Virological Suppression and Occurrence of Anemia in Hepatitis C Patients Treated with Taribavirin

[Guest guest]

Virological Suppression and Occurrence of Anemia in Hepatitis C Patients Treated with Taribavirin

By Liz HighleymanResearch shows that adding ribavirin to pegylated interferon reduces the likelihood of HCV relapse during or after therapy, but use of ribavirin is limited by the development of anemia. Taribavirin (also known as Viramidine), a prodrug of ribavirin that targets the liver, is associated with less toxicity to red blood cells.As reported recently, the Phase III VISER 1 and VISER 2 studies showed that while taribavirin was significantly less likely than ribavirin to cause anemia (5%-6% vs 22%-24%), it also was less effective, producing sustained virological response (SVR) rates of 38%-40% vs 52%-55% when combined with pegylated interferon. However, there was a trend toward greater efficacy among patients with higher exposure to taribavirin on the basis of body weight.

Two studies presented at the recent American Association for the Study of Liver Diseases (AASLD) annual meeting provided further information on outcomes with higher taribavirin exposure levels.Study 1Previous studies have shown that the later a patient experiences HCV RNA suppression during the course of treatment with pegylated interferon plus ribavirin, the more likely they are to relapse and the lower the likelihood of ultimately achieving SVR.To understand why taribavirin was associated with a lower SVR in VISER 1, researchers conducted a post-hoc analysis of the intent-to-treat population to examine the impact of treatment on viral kinetics and its association with factors such as patient age, body weight, and total taribavirin drug exposure. In VISER 1, 970 patients were randomly assigned (in a 2:1 ratio) to receive either fixed-dose taribavirin or weight-base ribavirin, in combination with pegylated interferon alpha-2b (PegIntron). Subjects were stratified on the basis of HCV genotype, baseline HCV viral load, and body weight.Results

Patients who achieved rapid virological response (RVR) at Week 4 had an SVR rate approaching 90% when treated with either taribavirin or ribavirin. Patients who had slower virological response -- in particular those who failed to achieve at least a 2-log drop in HCV RNA within the first 4 weeks of therapy -- had a marked increase in SVR when treated with taribavirin compared with ribavirin (63% vs 36%) if HCV RNA was undetectable at Week 12. If HCV RNA was undetectable at Week 24, the respective SVR rates were 23% and 12%.

In conclusion, the researchers suggested, "The improvement in SVR in patients who fail to clear HCV RNA early during treatment is likely secondary to the improved tolerability of taribavirin over ribavirin."

Taribavirin

Ribavirin

Week 4 / Week 12 / Week 24 HCV RNA response

N

age < 45 years, %

mean dose

mg/kg

SVR %

N

age < 45 years, %

mean dose

mg/kg

SVR %

neg / neg / neg

144

71%

16.4

87%

103

58%

14.8

88%

≥ 2 log drop / neg / neg

146

49%

16.1

57%

73

32%

14.7

78%

< 2 log drop / neg / neg

24

50%

15.6

63%

14

36%

13.7

36%

≥ 2 log drop / ≥ 2 log drop / neg

27

30%

15.6

26%

10

40%

12.6

20%

< 2 log drop / ≥ 2 log drop / neg

35

37%

15.8

23%

25

56%

14.7

12%

neg = undetectable HCV RNAStudy 2The second analysis, also from VISER 1, looked at the impact of taribavirin and ribavirin exposure based on weight with regards to both virological efficacy and rates of anemia, defined as a hemoglobin level less than 10 g/dL.Results

Higher mg/kg taribavirin exposure resulted in increased efficacy, while anemia rates remained relatively constant. Despite having the same drug exposure, patients with HCV genotype 2 or 3 treated for 24 weeks experienced less anemia compared to patients with other genotypes treated for 48 weeks. The risk of hemoglobin decline was present throughout the course of therapy, not just during the initial weeks of treatment. Dosing taribavirin at levels higher than 18 mg/kg yielded response rates similar to those observed with the current standard of care (pegylated interferon plus ribavirin). The researchers concluded that, "Future studies should be directed at examining higher drug exposures (mg/kg) of taribavirin to maximize efficacy potential without compromising safety."

Taribavirin dose

N

SVR%

Anemia Rate (%)

All genotypes

≤13 mg/kg

179

32

4

>13-15 mg/kg

147

31

4

> 15-18 mg/kg

182

38

7

> 18 mg/kg

138

52

7

Genotype 2/3

≤13 mg/kg

51

53

4

>13-15 mg/kg

38

63

3

> 15-18 mg/kg

42

64

0

> 18 mg/kg

43

70

2

Genotype non-2/3

≤13 mg/kg

128

23

4

>13-15 mg/kg

109

20

5

> 15-18 mg/kg

140

30

9

> 18 mg/kg

95

44

8

Hunter Holmes McGuire VAMC, Richmond, VA; Fundacion de Investigacion de Diego, Piso Oficina, Puerto Rico; Henry Ford Health System, Detroit, MI; Digestive Disease Center, Plainview, NY; Scripps Clinic, La Jolla, CA; Hopital Hotel-Dieu, Lyon, France; Valeant Pharmaceuticals International, Costa Mesa, CA. Weill Medical College, New York, NY; Scripps Clinic, La Jolla, CA; Hopital La Pitié-Salpétrière Service d'Hepato-Gastroentérologie, Paris, France; Hospital Vall d'Hebrón, Barcelona, Spain; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Klinica Obserwacyjno-Zakazna Akademii Medyczna W Bialymstoku, Bialystok, Poland; Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA; Valeant Pharmaceuticals International, Costa Mesa, CA.