NATAP REPORTS

Current Review & Update on Hepatitis C & HIV/HCV Cection

SUMMER 2001

Erythropoietin for interferon and ribavirin associated anemia

This initial pilot study suggests that EPO may be helpful in treating anemia for patients receiving HCV therapy (IFN/RBV). The study compared patients with reduced hemoglobin on IFN/RBV therapy receiving EPO vs standard of care management. Long-term adverse events data that could be related to EPO are not available since this is a pilot study. Preventing or treating anemia ought to improve a patient’s ability to tolerate therapy, to adhere to therapy and to remain on therapy. Interferon+ribavirin can result in significantly reduced hemoglobin (anemia) in the first few weeks of therapy. Doug Dieterich (Cabrini Hospital, New York University Medical Center) reported data (DDW May 2001) from a study showing that Epoetin alfa (EPO) once weekly increased hemoglobin levels (mean change 2.9 g/dL vs 0.3 g/dL, P<.05) after they had fallen on HCV therapy from 14.5 to 11. Also, patients were able to maintain taking a higher dose (926 mg/day vs 782 mg/dayof ribavirin, p<.05) (lower hemoglobin can lead to reducing RBV dose), which may translate into a better virologic response. And the data suggested patients benefiting from EPO had less depression (which is a side effect of interferon and ribavirin therapy) and patients reported a better quality of life. This suggests that depression experienced on RBV/IFN may be due to at least in part to fatigue and anemia. Another study reviewed below shows less anemia was experienced by patients taking Pegasys alone (without ribavirin) compared to patients taking standard interferon with ribavirin.

At DDW, Mark Sulkowski reported that women are 4.4 times more likely than men (20% vs 4.5%) to experience a Hb <10 g/dL. Men were at a greater risk (40%) than women to experience a decrease in Hb of 3 or more g/dL from baseline. But men generally have higher Hg levels, and women menstruating also lose Hg every month. Sulkowski also reported that daily IFN therapy was not associated with a greater decline in Hb than IFN three times per week by week 4 of treatment. In a subset of anemic patients with a mean Hb of 10.7 g/dL who had RBV dose reduced to 600 mg daily, Hb levels increased by a mean 1.1 g/dL at 4-8 weeks after the dose decrease.

Sulkowski retrospectively analyzed treatment-related changes in Hb in about 600 participants in 2 studies (IFN naïve and experienced) randomized to receive RBV 1000 mg daily or 1000-1200 mg daily (based on weight) plus various daily or three times per week dosing regimens of IFN. More than 80% of women at baseline had Hb 13 g/dL or greater, and more than 90% of men had 14 or more g/dl Hb.

As expected, 10.3% (57/551) of patients had a Hb <10 g/dL. Hb decreased 3 or more g/dL in 54% of all patients. About 27% of men & women reached a nadir (lowest point) of 11-11.9 Hb, while many more men were able to maintain Hb 12-12.9 (25% vs 17%) and 13 or more (30% vs 10%). Sulkowski also reported that in a univariate analysis, increased age, higher baseling Hb and platelet counts, and CrCl (decreases in creatinine clearance) were significantly (P<0.5) associated with the largest Hb decreases.

The initial dose of EPO was 40,000 Units subcutaneously once weekly. Patients with an increase in Hb of 1 or more g/dl continued EPO. Patients with less than 1 increase stopped EPO. If Hb increased to >14 g/dL for women or 16 for men, EPO was withheld. When Hb subsequently decreased to 13 g/dL for women or <15 g/dl for men, EPO was resumed at 30,000 Units once weekly. I think Dieterich said he titrated (incrementally increased doses) by 5,000-10,000 to a maximum of 40,000 Units once weekly.

Primary endpoints were change in Hb, secondary endpoints were change in RBV dose, and change in quality of life measured by SF-12. At study entry there were 36 patients (24 men, 12 women) receiving EPO and 28 standard of care (20 men, 8 women). Age was 50 in EPO arm, and 48 in SOC arm. Weight (kg) was 88 in EPO arm, and 78 in SOC.

RESULTS:

The Hb values before RBV/IFN treatment was 14.5 (10.6-16.9 range) for the 36 patients receiving EPO, and 14.6 for the SOC arm (range 11.6-17.0), so it was about the same before treatment.

--Prior to week 16 there were 15 (42%) discontinuations in the EPO arm vs 14 (50%) in the SOC arm.

--At the start of receiving EPO the mean Hb levels were 11.0 in the EPO arm vs 11.0 in the SOC arm.

--At week 16 (ITT analysis), the mean Hb was 13.9* (+/- 1.7; range 10.4-17.2) in the EPO arm vs 11.3 (+/- 1.2; range 9.2-13.3) in the SOC arm, and the mean change in Hb was a 2.9 (+/- 1.8)* g/dL increase (range –0.3-6.9) for patients receiving EPO vs a 0.3 (+/- 1.0) mean increase in the SOC arm (range –1.3-2.5), (* EPO vs SOC p<.05). Kaplan-Meier plot evaluating measures over time (on-treatment analysis) showed both arms with 11 Hb at baseline and at week 16 Hb level was 14.2 (+/-1.7) g/dL for the EPO arm (n=21) vs 11.2 (+/- 1.3) g/dL in the SOC arm, n=14, (EPO vs SOC p<.05).

--By ITT analysis, 88% (30/34) in the EPO arm had 1 g/dL or more increase in Hb compared to 28% (8/28) in the SOC arm.

--Perhaps more important, RBV dose was higher in the EPO arm at week 16 (ITT) suggesting patients may be helped to tolerate adequate RBV dose by taking EPO. At study entry the mean RBV dose was 956 (+/- 242; range 200-1200) in the EPO arm vs 961 (+/- 175; range 600-1200) in the SOC arm. At week 16, the EPO arm dose 926 (+/- 234)* mg/day vs 782 (+/- 244) in the SOC arm. The mean change was –179 (+/- 203) in the SOC arm vs –31 (+/- 160)* in the EPO arm (EPO vs SOC P<.05). Using on-treatment analysis at week 16, the RBV dose was 900 (+/- 238) mg/day in the EPO arm (n=20) vs 707 (+/- 217) mg/day in the SOC arm (n=14), EPO vs SOC p<.05).

--By ITT analysis a higher percentage of patients receiving EPO (85%, 29/34) were able to take 800 mg or more RBV per day vs 61% (17/28) in the SOC arm. Only 15% receiving EPO were taking <800 mg/day vs 39% not receiving EPO (EPO vs SOC p<.05).

--A greater percentage of patients (56% vs 39%) were able to achieve a higher weight based RBV dosing (>10.6 mg/kg) in the EPO arm compared to the SOC arm, but this was not statistically significant. This 10.6 mg/kg level was suggested by Schering as the level of RBV dosing based on weight that patients should be above to achieve a maximum virologic response using PegIntron+RBV. This has been controversial as Roche suggests RBV weight based is not necessary for Pegasys+RBV, and Roche is collecting data now to report on this question. (See section on weight-based dosing, page 7.)

--In both the physical and mental components of the Quality of Life Test SF-12, the patients receiving EPO had better scores (ITT analysis) in both the physical and mental components than those not receiving EPO (physical component mean 4.5 [+/- 9.1; range 14.8-28.4] vs 1.5 [+/- 9.6; -20.4-26.9]; effect size between groups 0.38. Mental component mean 3.0 [+/- 9.7; range –21.6-25.4] vs 0.2 [+/- 6.9; range –12.9-23.6]; effect size between groups 0.25.

--In total, 29 patients were treated with 40,000 Units once weekly of EPO. 5 patients were dose reduced to 30,000, 20,000 or 10,000.

--Safety & tolerability: Dieterech reported EPO was well tolerated, that adverse events were similar to those expected with RBV/IFN, and adverse events were not significantly different across the study groups (including ALT & HCV-RNA). Dieterich reported no adverse events were significantly more frequent in the EPO group. He reported a final list of adverse events which patients experienced at greater than 20% in either group. For some adverse events the differences between the 2 groups was larger. He reported more patients had headaches in the EPO arm (26%, n=9 vs 11%, n=3), and nausea (23%, n=8 vs 7%, n=2), and pain (20%, n=7 vs 14%, n=4). Interestingly, only 17% (n=6) reported depression in the EPO arm compared to 32% (n=9) in the SOC arm suggesting that fatigue may be related to depression experienced on RBV/IFN. In other categories of adverse events there were no differences or smaller differences between the EPO and SOC arms: fatigue 29%, n=10 EPO vs 25%, n=7 SOC; alopecia 20%, n=7 vs 28%, n=8; dyspnea 20%, n=7 vs 25%, n=7; rash 20.6%, n=7 vs 17.9%, n=5; anorexia 11.8%, n=4 vs 21.4%, n=6.

Less Anemia with Pegasys Alone vs Standard IFN a-2b+Ribavirin

Kenneth Rothstein (Albert Einstein Medical Center, Philadelphia, PA.) reported on a safety, tolerability, efficacy, and quality of life study comparing Pegasys alone to standard IFN a-2b+ribivarin therapy. About 200 patients in each arm received either Pegasys (IFN a-2a) 180 ug once weekly or IFN a-2b 3 MIU three times per week plus RBV 1000-1200 mg/day. Preliminary virologic response at week 24 showed the same response (56% in Peg alone arm vs 57% in the IFN/RBV arm).

The incidence of adverse events were reported as less in the Pegasys arm: less rigors, nausea, insomnia, myalgia, pyrexia, depression and pruritus (itching). Two percent were reported to experience anemia in the Pegasys arm vs 32% in the IFN/RBV arm. About 60% in the IFN/RBV arm vs 10% in the Pegasys arm had 10 or less g/dL Hb or a drop of 3 or more in Hb. 33% vs 2% (Peg vs IFN/RBV, respectively) had 10 g/dL or less Hb or a drop of 4 or more in Hb. There was also a wide disparity when looking at drops of 5 or 6 or more in Hb or 10 or less in Hb.

Patients reported better physical functioning scores, mental health, and better overall health & well-being at weeks 4 and 12 using Pegasys compared tostandrard IFN/RBV. Patients also reported better distress scores and positive well being scores. Patients also reported less work and activity impairment and impairment while working due to health when receiving Pegasys compared to RBV/IFN. Less patients taking Pegasys went from employed to unemployed at week 4 or 12 (7% vs 18%).

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