10101 as a treatment for hepatitis C were reported in the November 2007 Hepatology. CPG 10101 is a synthetic oligodeoxynucleotide that appears to have both immunomodulatory and antiviral activity. J.G. McHutchison and colleagues randomly assigned 60 chronic hepatitis C patients (50 with HCV genotype 1) to receive either a fixed dose of CPG 10101 (ranging from 0.25 to 20 mg) twice weekly, or a weight-based dose of CPG 10101 (0.5 or 0.75 mg/kg) once weekly, or placebo, all for four weeks. Dose-dependent increases in cytokine production (including natural interferon alfa, interferon gamma-inducible protein 10, and 2'5'-oligoadenylate synthetase) were observed after administering CPG 10101. Just over half the patients (55%) who received at least 1 mg CPG 10101 experienced a 1 log or greater decrease in HCV RNA, with the largest average reduction (1.69 log) seen in the group receiving the highest dose (0.75 mg/kg). CPG 10101 was well tolerated, and side effects were as expected given the drug’s effect on immune activation. The researchers concluded that, “The data support further clinical studies of CPG 10101 for treating chronic HCV infection.”

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Psychiatric Conditions
Some clinicians believe hepatitis C patients with a history of depression, substance abuse, or other psychiatric conditions are “difficult to treat” since they may experience worse psychiatric side effects from interferon. But this is not supported by recent evidence. In the October 2007 Hepatology, M. Schaefer and colleagues reported on a study of pegylated interferon plus ribavirin in 70 chronic hepatitis C patients with varying psychiatric histories: 22 with psychiatric disorders, 18 who had received methadone maintenance therapy, 13 former drug users, and 17 control subjects without prior psychiatric or substance abuse histories. The overall sustained virological response (SVR) rate was 59%, ranging from 50% for all patients with a psychiatric history, to 54% for former drug users, to 72% for methadone recipients, compared with 59% for control subjects. However, methadone recipients and former drug users had significantly higher dropout rates. On the whole, side effects of depression and psychotic symptoms did not differ significantly between the groups during treatment. But the control subjects had a lower average pretreatment score, and thus experienced a significant larger increase to reach a similar maximum score during treatment. In a multivariate analysis, psychiatric history, type of psychiatric diagnosis, degree of depression before or during treatment, and use of antidepressant drugs did not significantly affect response rates.

In a second study, published in the November 2007 American Journal of Gastroenterology, A. Jakiche and colleagues looked at trends in depression and use of psychiatric medications among 79 chronic hepatitis C patients (46 with a history of psychiatric conditions) receiving interferon-based therapy at the Albuquerque Veterans Affairs Medical Center. While the patients with a psychiatric history had minor fluctuations in depression scores compared with baseline, those with no prior psychiatric diagnoses experienced a significant increase in depression, and were more likely to require the addition or larger doses of antidepressants (64% vs 39%). Increased use of antidepressants led to a significant reduction in depression scores in both groups, though they remained higher than baseline scores. The overall SVR rate was 47.0%. “Hepatitis C patients with stable psychiatric history can be successfully treated with interferon-based therapy if followed closely by a multidisciplinary team that includes specialists in hepatitis C and behavioral health,” the researchers concluded.

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HCV Clearance in Children
It is estimated that about 25% of adults spontaneously clear HCV without treatment, though different studies have found rates ranging from around 10% to 50%. A meta-analysis published last year found an overall clearance rate of 26%, with rates being higher among women than men (40% vs 19%), and among those who experienced acute hepatitis symptoms [Micallef et al. J Viral Hepat 2006; 13(1):34-41]. As reported in the November 2007 Journal of Viral Hepatitis, L.T. Yeung and colleagues assessed the rate of spontaneous HCV clearance in children. Out of 157 children with HCV infection, 28% cleared the virus without treatment. More than three-quarters were infected through transfusions, and the spontaneous clearance rate was similar in this group and in those who acquired HCV through other routes (28% vs 29%). Younger age at follow-up predicted a greater likelihood of spontaneous clearance, since clearance (if it occurred) usually happened soon after infection. However, only 25% of patients infected as newborns cleared HCV after seven years. In contrast with adults, gender was not reported as a significant factor. According to this study, the rate of spontaneous HCV clearance is similar in adults and children – unlike hepatitis B, where the clearance rate is about 95% for adults but only 10% for infants.

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Fibrosis Progression in Coinfected Patients
Two recent studies added further support to previous research showing that HIV/HCV coinfected individuals experience faster liver disease progression than HIV negative people with hepatitis C alone. In the first study, published in the November 2007 Journal of Viral Hepatitis, P. Bonnard and colleagues from France retrospectively analyzed liver fibrosis progression in 32 coinfected patients who were not receiving hepatitis C treatment, based on two liver biopsies performed an average of 49 months apart. The patients had well-controlled HIV disease, with an average CD4 cell count of 470 and 79% taking antiretroviral therapy. On the first biopsy, most patients had absent (stage F0) or minimal (F1) fibrosis, except for two with moderate (F2) fibrosis. On the second biopsy, however, none had absent fibrosis, 41% had stage F1, 34% had stage F2, 19% had severe (F3) fibrosis, and 6% had progressed to cirrhosis (F4). The average fibrosis progression rate was 0.25 units per year, but 28% were rapid progressors with a mean rate of 0.5 units per year. There was no observed association between fibrosis progression and patient age, alcohol consumption, HCV genotype, ALT or AST levels, CD4 cell count, HIV viral load, or specific antiretroviral drugs. Based on these results, the researchers concluded that liver fibrosis in HIV/HCV coinfected patients should be evaluated at least every three years.

In the second study, published in the October 2007 AIDS, M.S. Sulkowski and colleagues from Johns Hopkins prospectively analyzed fibrosis progression among 174 HIV/HCV coinfected patients, of whom 21% received interferon-based anti-HCV therapy; the median interval between biopsies was 2.9 years. Here, too, the group had well-controlled HIV, with a median CD4 cell count of 379 and 60% with undetectable HIV viral load. On the first biopsy, 77% had absent or minimal fibrosis, 9% had moderate fibrosis, and 11% had severe fibrosis or cirrhosis (F3-F4). Between the first and second biopsies, 48% of study participants had no change in their fibrosis scores, and the overall median fibrosis progression rate was 0.83 units per year. However, 22% experienced fibrosis progression of at least 1 unit and 24% progressed by at least 2 units - approximately double the rate typically seen in HCV monoinfected patients. As in the French study, HCV genotype and viral load, CD4 count, HIV viral load, and duration or type of antiretroviral therapy did not differ significantly between progressors and nonprogressors. Among the 37 patients treated for hepatitis C, only 2.7% achieved SVR. While hepatitis C treatment was not associated with reduced fibrosis progression overall, the three people who achieved SVR were all nonprogressors.

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