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News Review

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HEPATITIS JOURNAL REVIEW:
A Bi-Monthly Publication of the Hepatitis Support Project

December 25, 2007
Volume 4, Issue 23


Liz Highleyman

To download pdf version click here


In This Issue:


Hepatitis C

• Eltrombopag Boosts Platelet Count

• G-CSF for Neutropenia

• Genotype 1b Linked to HCC, Post-transplant Recurrence

• Hepatotoxicity in HIV/HCV Coinfected Patients

• Antiretroviral Therapy Improves Cirrhosis in Coinfected Patients


Eltrombopag Boosts Platelet Count
Thrombocytopenia (low platelet count), which can cause blood clotting problems, is common among people with liver cirrhosis. Since it is a potential side effect of interferon alfa, experts typically recommend that people with severe platelet deficiency should avoid interferon or receive a reduced dose. Eltrombopag (Promacta or Revolade) is an oral blood cell growth factor that stimulates platelet production. As reported in the November 29, 2007 New England Journal of Medicine, J.G. McHutchison and colleagues studied 74 cirrhotic chronic hepatitis C patients with platelet counts ranging from 20,000 to 70,000 (150,000-400,000 is normal) who were randomized to receive eltrombopag (30, 50, or 75 mg) or placebo daily for four weeks. Those who achieved a platelet count of at least 100,000 could then start pegylated interferon plus ribavirin, while continuing eltrombopag or placebo for an additional 12 weeks. None of the placebo patients achieved a platelet count ≥ 100,000 cells/mm3, compared with 75%, 79%, and 95% receiving the eltrombopag 30 mg, 50 mg, and 75 mg doses. While 22% of patients taking placebo started anti-HCV therapy, the proportions were 71%, 74%, and 91% in the respective eltrombopag dose arms. Just 6% of participants in the placebo arm completed 12 weeks of antiviral therapy, compared with 36%, 53%, and 65% in the eltrombopag groups. The most common adverse event while taking eltrombopag alone was headache. The researchers concluded that, “Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy.”

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G-CSF for Neutropenia
Neutropenia (low level of neutrophils, a type of white blood cell) is another interferon side effect that often necessitates dose reduction, and it too can be managed using a blood cell growth factor, granulocyte colony-stimulating factor (G-CSF). J. Koirala and colleagues retrospectively analyzed 163 patients who completed treatment for chronic hepatitis C between 2003 and 2006; results were reported in the November 2007 Journal of Viral Hepatitis. Thirty participants whose absolute neutrophil count fell below 1,000 cells/mm3 (1,500 is the bottom of the normal range) while taking pegylated interferon received G-CSF, while those who did not develop neutropenia served as a control group. Interferon-induced neutropenia improved in most patients using once-weekly G-CSF. At the end of treatment, 77% in the G-CSF arm had undetectable HCV viral load, compared with 90% in the control group; the respective sustained virological response (SVR) rates were 61% and 76%, which was not a statistically significant difference. Timing of G-CSF administration did not have an effect on neutrophil recovery, but it seemed to be better tolerated when given two days before or after pegylated interferon rather than at the same time.

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Genotype 1b Linked to HCC, Post-transplant Recurrence
It is well known that HCV genotype has a major impact on response to interferon-based therapy, but it is less evident whether genotype also influences disease progression (though genotype 3 has a clear association with liver steatosis). In the November 2007 issue of Hepatology, S. Bruno and colleagues reported on a 17-year prospective cohort study of 163 chronic hepatitis C patients with cirrhosis in Italy. Participants were screened for HCC using ultrasound every six months. After a median follow-up of about 11 years, 44 of 104 patients with genotype 1b developed HCC (4.26 per 100 person-years), compared with 10 of 52 individuals with genotype 2a or 2c (1.69 per 100 person-years). Statistical analysis showed that having genotype 1b was an independent risk factor for HCC, along with male sex, age over 60 years, and development of esophageal varices. Based on these findings, the researchers recommended that, “Patients with cirrhosis that are infected with this genotype require more intensive surveillance for the early detection and aggressive management of neoplasia.”

In another study, reported in the November 2007 supplement of the Journal of Viral Hepatitis, B. Roche and D. Samuel looked at liver transplantation outcomes in France. HCV almost always infects the new liver graft, potentially leading to cirrhosis and its complications. The researchers found that a combination of several factors predicted fibrosis progression in the liver graft. The major contributing factors were high HCV viral load before or soon after transplantation, older donor age, prolonged ischemic time, excessive or abrupt changes in immunosuppressive therapy to prevent organ rejection, cytomegalovirus infection, HIV coinfection, and having HCV genotype 1b.

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Hepatotoxicity in HIV/HCV Coinfected Patients
HIV/HCV coinfected patients are at higher risk for drug-induced liver injury (DILI) than HIV monoinfected individuals, which is a concern because several antiretroviral drugs used to treat HIV can cause hepatotoxicity. In addition to the risk of life-threatening liver failure, DILI may necessitate discontinuation of antiretroviral therapy, leading to HIV disease progression. In the November 15, 2007 issue of Clinical Infectious Diseases, B. McGovern and colleagues reported on a study looking at whether interferon could reduce liver inflammation enough to make it safe for coinfected patients to restart antiretroviral therapy. Twelve AIDS patients (mean CD4 cell count 124 cells/mm3; mean HIV viral load about 115,000 copies/mL) with grade 3-4 symptomatic hepatotoxicity – including 7 with a history of recurrent DILI – were treated with interferon plus ribavirin. Liver biopsies revealed significant necroinflammation (mean grade 10.3) and fibrosis (mean stage F2.9). Three patients continued antiretroviral therapy along with interferon/ribavirin, while nine reinitiated anti-HIV drugs within four to 20 weeks after starting anti-HCV treatment. All 12 experienced “marked improvement” in ALT and AST levels and achieved HIV suppression and immune recovery over a mean follow-up period of about two years; only 1, however, achieved sustained response to hepatitis C treatment. “In patients with symptomatic DILI, treatment with [interferon/ribavirin] led to decreases in aminotransferase levels, which enabled the reinitiation of [antiretroviral therapy],” the researchers concluded. They suggested that this may be due to the anti-inflammatory effect of interferon, even in the absence of full HCV suppression.

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Antiretroviral Therapy Improves Cirrhosis in Coinfected Patients
A study by R. Bruno and colleagues, reported in the November 1, 2007 Journal of Acquired Immune Deficiency Syndromes, demonstrated how important it is for HIV/HCV coinfected patients to receive antiretroviral therapy. They retrospectively analyzed 392 HIV positive patients in Italy who were coinfected with either hepatitis B or C; participants were followed for at least six months. Of these, 69 patients (18%) had compensated cirrhosis at study entry (seven with HBV, 59 with HCV, and three with both); HIV/HCV coinfected and HIV monoinfected individuals without cirrhosis served as controls. About half the non-cirrhotic patients and 88% with cirrhosis had a CD4 cell count below 350; about 75% and 58%, respectively, were on antiretroviral therapy, but none were being treated for hepatitis C. Among the coinfected patients, the most common cirrhosis complications were ascites (39%), jaundice (39%), and hepatic encephalopathy (22%); 13% developed HCC. The overall five-year survival rates were 72% for cirrhotic patients and 97% for those without cirrhosis. However, among the cirrhotic patients, the survival rates after the first decompensation event were only 48% at one year and 18% at three years. Although lower CD4 cell count and higher HIV viral load were not independently associated with an increased risk of death, patients who received antiretroviral therapy after the first decompensation event had a higher survival rate (61% and 26% at one and three years, respectively), compared with untreated patients (27% and 0%). The researchers concluded that “significant morbidity and mortality” occurs during the first six years after diagnosis of compensated cirrhosis in coinfected patients, suggesting that “strategies for early intervention are needed to prevent disease progression in HIV infected patients with concurrent HBV and/or HCV infection.”

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