By Liz Highleyman

Neutropenia (low white blood cell count), anemia (low red blood cell count or hemoglobin level), and thrombocytopenia (low platelet count) are potentially dose-limiting side effects of interferon and ribavirin, respectively. Because reduced doses impair treatment response, adjunct therapies may be required.

G-CSF for Neutropenia

An open-label study assessed the use of granulocyte colony-stimulating factor (G-CSF or filgrastim) versus interferon dose reduction in 39 patients with genotype 1 hepatitis C who developed severe neutropenia (absolute neutrophil count [ANC] < 1000/L) while being treated with 1.5 mcg/kg/week pegylated interferon-alpha 2b (Peg-Intron) plus 800-1400 mg/day ribavirin.

Subjects were assigned to receive either a flexible dose scheme of 150-300 mcg G-CSF by subcutaneous injection twice weekly (one day after and two days before peginterferon injection), or else had their peginterferon dose reduced for two weeks (or discontinued for 1-2 weeks if neutropenia did not resolve).

Results

• After about 12 weeks, the mean decline in neutrophils was 1760/mm³ in the G-CSF arm and 1630/mm³ in the dose-reduction arm.

• Patients who received G-CSF maintained neutrophil counts between 1420/mm³ and 2720/mm³, and remained on G-CSF for a mean of 29 weeks (range 2-40).

• In the G-CSF group, 12 out of 20 patients (60%) had an early virological response (EVR) and 6 (30%) achieved sustained virological response (SVR).

• In the dose-reduction group, peginterferon was temporarily discontinued in 3 patients (16%) and reduced to 0.5 mcg/kg/week in 4 patients (21%).

• Patients who had their interferon dose reduced had neutrophil counts ranging from 1320/mm³ to 3400/mm³.

• In the dose-reduction group, 9 out of 19 patients (47%) achieved EVR and 4 (21%) achieved SVR; these response rates were significantly lower than those seen in the G-CSF group.

• All patients completed 48 weeks of peginterferon treatment with no major side effects or infections.

• No adverse events related to G-CSF were observed.

Conclusion

The researchers concluded that use of G-CSF is safe and enables adherence to full-dose peginterferon in patients with chronic hepatitis C who develop neutropenia during therapy. Use of G-CSF was also associated with higher early and sustained virological response rates.

Growth Factors vs Dose Reduction

In a related study, 160 patients with chronic genotype 1 hepatitis C and compensated liver disease were treated with Peg-Intron plus weight-based ribavirin. Participants were randomly assigned to either have their doses reduced in the case of hematological toxicity, or else were pre-emptively treated with adjunct therapy as follows:

• For anemia: darbepoetin alfa, 3 mcg/kg every two weeks by subcutaneous injection, starting when hemoglobin level fell below 12 g/dL or decreased by more than 25% from baseline level.

• For neutropenia: G-CSF, 300 mcg once weekly by subcutaneous injection, starting when ANC fell below 900/mm³.

• For thrombocytopenia: a more lenient cut-off was used to allow patients to stay on standard doses of peginterferon with lower platelet levels; peginterferon dose was reduced if the platelet count dropped below 55,000/mm³, and discontinued if the count fell below 30,000/mm³.

Results

At the time of abstract submission, 63 patients had been treated for at least 12 weeks. About one in 10 were African-American, a population that normally has lower average neutrophil counts compared with whites.

• In the dose-reduction arm, 10 patients had their doses reduced. Ribavirin dose was reduced twice for anemia and three times due to others symptoms (e.g., flu-like symptoms, shortness of breath). Peginterferon dose was reduced in 9 patients, 3 due to low ANC, 2 due to thrombocytopenia, and 4 due to other symptoms.

• In the adjunct therapy arm, 21 patients (64%) received growth factors (16 darbepoetin, 2 G-CSF, and 3 both); 4 patients (12%) nevertheless required temporary or permanent peginterferon and/or ribavirin dose reduction.


• Dose reduction occurred more often in the dose-reduction arm compared with the adjunct therapy arm (33% vs 12%, respectively; P = 0.04).


• Baseline hemoglobin fell significantly more in the dose-reduction arm (from 15.2 g/dL to 11.3 g/dL) compared with the adjunct therapy arm (from 15.9 g/dL to 12.2 g/dL).


• Among the 30 patients in the dose-reduction arm, 23 (77%) achieved EVR; in the adjunct therapy arm, 24 out of 33 patients (73%) achieved EVR.

Conclusion

The authors concluded that the use of growth factors prevents dose reductions of pegylated interferon and ribavirin and “maintains more physiologic hemoglobin levels” in patients receiving treatment for hepatitis C. The study will continue in order to determine whether use of growth factors allows for higher SVR rates.

Neutropenia and Infections

Finally, a study reported recently in the journal Clinical of Infection Diseases suggests that low neutrophil counts in patients receiving hepatitis C treatment are not associated with an increased risk of infection.

Researchers followed 192 patients who received 211 courses of therapy for HCV; none used G-CSF. After a median 17 weeks of therapy, 57 patients (30%) experienced 67 instances of infectious complications. Infection rate did not differ based on patient age, sex, race, body weight, HIV serostatus, extent of liver disease, or type of interferon used. The rates of fungal, viral, and bacterial infections did not correlate with nadir (lowest ever) neutrophil count or magnitude of decline from baseline.

The authors concluded that, “Neutrophil count is not correlated with infection rate in recipients of interferon-based therapy for hepatitis C,” and suggested that, “Reduction in interferon dose and/or dosing with granulocyte colony-stimulating factor in those with neutropenia is not supported by this analysis.”

6/06/06

References

G. Zacharakis, J. Koskinas, J. Sidiropoulos, and others. G-CSF is safe and improves adherence and SVR in HCV patients with genotype 1 who develop Peg-IFNa-2b related severe neutropenia. Abstract T1828. Digestive Disease Week 2006 (DDW 2006). May 20-25, 2006. Los Angeles, CA.

M. Kugelmas, A.L. Sabel-Soteres, G. Spiegelman. The impact of growth factors on Peg-Intron and Rebetol dose reduction in patients treated for genotype 1 chronic hepatitis C. Abstract S1058. DDW 2006. May 20-25, 2006. Los Angeles, CA.