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Pegylated Interferons: Management of Patients with Hepatitis C

Early Virologic Response: Predictor of Therapeutic Outcomes?

Approximately 4 million Americans suffer with hepatitis C virus (HCV) infection, a serious liver disease that can result in cirrhosis, end-stage liver disease, and malignancy. “Recent advances in the treatment of chronic HCV, using pegylated interferons [PEG-IFN] in combination with ribavirin [RBV], have led to a more effective standard of care—and in about 55% of cases, eradication of virus,” said Eugene R. Schiff, MD, Professor of Medicine; Chief, Division of Hepatology; and Director, Center for Liver Disease at the University of Miami School of Medicine. According to Dr. Schiff, early predictors of treatment outcomes are key to the identification of which patients will and will not respond to current therapies.

Early and Sustained Virologic Response
In patients with HCV receiving IFN-based therapy, early virologic response (EVR) is an established predictor of sustained virologic response (SVR) (Table 1) (Davis et al. Hepatology 2003;38: 645). According to Dr. Schiff, whether EVR is an accurate predictor of outcomes in patients receiving PEG-IFN therapy with RBV is under study. “In patients who are not likely to respond, treatment cessation may be considered to avoid unnecessary treatment side effects and cost,” Dr. Schiff explained.

Case in Point
To demonstrate the treatment issues associated with EVR, Dr. Schiff presented the case study of LB, a 52-year-old Hispanic woman with HCV, genotype 1A. LB received PEG-IFN a 2B 96 µg/wk and RBV 1000 mg daily (400 mg morning, 600 mg evening). After 12 weeks of therapy, her viral level had decreased by about 2 logs; however, it was still positive at 10,000 IU/mL.

In one recent Spanish study, patients who received PEG-IFN-based therapy, had a 2-log decrease but still positive HCV RNA at 12 weeks, and had a negative viral level at 24 weeks, were treated for 72 weeks. “The findings showed an SVR of 78%, in contrast with the historically documented 38%,” Dr. Schiff explained (Buti et al. Hepatology 2002; 35(4):930-6). In addition, data suggest that patients of certain racial or ethnic backgrounds, such as African Americans, may show a slower response to treatment and therefore require longer treatment duration (Davis et al. Hepatology 2003; 38:645). “These data, although preliminary, suggest that consideration of prolonged treatment in LB’s case may be appropriate,” Dr. Schiff noted.

In another study, Davis and colleagues analyzed data from 965 patients who received PEG-IFN a 2A or 2B plus RBV, 81% of whom achieved an EVR (positive and negative viral levels). Of those who had an EVR, nearly 70% had an SVR. Of those who did not have an EVR, the SVR was 1.6%. “These data suggest that EVR may be an accurate and cost-effective predictor of treatment outcomes in patients receiving PEG-IFN and RBV combination therapy,” Dr. Schiff said (Davis et al. Hepatology 2003;38: 645).

Future Directions
While patients who do not have an EVR are unlikely to have an SVR, other potential treatment-related benefits are also under study. “Three large trials are current ongoing to investigate the potential impact of PEG-IFN and RBV therapy on complications, cancer risk, and survival,” Dr. Schiff concluded.

Table 1.
Early Virologic Response and Sustained Virologic Response Defined

• Early virologic response
  --Reduction from baseline in HCV RNA by at least 2 logs after 12 weeks of treatment
•Sustained virologic response
  -- Absence of detectable HCV RNA 24 weeks after treatment cessation

Source: Davis et al. Hepatology 2003;38:645.

Treatment Challenges in HCV: Patients with Psychiatric Disorders

“The successful treatment of hepatitis C virus [HCV] is often hindered by psychiatric disorders, such as depression. Depression is present in 35% to 57% of patients at diagnosis and develops in an additional 20% to 30% in association with HCV treatment,” said Marcelo Kugelmas, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Denver (Lehman & Cheung. Am J Gastroenterol 2002;97:2640-6. Nguyen et al. Am J Gastroenterol 2002; 97:1813-20. El-Serag et al. Gastroenterology 2002; 123: 476-82). “Patients with depression are more likely than others to require antidepressive therapy before and during interferon-based therapy; however, there is no indication that they are less compliant or less likely to have a sustained virologic response [SVR],” Dr. Kugelmas explained (Russo et al. Gastroenterology 2003;124:1711. Zdilar et al. Hepatology 2000;31:1207).

Case in Point
To demonstrate the issues surrounding the treatment of persons with HCV and a psychiatric disorder, Dr. Kugelmas
presented the case study of GW. GW is a 40-year-old mother with chronic HCV-related cirrhosis, genotype 1. Her chief complaints at presentation were fatigue, headache, lower extremity swelling, and right upper quadrant discomfort. Her history includes bipolar disorder; no suicidal ideation or attempts. Her social history involves drug (no injection) use from age 19 to 36 and alcohol abuse from age 18 to 26. At presentation, GW had been sober for 4 years, and her current medications were gabapentin, sertraline, cetirizine, and herbal agents.

Importantly, Dr. Kugelmas noted, the recent National Institutes of Health Consensus states that all persons with HCV or HIV are potential candidates for therapy. “Patients need to be assessed on their present, rather than past circumstances. In a patient who is stable and closely monitored, a diagnosis of bipolar disorder is not a contraindication for HCV treatment,” he explained.

Dr. Kugelmas and colleagues proceeded to establish monthly consultations with GW’s community psychiatrist to ensure the patient’s stability. Endoscopy and ultrasound were utilized as surveillance for varices and malignancy. One year after presentation, GW began therapy with PEG-IFN a 2B and ribavirin (RBV), both with weight-based dosing. GW was also switched from sertraline to olanzapine. At week 12, GW’s HPV RNA level was undetectable. Her worst side effects were flu-like symptoms, which lasted for 3 days following injection. At week 28, GW’s psychiatrist added sertraline to her psychiatric regimen, as she was in a depressive cycle of bipolar disease. GW successfully achieved end-of-treatment response.

Issues of Compliance
According to Dr. Kugelmas, issues of compliance are no more significant in those with psychiatric disorders than in other groups with HCV. In one German study, four groups underwent therapy interferon a 2A therapy with RBV. The first group included control patients, the second patients with a current or pre-existing psychiatric disorder, the third those in a methadone substitution program but without comorbid chronic psychiatric disorders, and the fourth those with former intravenous drug addiction who were drug and alcohol free for at least 3 months prior to being enrolled (and had no schizophrenic, schizoaffective, or chronic affective disorder). The protocol included consultations with psychiatry every other week for the first 2 months and every month thereafter, as well as diagnostic interviews and monthly urine toxicology testing. The results showed drop out rates of 13% in controls, 14% in those taking methadone, 18% for those with current or pre-existing psychiatric disorder, and 43% in those with a history of intravenous drug addiction. “Other than the dropout rate, somatic psychiatric side effects, noncompliance, and drug relapse did not differ significantly among the four groups,” Dr. Kugelmas pointed out (Schaefer et al. Hepatology 2003;37: 443-51).

In closing, Dr. Kugelmas noted that the prevalence of psychiatric disorders and side effects in persons with HCV warrants a renewed commitment to this patient population. “With close mental health follow-up and careful selection of appropriate management strategies, I believe HCV therapy is feasible in the majority of patients with psychiatric
disorders,” he concluded.

Retreatment Strategies for the Patient Who Relapses

“Using a pegylated interferon [PEG-IFN] and ribavirin [RBV] combination, hepatitis C virus [HCV] can be eradicated in the majority of patients. However, treatment side effects can result in dose reduction, treatment cessation, and ultimately a decreased rate of sustained virologic response [SVR],” said Bruce R. Bacon, MD, James F. King MD Endowed Chair in Gastroenterology; Professor of Internal Medicine; Director, Division of Gastroenterology and Hepatology; Saint Louis University School of Medicine, St. Louis, Missouri (McHutchinson et al. Gastroenterology 2002;123(4):1061-9). According to Dr. Bacon, retreatment may be a consideration in patients who relapse, particularly for those who did not receive optimal treatment or did not achieve an SVR previously.

Case in Point
Dr. Bacon presented a challenging case study to demonstrate the various treatment issues for patients whose disease has relapsed. SA, a 50-year-old male, was diagnosed with genotype 1A HCV in early 2001, with an ALT of 73 IU/L, AST 55 IU/L, and normal albumin, bilirubin, and blood counts. His HCV RNA level was 1.9 million IU/mL. Liver biopsy showed mild-to-moderately active chronic HCV and stage 2 to 3 fibrosis. SA underwent PEG-IFN a 2B with RBV from January to June 2002. SA’s treatment was then stopped due to side effects of depression, irritability, fatigue, and anemia. At that time, his HCV RNA was undetectable. In fall 2003, SA presented to Dr. Bacon for a second opinion. He felt relatively well, with some fatigue. He weighed 205 pounds, with slightly elevated liver enzymes. Physical examination was normal, and hematologic parameters were greatly improved. His HCV RNA levels were slightly greater than 1 million IU/mL. SA was interested in retreatment with experimental therapies.

Considerations for Retreatment
Options for SA included reassuring him that no further therapy was needed at this time, repeating a liver biopsy to aid decision making, waiting for new improved treatments, or retreating with better management of treatment side effects. According to Dr. Bacon, waiting was not a feasible option, since new HCV treatments are likely still years away and 35% of patients with stage 2 fibrosis progress to cirrhosis within 5 years (Yano et al. Hepatology 1996;23:1334-40). In addition, repeat liver biopsy is often helpful, but it was felt it would be unlikely to show a change from SA’s first biopsy 2 years ago.

“SA received inadequate therapy initially; therefore, I recommended retreatment with effective management of side effects. He again developed RBV-induced hemolytic anemia, which was successfully managed with recombinant erythropoietin,” Dr. Bacon noted. Fatigue is the most frequent side effect of HCV treatment, affecting more than 50% of patients (Manns et al. Lancet 2001; 22;358(9286):958-65). Anemia, however, is the most common indication in those undergoing HCV therapy for dose reduction and treatment cessation (Dieterich et al. Am J Gastroenterol 2003; 98(11):2491-9). To manage anemia and anemia-induced fatigue during HCV therapy, recombinant erythropoietin agents may be beneficial in patients who have a significant drop in hemoglobin. Recent studies have shown that recombinant erythropoietin therapy in patients undergoing HCV therapy can improve quality of life and reduce the need for RBV dose reductions (Dieterich et al. Am J Gastroenterol 2003;98(11):2491-9).

In addition, one recent study showed that patients who managed to take 80% of their prescribed PEG-IFN dose and 80% of their prescribed RBV dose for 80% or more of the time, had significantly improved SVR rates than those who had greater reductions in doses (McHutchinson et al. Gastroenterology 2002;123(4):1061-9). Similarly, Shiff-man and colleagues showed that a reduction in average RBV dose by as little as 125 mg/day was associated with a 50% reduction in SVR rates (Shiffman et al. Hepatology 2002;36:295A, Abstract 527).

Future Directions
In closing, Dr. Bacon concluded, “Further study is warranted to investigate the use of PEG-IFN and RBV in patients whose disease has relapsed. In retreating such patients, it is key to monitor and manage treatment-related side effects to avoid reductions in treatment doses and ensure optimal outcomes.”

Management of the Patient with HCV/HIV Co-Infection

“Increasing survival associated with highly active antiretroviral therapy [HAART] has led to the need to address hepatitis C [HCV] treatment in many HCV/HIV co-infected persons. Further-more, patients with HIV co-infection often suffer more rapid progression of HCV. Indeed, liver disease is now a leading cause of death in persons with HIV,” said Mark Sulkowski, MD, Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore. According to a recent National Institutes of Health (NIH) Consensus, all persons with HCV should be screened for HIV, and co-infected persons assessed for treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) on a case-by-case basis (NIH. Gastroenterology 2002;123:2082-99).

Case in Point
To demonstrate the challenges in treating patients with HCV and HIV co-infection, Dr. Sulkowski presented the case of MJ, a hemophiliac with HIV, genotype 1A HCV, and a 30-year history of alcohol abuse. MJ had a 15-year his-
tory of HIV and 30-year history of HCV, but had never had AIDS. His CD4 count was 452 cells/mm3; his HCV RNA was undetectable. His ALT was about 100 IU/L, albumin and bilirubin were normal, and a computed tomography (CT) scan of the liver was normal. MJ was taking nelfinavir as well as d4T and ddI. |

MJ was admitted to the hospital and underwent a transjugular liver biopsy, as according to Dr. Sulkowski, this biopsy method is often accepted by persons with hemophilia. The biopsy showed that, despite a normal CT scan, MJ had cirrhosis with mild activity and moderate portal hypertension. MJ had no significant varices, and no depression or cardiac disease. “Given the biopsy results, there was no question he would require treatment for HCV,” Dr. Sulkowski noted.

In MJ’s case, HIV therapy was maintained and treatment with PEG-IFN and RBV was initiated. MJ tolerated the regimen well, with chief complaints including mild fatigue, weight loss, and decrease in hemoglobin (3.4 g/dL) and platelets. In addition, MJ experienced a drop in CD4 count from 456 to 306 cells/mm3. “Patients need to be reassured that CD4 counts drop due to PEG-IFN’s suppressive effect on the bone marrow. However, research also suggests that this decrease does not negatively affect immune function,” Dr. Sulkowski explained. At week 12, MJ received epoietin therapy due to a further decrease in hemoglobin and increase in fatigue. MJ also developed peripheral neuropathy, which was treated successfully with amitriptyline.

At 24 weeks, MJ’s HCV RNA remained undetectable, but he had lost 23 pounds and was taking an appetite stimulant and medicinal marijuana. His platelets had also fallen to 65,000 uL, his albumin dropped, bilirubin increased, and pain increased. “This hepatic dysfunction was determined to be due to mitochondrial injury in the setting of cirrhosis,” Dr. Sulkowski said. MJ’s HIV therapy was switched to AZT and 3TC. His neuropathy improved, and blood levels stabilized.

At week 36, MJ’s only complaint was further weight loss. After his TSH levels proved normal, MJ was tested for and diagnosed with type 2 diabetes. Two years later, after treatment for diabetes, MJ’s HCV RNA level remains undetectable, albumin and bilirubin have stabilized, his CT scan also appears stable, and he is feeling well. MJ achieved a sustained virologic response (SVR).

Few studies have documented SVR in patients with HCV and HIV co-infection. In one recent Spanish study, co-infected patients received PEG-INF a 2B and RBV. Those with genotype 1 disease showed a response rate of 18%, genotype 2 and 3 disease, 45%. However, treatment duration was only 24 weeks, and the relapse rate ranged from 45% to 70%. “Based on the risk for relapse, a longer HCV treatment duration for patients with genotype 2 or 3 disease should be considered in the setting of HIV,” Dr. Sulkowski said. Data from other recent research are scheduled for publication in 2004.

Future Directions
The NIH Consensus recommends that HCV treatment with PEG-IFN and RBV be considered for all patients with HIV on a case-by-case basis. “A thorough assessment of HIV and HCV history, liver biopsy, and other individual patient and disease factors is key to determining which individuals will benefit from HCV therapy,” Dr. Sulkowski concluded (Table 1).

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