Pegylated Interferon Alfa-2a Maintenance Therapy and Liver Disease Progression in People Infected With Both HIV and Hepatitis C Virus (HCV)

Rapid progression of liver disease to liver failure has been observed in people coinfected with HIV and HCV. This observation appears to be directly related to an increase in the rate of fibrotic progression in the liver compared to people infected with HCV alone. PEG-IFN and ribavirin are used in standard treatment of HCV. This study tested the effectiveness of using PEG-IFN in reducing the rate of liver fibrosis progression in participants coinfected with HIV and HCV who could not lower their HCV viral load to undetectable or who could not maintain their HCV viral load at undetectable on PEG-IFN and ribavirin treatment.

Participants entered Step 1 (initial run-in period) to receive 12 weeks of 180 mcg PEG-IFN subcutaneously once weekly plus 1 to 1.2 g/day ribavirin based on body weight. At week 12, HCV RNA testing was performed.

Participants with early virologic response (EVR), defined as >=2 log10 drop in HCV RNA from baseline or undetectable HCV RNA (<600 IU/ml with quantitative assay used in Step 1) at Week 12, who had tolerated Step 1 treatment, entered into Step 3 to continue receiving the Step 1 treatment for a total of 72 weeks (Arm C). Participants who did not meet the criteria for entry into Step 3 were discontinued from the study. In Step 3, participants were followed for an additional 24 weeks after treatment discontinuation to determine sustained virologic response (SVR). Initially, Step 3 participants who had a detectable HCV viral load (>=60 IU/ml with the qualitative assay used in Step 3) at Week 36 were eligible to enroll in Step 2. After early closure of Step 2, such participants remained in Step 3 until study completion.

Participants with <2 log10 drop in HCV RNA from baseline and detectable HCV RNA at Week 12 (non-EVR) discontinued Step 1 treatment. Non-EVRs who met the Step 2 eligibility criteria, were enrolled in Step 2 and randomized to receive 180 mcg PEG-IFN subcutaneously weekly for 72 weeks (Arm A) or observation for 72 weeks (Arm B). Participants who did not meet the criteria for entry into Step 2 were discontinued from the study. Step 2 of the study was closed prematurely in May 2007 due to lower than expected progression rates among the participants in the observation arm such that the primary objective could not be reached. There were no safety concerns.

Liver biopsies were conducted at study screening, and at Step 2 entry and exit until the early closure of Step 2. Medical history assessment, physical exams, and blood collection were conducted every 4-12 weeks for participants in Steps 1, 2, and 3. Participants were followed for up to 18 weeks in Step 1, followed by a total of 72 in Step 2 or by up to a total of 84 weeks in Step 3.

Inclusion criteria

for Step 1:

• HIV infected
• Stable antiretroviral therapy for at least 8 weeks prior to study entry OR have not received any antiretroviral therapy for at least 4 weeks prior to entry
• HIV viral load less than 50,000 copies/ml within 6 weeks prior to study entry
• CD4 count greater than 200 cells/mm^3 within 6 weeks prior to study entry
• Hepatitis C virus (HCV) infected
• Either HCV treatment naive OR previously treated with interferon (IFN), PEG-IFN, IFN and ribavirin, or PEG-IFN and ribavirin for at least 12 weeks and HCV RNA positive following their last course of HCV treatment
• Chronic liver disease consistent with chronic viral hepatitis
• At least stage I fibrosis on a liver biopsy obtained within 104 weeks of study entry
• If at stage VI fibrosis, Child-Pugh-Turcotte (CPT) score of 5 or less and no more than Child-Pugh Class A
• Liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase) levels 10 times or less than upper limit of normal
• Agree to use acceptable methods of contraception

Inclusion criteria

for Step 2:

• Currently enrolled in Step 1 or received 12 weeks of PEG-IFN plus ribavirin outside this study
• Detectable HCV viral load and <2 log10 decrease from baseline in plasma/serum HCV viral load at Week 12.
• On Step 1 study treatment for no longer than 18 weeks

Inclusion criteria

for Step 3:

• Currently enrolled in Step 1
• Undetectable HCV RNA or a 2-log or greater decrease in plasma/serum HCV viral load.
• On Step 1 study treatment for no longer than 18 weeks

Exclusion criteria

for Steps 1 and 3:

• Have received HCV treatment within 4 weeks of study entry. Participants currently receiving treatment for HCV, if non-EVRs, were considered for direct entry into Step 2, without the run-in period in Step 1.
• Could not tolerate treatment with PEG-IFN, defined as missing 3 or more consecutive PEG-IFN doses during the first 12 weeks or a total of 5 doses prior to Step 3 entry. Participants who have missed doses of ribavirin will not be excluded from Step 3 entry.
• Use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days prior to study entry
• Alpha feto protein level 400 ng/ml or greater within 24 weeks prior to study entry, or alpha feto protein level greater than 50 ng/ml and less than 400 ng/ml (unless computed tomography [CT] scan or magnetic resonance imaging [MRI] shows no evidence of hepatic tumor) within 24 weeks prior to study entry
• Decompensated liver disease, including presence or history of ascites, variceal bleeding, and brain or nervous system damage as a result of liver damage
• Other causes of significant liver disease, including hepatitis A or B, excess iron deposits in the liver (hemochromatosis), or homozygote alpha-1 antitrypsin deficiency
• Use of systemic corticosteroids, interferon gamma, TNF-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid, ganciclovir, or hydroxyurea within 2 weeks prior to study entry
• Known allergy/sensitivity to PEG-IFN alfa-2a or ribavirin or their formulations
• History of uncontrolled seizure disorders
• Clinically active thyroid disease. Thyroid hormone replacement therapy is permitted, but thyroid-stimulating hormone (TSH) and free thyroxine index (FTI) must be in normal range.
• History of autoimmune processes, including Crohn's disease, ulcerative colitis, severe psoriasis, and rheumatoid arthritis, that may be made worse by interferon use
• Any systemic antineoplastic or immunomodulatory treatment or radiation within 24 weeks prior to study entry
• Malignancy
• Active coronary artery disease within 24 weeks prior to study entry
• Acute or active AIDS-defining opportunistic infections within 12 weeks of study entry
• Hemoglobin abnormalities (e.g., thalassemia) or any other cause of or tendency to break down red blood cells (hemolysis)
• History of major organ transplantation with an existing functional graft
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with study adherence
• Uncontrolled or active depression or other psychiatric disorder, such as untreated Grade 3 psychiatric disorder, medically untreatable Grade 3 disorder, or any hospitalization within 52 weeks of study entry that, in the opinion of the investigator, may interfere with study requirements
• Other serious illness or chronic medical condition that, in the opinion of the investigator, may have prevented participant's completion of the study
• Pregnant or breastfeeding