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Lower-than-standard dose peg-IFN alfa-2a for chronic hepatitis C caused by genotype 2 and 3 is sufficient when given in combination with weight-based ribavirin
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Journal of Viral Hepatitis Sept 2008
O. Weiland 1 , A. Hollander 1 , L. Mattsson 1 , H. Glaumann 1 , K. Lindahl 1 , R. Schvarcz 1 , G. Lindh 1 , R. Enquist 1 and A. Quist 2
1 Division of Infectious Diseases, Department of Medicine ; and 2 Division of Virology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
ABSTRACT
Summary. Mono-therapy with pegylated interferon (peg-IFN) has shown that a lower-than-standard dose yields the same sustained viral response (SVR) rates as standard doses for chronic hepatitis C virus (HCV) infection caused by genotypes 2 or 3. Our aim was to see if a fixed, lower-than-standard dose of peg-IFN alfa-2a (135 νg weekly) in combination with ribavirin 11 mg/kg daily for 24 weeks yields sufficient SVR rates for genotypes 2 or 3. Hundred consecutive patients with a mean age of 44 years (range 20-69 years), 59 with genotype 3 and 41 with genotype 2, were studied. Rapid viral response (RVR) with HCV-RNA <15 IU/mL at treatment week 4 and SVR were calculated. RVR was achieved by 28/40 (70%) patients with genotype 2 and 41/58 (71%) with genotype 3. Significantly more genotype 2 patients with RVR achieved SVR 27/28 (96%) than genotype 2 patients who failed to achieve RVR, 8/12 (66%), P = 0.009. The corresponding figures for genotype 3 patients were 39/41 (95%) vs 11/17 (65%), respectively, P = 0.002. In total, SVR was achieved by 35/41 (85%) patients with genotype 2 and 51/59 (86%) patients with genotype 3, respectively. We found that 135 νg peg-IFN alfa-2a weekly was sufficient for treatment of genotype 2 and 3 chronic hepatitis C when combined with RBV dosed daily according to body weight. This combination yielded high SVR rates (85-86%) and may be cost-saving....the estimated cost for peg-IFN alfa-2a was 14% lower than with standard dosing.
Introduction
Treatment of chronic hepatitis C virus (HCV) infection with pegylated interferon (peg-IFN) in combination with ribavirin (RBV) has become the standard of care [1]. Until now, genotypes 2 and 3 have generally been treated during 24 weeks and genotype 1 and 4 during 48 weeks based on the results of three randomized controlled studies [2-4]. The IFN dose used has either been weight-based for peg-IFN alpha-2b (1.5 mcg/kg body weight weekly) or fixed for peg-IFN alpha-2a (180 νg weekly) [2,4]. Mono-therapy studies with lower doses of peg-IFN (peg-IFN alfa-2b 1 mcg/kg body weight daily and peg-IFN alfa-2a 135 νg once weekly) have yielded the same or even better sustained viral response (SVR) rates as the higher doses generally used [5,6]. Because lower doses are expected to cause fewer adverse events and less overall cost, it is important to find out if lower doses than standard in combination with RBV can be used with preserved efficacy. Ribavirin is generally given at a fixed dose of 800 mg daily for genotype 2 or 3 infections when combined with peg-IFN alfa-2a and at a dose of at least 10.6 mg/kg body weight when combined with peg-IFN alfa-2b [3,4]. We have earlier shown that a combination of peg-IFN alfa-2b 1 νg/kg body weight or peg-IFN alfa-2a 135 νg once weekly in combination with RBV 11 mg/kg body weight daily offers high SVR rates for genotypes 2 and 3 when given during 24 weeks [7,8]. Recently, several studies have shown that patients with genotypes 2 or 3 who have a rapid viral response (RVR), meaning that HCV-RNA becomes negative already at treatment week 4, can be treated for shorter periods than standard with high SVR rates [9-12]. This is also true for patients with genotype 1 who can be treated for only 24 weeks when they have RVR and low baseline viral load [13,14]. The largest study published so far comparing a shorter 16-week course with the standard 24-week course for patients with genotype 2 or 3 infection and including more than 1400 patients showed, however, that 24-week treatment was superior and yielded significantly higher SVR rates than the shorter course [15].
Here, we studied the SVR rate, HCV-RNA decline and frequency of early viral eradication weeks 1, 2, 4 and 8 achieved with low-dose peg-IFN alfa-2a (135 νg once weekly) when given in combination with weight-based RBV given daily in 100 consecutive patients with chronic hepatitis C genotype 2 or 3 infection in a Swedish university clinic.
Methods
One hundred consecutive naive patients with chronic hepatitis C caused by genotype 2 or 3 were recruited between September 2003 and November 2005 at the Karolinska University Hospital Huddinge, Stockholm, Sweden. All patients had a known duration of their chronic HCV infection of more than 6 months. Patients with hepatitis B or HIV were excluded as were patients with other concomitant liver diseases. Patients were frequently monitored during treatment by experienced nurses. To achieve maximal adherence, patients were offered instant help when adverse events occurred and were referred for evaluation to a psychiatrist, nutritionist or dermatologist when necessary. Follow-up was performed 1, 3 and 6 months post-treatment stop.
Treatment
All patients were treated with peg-INF alpha-2a (Pegasys) 135 mcg weekly during 24 weeks in combination with RBV (Copegus) 11 mg/kg body weight daily in two divided doses. Growth factors were not used.
Virological methods
Serum were analysed for HCV-RNA levels at baseline, day 2, week 1, 2, 4, 8, 12, 24 and at follow-up 1, 3 and 6 months after treatment stop by the COBAS AmpliPrep/COBAS TaqMan HCV test, which combines automated extraction of nucleic acids on the COBAS AmpliPrep Instrument with real-time PCR on the COBAS TaqMan and has a >6-log dynamic range of 43-6.90E + 7 IU/mL, and a sensitivity (95% hit rate) of at least 15 IU/mL for HCV WHO Standard and a comparable quantification of genotypes 1-6 [16]. HCV genotyping was performed with a line probe assay (Inno-LiPA HCV II, Innogenetics NV, Gent, Belgium) [17] or an in-house method [18].
Definition of response
Rapid viral response was defined as a negative HCV-RNA test at treatment week 4. Patients who did not achieve early viral response (EVR) defined as at least a 2 log10 drop in HCV-RNA levels or a negative HCV-RNA by treatment week 12 stopped treatment. SVR was defined as a negative HCV-RNA test at treatment stop and 24 weeks after treatment cessation, and an end-of-treatment viral response (ETR) as a negative HCV-RNA when treatment was stopped.
Liver biopsies were not performed in any patient according to Swedish consensus, which concludes that genotypes 2 and 3 can be treated without a prior biopsy [19,20].
Statistics
The primary end-point of the analysis was virological RVR, EVR, ETR and SVR. The statistical evaluation was based on intention to treat analysis. Baseline demographic data are presented as proportions, mean or median levels with ranges. HCV-RNA levels of <15 IU/mL were set to 14 IU/mL for statistical analyses. The Chi-squared test or Fisher's exact two-tailed test was used to test categorical variables and the Wilcoxon test for continuous variables. A P-value < 0.05 was considered statistically significant.
Results and Discussion
In total, 48 men and 52 women were included with a mean age of 44 years (range 20-69 years). The 59 (59%) patients with genotype 3 were slightly older than the 41 (41%) patients with genotype 2, and had significantly more often acquired their infection from a remote prior intravenous drug use (IVDU) 46/59 (78%) vs 22/41 (54%), respectively, P = 0.007.
Virological response according to genotype
The percentage of patients with a negative HCV-RNA test (<15 IU/mL) according to treatment week and genotype is depicted in Fig. 1. The number of patients who achieved a negative HCV-RNA test increased from 20% to 70% between week 2 and week 4 during treatment, hereafter nearly all became HCV-RNA negative from treatment week 8 onwards.
Rapid viral response at treatment week 4 with a HCV-RNA level <15 IU/mL was analysed in 98/100 patients from whom sera were available. It was achieved by 28/40 (70%) patients with genotype 2 and 41/58 (71%) patients with genotype 3.
Significantly more genotype 2 patients who achieved RVR achieved a final SVR 27/28 (96%) than genotype 2 patients who failed to achieve RVR, 8/12 (67%) P = 0.009. The corresponding figures for genotype 3 patients were 39/41 (95%) vs 11/17 (65%), respectively, P = 0.002 (Fig. 2).
A stopping role for patients who lack EVR defined as a 2 log10 drop in HCV-RNA levels or a negative HCV-RNA by treatment at week 12 has been used in most treatment algorithms [1]. This stopping role is appropriate in particular for patients with genotype 1 or 4 but inadequate for genotype 2 and 3 infections for which a decision to stop treatment probably can be made earlier. In this study, 95-96% of all patients who achieved a RVR at week 4 eventually achieved SVR (Fig. 1). On the contrary, among patients who failed to achieve RVR, significantly fewer achieved SVR 65-66%, P < 0.009. Still two out of three patients who failed to achieve RVR at week 4 finally achieved SVR. On the contrary, at treatment week 8, all three patients with genotype 3a infection who became non-responders were HCV-RNA positive, whereas the only patient with genotype 2 who had a non-response was negative at treatment week 8 with a later breakthrough.
Only 3/98 (sera missing from two) patients failed to become HCV-RNA negative at treatment week 12.
Virological ETR was seen in all but one patient with genotype 2 and all but three patients with genotype 3. Relapse during follow-up among patients with ETR was seen in 5/40 (12.5%) patients with genotype 2 and in 5/56 (8.9%) patients with genotype 3.
In this study, SVR rates of 85% (35/41) for genotype 2 and 86% (51/59) for genotype 3 were achieved with a lower-than-standard dose of peg-IFN alfa-2a used in combination with a weight-based daily RBV. These figures are well in line with the SVR rates (76-84%) noted for genotype 2 and 3 patients in the pivotal randomized controlled studies that formed the basis for approval of this treatment [2-4]. In mono-therapy studies, lower doses of both peg-IFN alfa-2a and alfa-2b, however, have yielded the same or even better SVR rates as the higher doses accepted in the labelling authorized in US and Europe, which are generally used during combination therapy with RBV [5,6]. The present study shows that this is true also for combination therapy when a low peg-IFN alfa-2a dose is used in combination with a daily RBV dose based on weight. Hence, a lower-than-standard dose of peg-IFN alfa-2a can be used for genotype 2 and 3 infections with preserved high SVR rates.
Virological response according to baseline viral load
Recently, several studies have indicated that patients with RVR, meaning HCV-RNA negativity already at treatment week 4, can be treated for shorter time periods than patients who fail to achieve RVR [11-14,21]. Thus, patients who achieve RVR with genotype 2 or 3 can be treated for 12-16 weeks [11,12,21] and patients with genotype 1 and 4 for 24 weeks [13,14] with the same or only slightly lower SVR rates compared with those generated with treatment during 24 and 48 weeks, respectively. Patients with genotype 3 infection who have high baseline viral load seem to respond less well than patients who have low viral load, in particular, when treated for shorter-than-standard periods [11]. This, however, was not seen in our study where patients with genotype 3 who had high and low viral loads (more or less than 800.000 IU/mL) achieved SVR in 85% (34/40) vs 89% (17/19), respectively, a difference which was not significant. In the largest study so far comparing 16 vs 24 weeks treatment for genotype 2 or 3 HCV infection, however, 24-week treatment was superior to 16-week treatment when peg-IFN alfa-2a was given at a standard dose and RBV at a fixed dose of 800 mg daily [15].
In patients with genotype 2 who had high viral load, SVR was achieved by 82% (28/34) vs 100% (7/7) in patients with low viral load, a difference which was not significant.
Adherence
By using a lower dose of peg-IFN, it is likely that the adverse events will diminish and adherence improve, both factors act in favour of the high SVR rates noted in our study [22]. Hence, only one of our patients withdrew from treatment prematurely because of a severe adverse event. Three patients stopped treatment due to non-response at week 12. The high adherence to a complete treatment course was mainly achieved because of the excellent monitoring performed by our specialist nurses who were available by phone all office hours, and who, without delay, took care of adverse events, and referred the patients to their attending physician and, if needed, to a psychiatrist, dermatologist or nutritionist.
Adverse events
Although a lower-than-standard dose of peg-IFN alfa-2a was used in our study, 20% of our patients had adverse events requiring temporal or permanent peg-IFN dose reductions. Hence, thrombocytopenia or neutropenia requiring peg-IFN dose reduction to 90 mcg daily was seen permanently in 11 patients from mean treatment week 9 (range 2-20) and transiently in 9 patients. One patient stopped treatment at week 14 because of severe generalized toxicodermatitis. Three patients developed sarcoidosis, two as skin scars and one in the lung; the two former achieved SVR and the latter relapsed after having had ETR. One patient developed diabetes and required insulin treatment, and one each developed hyperthyroidism and hypothyroidism. All three, however, completed their treatment and achieved SVR.
The median haemoglobin fall during treatment was 27 g/L (range 5-54 g/L). Ribavirin dose reduction because of anaemia was carried out permanently in eight patients from mean treatment week 8 (range 2-20) and temporarily in four patients.
Conclusion
A fixed peg-IFN alfa-2a dose of 135 νg weekly was sufficient for treatment of genotype 2 and 3 chronic hepatitis C when combined with RBV dosed daily according to body weight and yielded high SVR rates when given during 24 weeks. Furthermore, by using a lower dose of peg-IFN, the cost for the drug decreased, rendering it a further advantage [23]. Hence, the estimated cost for peg-IFN alfa-2a was 14% lower than with standard dosing.
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