Fatigue, HCV/HIV Coinfection, Transmission, Disease Progression & Interferon
Written by David Bernstein, MD, Chief of Hepatology at North Shore Hospital, Manhasset, NY With thanks to NATAP

The 103rd Annual Meeting of the American Gastroenterological Association was held in San Francisco, California from May 19-23, 2002. During this meeting, new developments in hepatitis C and HCV/HIV co-infection were discussed. The topics were varied and ranged from leptin as a cause of fatigue to the evaluation of various treatment regimens.

Several risk factors for acquiring hepatitis C infection, such as intravenous drug use, cocaine use or being the recipient of contaminated blood products are well-known and potentially avoidable risks. Concerns are frequently raised regarding the intrafamilial transmission of hepatitis C. Keiserman et al. tried to determine if HIV is a cofactor for the intrafamilial transmission of hepatitis C. 87 family members of 53 HIV/HCV co-infected patients and 134 family members 73 HCV mono-infected patients were evaluated. The study found that risk factors for the transmission of hepatitis C among family members of co-infected patients included the sharing of needles used for tattooing and vertical transmission. Among HCV mono-infected patients, no identifiable risk factors were noted except for sexual contact. Interestingly, condom use was more frequent among the HIV/HCV co-infected group than the HCV mono-infected group. Overall, the study found that intrafamilial transmission of hepatitis C is uncommon and that it is not increased by the presence of HIV disease.

Fatigue

Fatigue is a major complaint in people infected with the hepatitis C virus and in those co-infected with the HIV/HCV viruses. Fatigue can be debilitating and frustrating to patients and physicians as its presence is difficult to explain in the context of the overall disease process. The presence and degree of fatigue in hepatitis C appears to be unrelated to viral load, genotype, or the amount of inflammation or fibrosis seen on liver biopsy. Recently, attention has been focused on the role of leptin and energy expenditure in hepatitis C. Leptin is a peptide hormone that regulates food intake and energy expenditure. Elevated leptin levels have been associated with steatosis and it was recently shown by Hofer et al. that weight loss during anti-viral therapy is associated with a decrease in bound leptin levels. Thierry et al. reported on the relationship of circulating leptin with fatigue in patients with chronic hepatitis C. Approximately 50% of the hepatitis C patients in this study listed fatigue as the worst or initial symptom of the disease. Fatigue scores, using the Fatigue Severity Index, were significantly higher in hepatitis C patients than in controls. Women were more likely to complain of fatigue than men. In hepatitis C patients, the fatigue score correlated significantly with leptin levels when corrected for body fat mass. No correlation with fatigue was found with the following variables: age, liver function tests, viral load, degree of liver disease on biopsy or resting energy expenditure. This study highlights two important points. The first is that the finding of fatigue in hepatitis C is common, potentially disabling and cannot be ignored. The second important point is that these findings suggest that the fatigue seen in hepatitis C may be due in part to elevated leptin levels. Further studies need to be performed in this area.

Does Interferon Slow HCV Disease & Improve Survival

Interferon therapies are associated with significant side effect profiles and an overall sustained viral response rate of approximately 50%. Interferon is known to possess anti-fibrotic properties and its use has been shown to reduce the risk for the development of hepatocellular carcinoma in patients with cirrhosis secondary to hepatitis C. Yoshida et al. attempted to answer the question of whether or not interferon therapy prolongs life expectancy in patients with hepatitis C. 2889 patients with hepatitis C were included in the study group. The group included 459 untreated patients, 817 sustained virological responders, and 1613 non-responders to therapy. 86 deaths were noted amongst the group with 58 (67%) attributable to liver disease. 39 deaths were due to liver cancer, 12 secondary to liver failure, and 7 secondary to variceal bleeding. The authors found that the standardized mortality ratio, when compared to the general Japanese population, was 1.9 with a confidence interval of 95% for untreated patients and 0.9 for interferon treated patients. The risk of death as a whole was reduced in the group receiving interferon therapy. This finding was secondary to the reduction in risk of death from liver disease in the treated group as the risk of dying from non-liver related causes was unchanged in both groups. These findings suggest that interferon therapy improves survival of chronic hepatitis C patients by preventing hepatic deaths.

HCV Therapy in HIV Coinfection

Oliver et al. evaluated the safety and efficacy of interferon alfa-2b at a dose of 3-5 million units thrice-weekly plus ribavirin 800 mg a day in 14 patients co-infected with HIV/HCV. Fifty percent of the patients had undetectable HIV viral loads and the mean CD4 count was 370+257. Six of the 14 patients (43%) had a sustained viral response. Two patients were discontinued secondary to adverse effects. Mannah et al. also assessed the efficacy, safety and tolerance of high dose induction interferon alfa-2b plus ribavirin in the treatment of patients with HCV/HIV co-infection. In this small study, 23 HCV treatment-na.ve co-infected patients were treated with 2 weeks of ribavirin monotherapy followed by interferon alfa 2b 5 million units daily plus ribavirin 1200 mg a day for 10 weeks followed by interferon alfa-2b 3 million units three times a week plus ribavirin 1200 mgs day for another 36 weeks. The total treatment regimen was 48 weeks. The sustained viral response in this group was 13%. 87% of patients discontinued therapy prior to treatment week 48. 39% of the discontinuations were due to adverse events and the remainders were secondary to non-response. These data suggest that high dosages of interferon and ribavirin are associated with significant more toxicity in HIV/HCV co-infected patients and may limit the uses of high dose interferon in this population.

Cargnel et al. report preliminary data of the treatment of hepatitis C infection in HIV infected patients with combination pegylated interferon alfa-2b plus ribavirin. Entry criteria for the study required stable HIV-RNA levels of less than 400 cp/ml, CD4+ count of more than 300 cells/mm3 , and no previous hepatitis C therapy. Patients were randomized to receive either pegylated interferon alfa-2b 1.5 ug/kg/week plus ribavirin 800 mg daily or pegylated interferon alfa-2b 1.5 uk/kg/week alone. 49 patients have completed 24 weeks of therapy. To date, seventeen patients have had an on-treatment response with 14 of 25 responding in the combination therapy group and 3 of 24 responding in the pegylated interferon monotherapy group. Thirty-five patients have had therapy discontinued. Most of these discontinuations occurred in the first month of therapy and were secondary to flu-type symptoms. Neither life threatening adverse events nor lactic acidosis occurred in patients on HAART therapy. The authors conclude with this preliminary data that the combination of pegylated interferon plus ribavirin appears to be safe and well tolerated in this group of co-infected patients. Although the authors recommend that this therapy should currently be recommended in this patient population, I believe that it is prudent to wait until the study is complete and we have the sustained viral response rates before issuing any preliminary recommendations.

Pegylated interferons, with improved efficacy over standard thrice weekly interferons, are promising new developments in the treatment of chronic hepatitis C. The precise mechanism of interferon's effect in the treatment of hepatitis C is unknown with speculation that it has both immunomodulatory and directly toxic to the virus. Kamal et al. evaluated the potential modulation of immunological responses to pegylated interferon therapy. The authors found that pegylated interferons with and without ribavirin induced a significant increase in the frequency, strength and breadth of the HCV-specific CD4+ T helper one response. Sustained viral responders exhibited enhanced interferon gamma production and IL-10 suppression. Pegylated interferon alfa-2a may achieve increased efficacy by restoring and maintaining a significant multi-specific HCV-specific CD4+ T helper cell and CTL response.

References

Cargnel A, Casella A, Angeli E et al. Pegylated interferon alfa 2b plus ribavirin for treatment of HCV/HIV co-infected patients: an open, multi-center, randomized trial. Gastroenterology 2002; Vol 122; A115

Hofer H, Steindl-Munda P, Oesterreicher C et al. Leptin and leptin receptor in patients with chronic hepatitis C: effect of interferon/ribavirin combination therapy. Gastroenterology 2002, Vol 122; A 477.

Kamal SM, Fehr JE, Roesler B et al. Peginterferon alpha 2a alone or in combination with ribavirin enhances restoration of the HCV specific T cell responses in patients with chronic hepatitis C. Gastroenterology 2002, Vol 122; A 474

Mannah M, Rockstroh JK, Gslz J et al. Long-term efficacy of dose intensified interferon-_ 2b and ribavirin therapy for hepatitis C in HIV-coinfected patients. Gastroenterology 2002, Vol 122. A W902 Oliver DL, Stewart M, Chatfield E et al. Efficacy of interferon alfa-2b plus ribavirin combination therapy in HIV/HCV co-infected patients. Gastroenterology 2002, Vol 122; A T1398

Rodrigues-Keiserman D, Both CT, Mattos AA et al. Intrafamilial transmission of hepatitis C in patients with hepatitis C and human immunodeficiency virus coinfection. Gastroenterology 2002, Vol 122; A 1456

Thierry P, Eve G, Xavier H et al. Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gastroenterology 2002, Vol 122; A M1589

Yoshida H, Arakawa Y, Sata M et al. Interferon Therapy Prolongs Life Expectancy Among Chronic Hepatitis C Patients: National Surveillance Program In Japan. Gastroenterology 2002, Vol 122; A T1375