G3 Study

I came across the following Canadian study on j Viral Hepatitis.

http://www.blackwell-synergy.com/toc/jvh/15/1
You will need to create an account, but Its free if anyone is interested in reading it.

Exploring differences in response to treatment with peginterferon alpha 2a (40kD) and ribavirin in chronic hepatitis C between genotypes 2 and 3

SUMMARY. Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expandedaccess, non-randomized, open-label trial, evaluating 180lg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24–48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR.


INTRODUCTION
Antiviral therapy for the treatment of hepatitis C virus (HCV) infection has evolved over time from interferon monotherapy to combination therapy with interferon and ribavirin (RBV), to the present standard of care, namely pegylated interferon (peg-IFN) and ribavirin [1–7]. Several factors have become evident as predictors of response to antiviral therapies; however, none are more powerful than genotype. Genotype 2 and 3 infections are consistently associated with significantly higher rates of sustained virological response (SVR) compared with genotype 1 infections.
Although the precise biological explanation for the difference in sustained virological response (SVR) rates among genotype 1 vs genotype 2 and 3 remains elusive, it has been clearly demonstrated that viral kinetics in response to interferon therapy differ between the two groups in both the first and second phase of viral decline. The viral decline among genotype 2 and 3 infections is up to eight times faster than that of genotype 1 [13,14]. This rapid virological response to therapy has prompted the development of shorter courses of therapy for genotype 2 and 3 from the traditional 48 weeks to as few as 12–16 weeks in investigative protocols, whenever a rapid virological response (RVR) is achieved with HCV polymerase chain reaction (PCR) negativity after 4 weeks of therapy.

As a result of their favourable antiviral response, genotype 2 and 3 infections are frequently grouped together when the results of clinical trials are evaluated and hence also in treatment guidelines [9,11,12]. More recent studies, however, have reported that genotype 3 infections are associated with lower rates of SVR than genotype 2 infections in clinical trials of treatment with pegylated interferon and ribavirin [8,9,11,12].
Although genotype has been a consistent factor associated with treatment response among genotype 2 and 3 patients, there is little consensus regarding other factors associated with differential response between patients with genotype 2 and genotype 3.
Dalgard et al. in a pilot study of a short course (14 weeks) of therapy with peg-IFN alpha-2b and RBV demonstrated that the lack of bridging fibrosis/cirrhosis was an important factor associated with SVR in a mixed genotype 2/3 cohort of patients.
Von Wagner et al. [12] and Zeuzem et al. [8] found that a high baseline viral load but not fibrosis was associated with a lack of SVR, especially among patients with genotype 3.
Finally, a study by Mangia et al. did not identify any factors other than genotype that predicted response among the study population consisting primarily of patients with genotype 2.

Response to antiviral therapy is not the only differentiating characteristic between the two genotypes. Genotype 3 has long been known to be associated with hepatic steatosis independent of other factors such as body mass index (BMI) and alcohol intake, whereas no such relationship exists between hepatic steatosis and genotype 2. Genotype 3 has also been demonstrated to have considerable differences in E2 glycoprotein compared with genotype 1, which appears to preferentially induce apoptosis, possibly promoting hepatic fibrogenesis
The most striking evidence demonstrating the direct impact of genotype 3 infection on hepatocytes is the reversal of steatosis with successful antiviral therapy.

Thus genotype 2 and 3 appear to behave differently in the host as well as in their response to antiviral therapy. The aim of our study was to confirm the difference in SVR among genotype 2- and genotype 3-infected HCV patients and determine factors associated with antiviral response to peg- IFN alpha-2a and RBV, as well as exploring interactions between these factors and genotype.
RESULTS
Among the 67 genotype 2 patients who had undergone at least 12 weeks of therapy, 54 (81%) achieved an SVR compared with 71 of 101 (70%) genotype 3 patients. Factors significantly associated with SVR in the whole cohort of 180 patients on univariate analysis included
METAVIR fibrosis score (P = 0.004), BMI (P = 0.018) and treatment group (P = 0.033). As shown in Table 2, age, gender and baseline log viral load were not significant on univariate analysis Genotype, METAVIR fibrosis score, treatment group and BMI were then assessed in an MLR model with fibrosis score considered as a categorical variable with values from 0 to 4.

In this initial model, genotype and hepatic fibrosis were the only independent variables significantly associated with SVR.
The odds ratios associated with lack of SVR are presented in Table 3. Genotype 3 infections had an overall 2.29 greater odds for lack of SVR compared with genotype 2 infections, while a fibrosis score of F3 or F4 compared with F0 had 10.90 and 27.90 greater odds for lack of SVR, respectively.
Those assigned to the 48-week treatment duration also had lower SVR; however, when the 12 subjects who withdrew early (before 12 weeks of therapy) were removed from the analysis this factor lost significance (P = 0.167).


Table 3 Multivariate analysis of factors associated with lack of SVR

Variable  Odds ratio (95% CI)  p-value
Genotype
2             1
3             2.29 (1.08–4.83)       0.030

METAVIR fibrosis score          0.014
0             1
1             5.50 (0.63–48.32)     0.124
2             7.58 (0.91–63.19)     0.061
3             10.90 (1.23–96.40)   0.032
4             27.90 (2.93–265.73) 0.004
BMI         1.07 (0.99–1.16)      0.102

One patient did not have data on BMI available and was not  included in the MLR model.

In order to further explore the possibility of an interaction between genotype and fibrosis, SVR rates were plotted according to genotype and METAVIR fibrosis score. Figure 1 demonstrates that patients with genotype 3 and cirrhosis had lower rates of SVR compared with genotype 2 patients with cirrhosis. Patients with genotype 3 and cirrhosis had an SVR rate of 17% (2/12) compared with 78% (7/9) among those with genotype 2 and cirrhosis (P < 0.001; 95% CI for difference 0.27–0.95).
This was assessed statistically by constructing an MLR model including genotype, cirrhosis (presence/absence), treatment group and BMI as well as the cross-product of genotype and cirrhosis. This MLR model demonstrated that there is a significant interaction between cirrhosis and genotype, where genotype is an important effect modifier of the negative impact of cirrhosis on response (P = 0.027).
Those patients with genotype 3 and cirrhosis do worse than those with genotype 2 and cirrhosis. This difference was not due to adherence as the latter finding remained intact even when data were reanalysed after excluding the 12 patients who withdrew early (before 12 weeks of therapy) or the 12 patients who did not submit a blood sample for determination of SVR 24 weeks after completing the treatment course

Continued
CS

[CockSparrow]

DISCUSSION
Therapy with peg-IFN alpha 2a and ribavirin 800 mg/day achieves SVR rates in over 70% when those with genotype 2 and 3 infections are treated as a homogenous group [10]. The remainder either does not respond to antiviral therapy or relapses after cessation of therapy. This study demonstrates that there was a significant interaction between cirrhosis and genotype 3 infections. The SVR rate among genotype 2 infections with cirrhosis was 78% compared with 17% among those patients with genotype 3 and cirrhosis.
Our findings show the negative effect on treatment response of advanced fibrosis, especially cirrhosis, is limited to genotype 3 infections with no demonstrable effect on genotype 2.
The influence of hepatic fibrosis on responsiveness to antiviral therapy has been previously demonstrated in one other clinical trial involving patients with genotype 2 and 3 infections [9]. Other investigators, however, have not found the same association between hepatic fibrosis and SVR among genotypes 2 and 3 [8,11,12].
There are several possible explanations for the discrepancy between our results and those of other trials of peg-IFN for the treatment of genotype 2 and 3. Similar to the study by Dalgard et al. [9], more than a quarter of our patients had advanced fibrosis (17% F3 and 11% F4); this compares well with the 18% F3 plus only 6% F4, and 18% of patients with METAVIR fibrosis score of ‡3 in the studies of Zeuzem et al. [8] and Mangia et al. [11], respectively. In these two studies, demonstrating an association between baseline viral load and SVR among genotype 3, the focus was on courses of therapy of ≤24 weeks. In the study by Von Wagner et al. [12], the group treated for 16 weeks with genotype 3 and a high baseline viral load, had a poorer response

Our finding of an interaction between genotype and cirrhosis is limited by the sample size of 21 patients with cirrhosis in our study. Of course there are problems with inter-observer variability for the histological scoring of liver biopsies. This is less of a problem in staging of fibrosis compared with grading of activity especially with expert pathologists [26]. However, one would expect that any variability in identifying cirrhosis would occur equally in patients with genotype 2 or 3.

Current recommendations for the treatment of genotype 2 and 3 infections do not include pretreatment liver biopsy.
The most recent NIH recommendations state that as the favourable response to current antiviral therapy that occurs in more than 70% of patients infected with genotype 2 or 3, it may not always be necessary to perform a liver biopsy [27]. Our data would support this recommendation for those with genotype 2 infections, yet in genotype 3 infections a pretreatment liver biopsy would yield important information on the patient_s subsequent response to antiviral therapy and perhaps question their appropriateness for shorter courses of therapy.
Although rapid virologic response is also a valuable tool predicting ultimate SVR among genotype 3 patients, it may not alleviate the need for pretreatment liver biopsy. In order to provide patients with subsequent information about the likelihood of achieving a clinical cure, they need to endure a minimum of 4 weeks of therapy

In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3.
The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.


This study raises some important questions. Along with Accelerate, NV15492, the Zeuzem study and the short course studies we are starting to get a picture of when G3s are difficult to treat.

Some of the negative predictors could well be differences in efficacy between PegIntron and Pegasys.
The studies using PegIntron tend to have HVL as a negative predict for G3s. Zeuzem, others
The studies with Pegasys seem to have Fibrosis stage as a negative predict. Dalgard et al, and the one above
Although the von Wagner study also found Fibrosis was a negative and that used Pegasys.

What I found interesting was that G3s got progressively more difficult to Tx at each Fibrosis stage. Kinda says to the earlier you Tx the greater the SVR chances. More likely the longer you wait to Tx the more likely you have multiple negative predicts such as HVL, steatosis etc thus becoming more difficult with increasing fibrosis stage.

What it also says is make sure you have a Biopsy done. Has important Tx implications.

Hope everyone has a Merry Chrismas (well not to merry) and a SVR New Year.
CS

[CockSparrow]

Below are a couple of studies on Asian response to treatment. For some reason Asian G1s seen to have a much higher SVR rate than everone else. There is not much difference in Asian response rates with G2/3.

A randomized trial of 24-vs.48-week courses of PEG interferon a-2b plus ribavirin for genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan
Liver International 2006: 26: 73–81

Abstract: Background: To assess the efficacy of 24- or 48-week peginterferon/ribavirin treatment of Taiwanese patients with chronic hepatitis C virus genotype-1b (HCV-1b) infection, and to identify subgroups of patients in whom the 48-week treatment has benefits. Methods: We assigned 60 patients receiving peginterferon-a-2b (80–100 mcg/week) plus ribavirin (1000–1200 mg/day), depending on body weight, for 24 or 48 weeks, with a 3:1 randomization ratio. Results: The sustained virological response (SVR) rate was significantly higher in the 48-week (80.0%, 12/15) than in the 24-week group (48.9%, 22/45, Po0.05). The 60 patients were classified into two subgroups according to the presence of unfavorable baseline predictors: viral loads _ 400 000 IU/ml or a hepatic fibrosis score of 3–4. In 19 patients without an unfavorable predictor, the SVR rate was comparable in the 24-week (78.6%) and 48-week (75.0%) groups; in patients with either unfavorable predictors, the SVR rate was significantly higher in the 48-week (81.1%, 9/11) than in the 24-week group (36.7%, 11/30, P50.015). The discontinuation rate was significantly higher in the 48-week (20.0%, 3/15) than in the 24-week group (2.2%, 1/45, Po0.05). Conclusion: A 48-week course of peginterferon-a-2b/ribavirin was more effective than a 24-week course in Taiwanese HCV-1b patients, mainly in those with high viral loads and/or advanced hepatic fibrosis.

Now I mentioned this study because the Canadian study posted above also did some research into Asian patients response. The abstract above is to show that the results are not a quirk of the study. The results are below.

Impact of Asian Race on Response to Combination Therapy With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C
American Journal of Gastroenterology doi: 10.1111/j.1572-0241.2007.01431.

The overall SVR rate achieved in Asians was significantly higher than in whites (65% vs 45%) and was in keeping with response rates in other studies of Asian patients treated with pegylated interferon based therapy (25, 26). When stratified by genotype, the unadjusted rates of SVR show a significant difference between Asian and white patients with genotype 1 infections (65% vs 36%), a finding not seen in patients infected with genotype 2 or 3.
Response rates in Asians, in fact, were similar across the three genotypes. Thus, the racial differences in treatment response noted in our analysis are fully explained on the basis of differences in treatment response among genotype 1 infections. The reasons for this finding warrant further study. A partial explanation is suggested by the nonsignificant racial difference in rates of EVR, and the strong trend toward a higher PPV of an EVR for predicting SVR in Asians with genotype 1 infections. This makes it likely that a higher proportion of the Asian subjects were rapid virological responders with a consequently lower rate of relapse or breakthrough and a higher rate of SVR (32)

Early and Sustained Virological Response
Unadjusted rates of EVR and SVR for Asians and whites with genotypes 1, 2, and 3 are presented in Figure 1. The overall rate of SVR was 47% (205/436) while rates among patients with HCVgenotypes 1, 2, and 3 were 38% (113/297), 77% (43/56), and 59% (49/83), respectively. SVR occurred in 65% (34/52) of Asian patients and 45% (171/384) of white patients (P = 0.005). When comparing the two groups by genotype, there was no racial difference observed in SVR rates among patients with
genotype 2 (75% among Asians vs 77% among whites, P = 1.00)
genotype 3 (64% among Asians vs 57% among whites, P = 0.55)
but Asian patients with genotype 1 had a significantly higher response rate than their white counterparts (65% among Asians vs 36% among whites, P = 0.005).

This variation in genotype 1 patients persisted even after adjusting for BMI, fibrosis, and doses of study drugs (OR 2.87, 95% CI 1.40–5.88, P = 0.03). Among patients with genotype 1 infections, EVR was achieved in 68% (201/297) overall; 53% (106/201) of whom ultimately achieved an SVR and 47% (95/201) of patients who did not.
There was no statistically significant racial difference in rates of EVR (78% among Asians vs67%amongwhites,P=0.26).

A couple of things are of interest to me at least.
1. The relatively low G3 SVR rate of 57 % & 64%
2. Asian Patients have similar responses across Genotypes.

Why is this?
Now I not a big fan of racial differences in response rate, we cant be that much different. I would like to know if the poor response of African Americans is also seen in European Africans or African Africans. Does anyone know.

I would also like to know if the above results were in seen resent migrants to Canada or in 2nd/3rd generation Asian Canadians.

Who says G1s a difficult to treat. Seems to be no harder than G3s unless you live in Europe, North America or Australia that is.

The question is why do Asians have this similar response rate across genos. To me it indicates that like the G3 interaction with steatosis maybe G1 interacts with something? That makes it harder to Tx than if this interaction hasn’t occurred.

Cause I could be wrong
CS

[GoofyDad]

This struck me as odd:

Although rapid virologic response is also a valuable tool predicting ultimate SVR among genotype 3 patients, it may not alleviate the need for pretreatment liver biopsy. In order to provide patients with subsequent information about the likelihood of achieving a clinical cure, they need to endure a minimum of 4 weeks of therapy

It seems the author is saying using RVR as a predictor in cirrhotic patients is problematic because you need to endure 4 weeks of tx to find out how well it's going to work. Like they would recommend no treatment for cirrhotics??? That's the only way I see they would have to 'endure' 4 weeks of treatment.

All in all - without studying all of it - it seems like it reinforces the GT3 protocol of RVR and 24 weeks or fewer, no-RVR buckle-up for the 48 week scenic tour.....

[merryBe]

OK, just pure conjecture here, but based on the study saying these stats held after BMI adjustments etc. My guess would then be not as much genetic response differences, although that certainly could be a factor, but I'd suspect dietary differences may pay a larger part.

Especially in light of the recent stuff that HR has written regarding PPC etc. We do know the Asian diet is traditionally higher in soy products, fiber, and seafood, excellent sources of Omega's etc. The diet itself produces far less obesity and may give their livers much more resiliency. They also have much lower rates of cancer that many attribute to the differences in diet, Just a guess based on a few factoids is all.
maryB

[CockSparrow]

GoofyDad
RVR not alleviating the need for a Biopsy got to me a bit too.
Dont know why they didnt say that it would also give a accurate steatosis grade as well.
Not sure i believe the 17 % F4 stat though. Well i believe it just dont think it will be reproduced in another study. Might though seeing as G3s dont have biopsys done that often even in studies.

If Accelerates stats get reproduced then it could well be RVR and do 16 else 48.
Surprised the hell out of me how little benefit G3s gained from the extra 8 weeks.

MerryBe
I kinda think it got something to do with diet also. Either that or they are sneakingly taking TCM or Oxymatrine and not telling anyone.

That Taiwan study certainly got high SVR rates for G1s even with 6 months and it would be real interesting to know why or how.
CS