Low-dose Interleukin-2, Pegylated Interferon Alfa-2b and Ribavirin for the Treatment of HCV in HIV Patients: A Pilot Study

Patients infected with hepatitis C virus (HCV) and HIV have a diminished HCV virologic response to standard interferon (IFN) based therapies. In an ACTG pilot study, researchers explored the strategy of initial immunostimulatory therapy with interleukin 2 (IL-2), followed by the addition of specific anti-HCV therapy (pegylated interferon alfa-2b [Peg-Intron] plus ribavirin), as a possible synergistic approach to treatment.

Coinfected subjects (n = 23) with CD4 cell counts >300 cells/ L received low-dose IL-2 daily for 12 weeks, followed by pegylated IFN- 2b and ribavirin for an additional 48 weeks.

The primary end point was permanent discontinuation of treatment before week 24 due to toxicity or intolerance.

Adverse Events

Eighteen subjects reported a grade 2 or higher sign or symptom during follow-up, and 3 reported a grade 3 or 4 sign or symptom. The median time to first grade 2 or higher sign or symptom was 4 weeks. Fourteen subjects developed a grade 2 or higher laboratory toxicity, and 7 developed a grade 3 or 4 toxicity. Grade 3 adverse events were fatigue/malaise (n = 2), neutropenia (n = 2), ache/pain (n = 1), diarrhea/loose stools (n = 1), and nausea/vomiting (n = 1). Grade 4 adverse events were neutropenia (n = 3), anemia (n = 1), and hyperglycemia (n = 1).

Results

Six subjects (26.1%) discontinued treatment before week 24, and 11 (47.8%) discontinued treatment before week 60. Overall, 4 subjects discontinued because of adverse events. Four of 23 (17%; 95% confidence interval, 5% 39%) had sustained virologic responses. Of 17 subjects with increased levels of alanine aminotransferase at baseline, 13 had follow-up measurements at week 60, of which 6 (46%) were normal.

Conclusion

The authors conclude, “Low-dose IL-2 plus PEG-IFN and ribavirin was associated with a high discontinuation rate. Although the study was not powered for efficacy, confidence intervals surrounding the treatment response rate suggest that this strategy should not be pursued in larger trials.”

Discussion

This pilot study found that the coadministration of low-dose IL-2, PEG-IFN, and ribavirin to subjects with HCV-HIV coinfection was safe, with a 26% discontinuation rate before week 24. However, it was associated with a high discontinuation rate (48%) before the completion of therapy that the investigators consider to be unacceptably high.

The study was, in fact, powered to detect an unacceptably high discontinuation rate (50%) through week 24 and distinguish it from a null rate of 25%. Treatment-limiting toxicities were uncommon, although the most frequent reason for premature discontinuation was dissatisfaction with daily IL-2 injections.

These findings are consistent with results of a phase 2 trial of low-dose IL-2 in HIV-infected patients in which clinically significant toxicities related to IL-2 were uncommon, but only 32 (57%) of 56 IL-2 recipients completed the 26-week study, compared with 55 (93%) of 59 control subjects.

Whether higher doses of IL-2 would lead to greater and sustained increases in CD4⁺ cell counts in the presence of PEG-IFN is not known, although tolerability issues may preclude the coadministration of the 2 drugs because of the potential for greater systemic adverse effects when higher doses of IL-2 are administered.

Furthermore, the functional consequences of potential IL-2induced increases in CD4⁺ cell counts in HIV-infected patients are uncertain. Studies of antiretroviral regimens with and without interleukin-2 have yielded conflicting results regarding this issue.

02/04/05

Reference
M J Glesby and others (for the AIDS Clinical Trials Group A5088 Protocol Team). Pilot Study of Low-Dose Interleukin-2, Pegylated Interferon alfa-2b, and Ribavirin for the Treatment of Hepatitis C Virus Infection in Patients with HIV Infection. The Journal of Infectious Diseases 191(5): 686-693. March 1, 2005.