Highlights from The 36th Annual Meeting of EASL

Perhaps one of the more interesting clinical presentations at EASL 2001 that potentially could have a major impact on treatment outcome for patients with chronic hepatitis C was the Benelux Study. Benelux Study results were first reported at AASLD November 2000 (see NATAP Report.) Dr. J.T. Brouwer of University Hospital in Rotterdam, The Netherlands presented the study results. Even though the study used the older standard combination (non-pegylated) interferon alfa plus ribavirin, the low relapse rate of only 13% in a predominant genotype-1 population has significant potential implications, if similar [or better] results were to occur after 18 months of pegylated interferon alfa plus ribavirin.

Given that end-of-treatment virologic response (ETR) rates when treating chronic hepatitis C have always been higher than their associated sustained virologic response (SVR) rates, the researchers in this study were trying to determine whether longer treatment might increase either ETR, SVR or both.

A total of 300 treatment-naïve (no previous therapy) patients with chronic hepatitis C (positive HCV RNA, increased liver enzyme ALT, abnormal liver biopsy) were randomized to one of 3 treatment arms in a double-blind fashion (treatment unknown to patient or treating physician). They were: (1) interferon alfa 2b (Intron A), 3 MIU (million international units) injected 3-times weekly plus oral ribavirin 1,000-1,200 mg daily for 18 months*; (2) the same drug regimen in (1), except for only 6 months; or (3) interferon alfa 2b monotherapy, same dose as above, plus oral placebo (inactive drug) for 18 months*. *Note that after 6 months, the duration of the treatment arms only was revealed (unblinded), and all patients who were non-responders at that time (detectable viral load and ALT greater than 1-times the upper limit of normal) stopped therapy (due to evidence that they would not respond [virologically] thereafter).

The 3 study arms were well randomized in terms of age (mean 43-47 years), gender (sex, 63% men in combination arms, although monotherapy arm had 46% men), ("compensated," stable) cirrhosis rate (liver scarring, F4, 13-15%), genotype 1 (most difficult to treat, 66-75%), and baseline HCV RNA greater than 3 million copies/mL (50-55%) with 57% overall having greater than 2 million copies/mL. Patients were from 25 centers in Belgium, Luxembourg and the Netherlands.

The results were as follows. Stopping at 6 months due to non-response included 10% from arm 1 (combination 18 months) and 28% of arm 3 (interferon 18 months); all in arm 2 stopped at that time as per protocol. Withdrawal from study due to any reason during the first 6 months included 10% each of arms 1 and 2 and 5% of arm 3. Withdrawal due to any reason between months 6 and 18 included 13% of arm 1 and 20% of arm 3. Reasons for withdrawal were not presented. Using a strict "intent-to-treat" (ITT) analysis (all patients included), the end-of-treatment (ETR) viral undetectability (limit 100 copies/mL) response rates were 51% (arm 1, combination 18 months), 55% (arm 2, combination 6 months) and 27% (arm 3, monotherapy 18 months). There was no significant difference between arms 1 and 2, with very little additional response in arm 1 after 6 months.

	Arm 1: interferon alfa 2b* plus ribavirin**	Arm 2: interferon alfa 2b* plus ribavirin **	Arm 3: interferon alfa 2b* plus oral placebo
Duration of therapy	18 months	6 months	18 months
End of Treatment Response *** Rate, ITT #	51%	55%	27%
Relapse Rate (see text), ITT #	13%	38%	39%
Sustained Virologic Response Rate, ITT #	43%	34%	16%
Withdrawal, 0-6 months	10%	10%	5%
Withdrawal, 6-18 months	13%	Not applicable	20%

* Interferon dose was 3 million international units injected 3-times weekly (see row 2 for duration)
** Ribavirin dose was 1,000-1,200 mg orally each day (see row 2 for duration).
*** Percentage undetectable HCV RNA, limit 100 copies per milliliter
# ITT = Intent-to-treat analysis, including all enrolled patients

However, after 6 months of follow-up in each arm, the relapse rate (virus becoming detectable after being undetectable at the end of treatment) was significantly lower in arm 1 (combination 18 months) than in arm 2 (combination 6 months). Those relapse rates were: 13% (arm 1), 38% (arm 2) and 39% (arm 3), using an ITT analysis. Therefore, this led to a SVR (sustained virologic response) rate of 43% (arm 1), 34% (arm 2) and 16% (arm 3).

In a separate "as-treated" analysis including patients who completed 80% of therapy for 80% of the intended duration or who stopped therapy according to protocol, among patients in arm 1 (combination 18 months), those with cirrhosis had a higher SVR (57%) than those without cirrhosis (42%). The usual, opposite trend occurred in arm 2 (combination 6 months), with a SVR of 29% for those with and 37% for those without cirrhosis ("as-treated" analysis). And the usual trend also occurred in arm 3 (monotherapy), with a SVR among 10% for those with and 18% for those without cirrhosis. (Note that "as-treated" ETR was 56% in arm 1, 60% in arm 2 and 25% in arm 3. "As treated" relapse rates were 7% (arm 1), 38% (arm 2) and 32% (arm 3). "As-treated" SVR was 52% (arm 1), 36% (arm 2) and 17% (arm 3).

(Editorial note from Jules Levin: The preliminary ETR for Pegasys+ribivarin reported at EASL were 58% for monotherapy and 68% for combination therapy. In this or any study, if you were to look at the response rates for patients who are adherent and complete the course of treatment the response rates would be expected to be considerably better. This was reflected in the Benelux study as the SVR for arm 1 was 43%, while in the "as-treated" analysis the SVR was 57% for cirrhotics and 42% for non-cirrhotics. This emphasizes the importance of adherence. Adherence support for coinfected patients receiving IFB+RBV will be helpful. We will have to see if HIV-infected can tolerate ribivarin for 18 months due to reduced hemoglobin and similar adverse effects on other blood tests).

Interestingly, the SVR was higher only for genotype 1 patients taking combination treatment for 18 months (arm 1, 36%) than for those taking it for 6 months (arm 2, 23%), since those with genotype 2 or 3 had a nearly identical SVR whether they took combination therapy for either 18 months (arm 1, 71% SVR) or 6 months (arm 2, 72%). However, the genotype analysis was only presented "as-treated." In a similar pattern, the SVR was higher for those with a higher baseline viral load (greater than 3 million copies/mL) taking combination treatment for 18 months (arm 1, 42%) than for those taking it for 6 months (arm 2, 18%), since those with a low baseline viral load (less than 3 million copies/mL) had a nearly identical SVR whether they took combination therapy for either 18 months (arm 1, 47%) or 6 months (arm 2, 49%). Again, however, the baseline viral load, SVR analysis was presented only "as-treated."

Taken together, the "as-treated" results (cirrhosis, genotype and baseline viral load) suggest that a longer duration of therapy, here 18 months, may be particularly beneficial for those patients who previously have been more difficult to treat, i.e., with "unfavorable" baseline characteristics. This suggests that "longer" might be better in terms of being able to eradicate more HCV from more hepatocytes (liver cells) or by having more time for the immune system to remove more HCV-infected hepatocytes. Yet, those with genotypes 2 or 3 or those with a low baseline viral load did not derive any additional SVR benefits by treatment with combination therapy for more than 6 months.

Dr. Brouwer concluded that prolonged (18 months) combination therapy had "no effect on response beyond 6 months [but had a] clear effect on relapse rate (less than 10%) if [the] therapy is maintained." Note that liver biopsy results at the time of SVR were not reported. However, it is likely that similar or possibly more (or better) improvements on liver biopsy would be observed for those in arm 1 than in arm 2. However, specific types and rates of adverse events and reasons for withdrawal were not presented.

A similar study would need to be undertaken using a "control" arm with today's standard of pegylated interferon alfa plus ribavirin for 12 months (versus 18 months) to determine whether similar additional benefits might be derived, particularly for those with unfavorable baseline characteristics. However, since the SVR could only be measured 24 months (2 years) after entering into such a study (for the 18-month arm), it is quite possible that a new standard-of-care would replace the current one when such a study were finished. In the mean time, with the limitation that this is only one study with these results and considering data not reported (as discussed above), those with genotype 1, a high baseline viral load and/or cirrhosis might want to have their physicians consider longer treatment for 18 months, preferably in a study or at least in an observational study. (Editorial note: as mentioned above, an 18-month study in HCV/HIV coinfected would be useful to evaluate tolerability and adverse effects on bloodwork).