Treating patients with HCV genotype 1 and low viraemia: More than meets the eye
Article Outline
When a drug or a combination of drugs is first assessed to evaluate its effectiveness in curing an illness, every effort is made in order to maximize efficacy while still keeping side effects at an acceptable level. It is hence not surprising that the pivotal phase III trials [1], [2] which led in the early 2000s to the registration of pegylated alfa interferons (PEG IFNs) in combination with ribavirin for the treatment of naïve patients with chronic hepatitis C have exploited the maximum permissible doses of PEG IFN evaluated in earlier monotherapy trials [3], [4] over a 48-week treatment period. This duration of treatment had been shown to be the most effective with the combination of standard IFNs and ribavirin [5], [6], and was in fact dictated by the need to demonstrate superiority of PEG over standard IFNs, already registered for a 48 week combination schedule. Both studies were concordant in showing a better efficacy of combination therapy with PEG IFNs, but confirmed that genotype 1 was still harder to eradicate than genotypes 2 and 3, and that subjects with severe fibrosis were less responsive to therapy. An important and concordant finding among these trials was that 12 weeks of treatment were enough to assess, by measuring the drop in viral load, whether sustained virological response was likely to be reached [7], [8]. This early virological response (EVR) rule, allowing to stop ineffective therapy at an early stage, and save unnecessary treatment related morbidity could not be reliably used on standard IFN/ ribavirin regimens before 24 weeks of therapy [5], [6]. A further step towards optimization was made by Hadziyannis et al. [9], who used a 4-arm design to assess the relevance of duration (24 vs. 48 weeks) and of ribavirin dose (800 vs. 1000–1200
mg). This trial made it clear that genotype 1 patients should receive the more intensive approach with a longer treatment duration and higher doses of ribavirin, while genotypes 2 and 3 could do with shorter schedules and lower amounts of ribavirin. Optimization of treatment was thus initially addressed with the distinction between hard and easy to treat genotypes. Still, there was a long way to go towards true individualization of therapy, since the risk of overtreatment was still present for many patients not accurately classified by a genotype-based approach. It has long been known that viral load is also a major determinant of responsiveness to IFN-based therapy, whatever the schedule used for monotherapy [10] or for combination [11]. Problems with the reproducibility of quantitative measurements of HCV-RNA [12], [13] have hampered a more widespread use of this predictor. Real-time PCR testing will probably be able to solve inconsistencies and allow clinicians to progress further into individualization of anti-HCV therapy.
The current 12 weeks EVR rule, when applied to genotype 1 patients, has a negative predictive value approaching 100% [7], [8] and is hence able to solve the issue of overtreatment of nonresponders. It, however, leaves the field open to the possibility of overtreating some genotype 1 patients with a higher propensity for a sustained viral response, i.e. those with a pre-treatment low viral load. These subjects, representing in our experience 15–20% of all genotype 1 infected cases, could hypothetically be cured by shorter and/or less intensive treatment courses thus reducing costs and improving acceptance and tolerability.
In this issue of the Journal, Zeuzem et al. [14] test the hypothesis that patients infected with HCV 1 with low pretreatment HCV-RNA (≤600,000IU/ml at baseline) can receive PEG IFN alfa2b 1.5μg/kg weekly plus weight-based Ribavirin (800–1400mg daily) for 24 weeks and obtain the same rate of SVR as those treated for 48 weeks. The study is a single-arm, open-label historical control trial conducted in 43 European Centres between 2001 and 2004, in which 724 patients were screened and 237 enrolled. As a comparator, 38 comparable patients originally enrolled in the Manns' trial [1], who had received PEG IFN alfa2b 1.5μg/kg weekly plus Ribavirin ≥10.6mg daily for 48 weeks, were re-analyzed. At first glance the results do not look encouraging as a whole since, after reaching end-of-treatment response (ETR) at a comparable rate (81% for 24 weeks and 74% for 48 weeks of treatment), sustained virological response (SVR) was obtained only by 50% in the 24 weeks as compared to 71% in the 48 weeks historical control group. This difference was due to the high rate of post-ETR virologic relapse (37%) on the short regimen.
The relevant information comes from the analysis of early virologic response (EVR) at 4, 12 and 24 weeks. A very high rate of SVR (89%) was in fact found in the subgroup of patients who were already HCV-RNA negative at week 4 (47% of all cases treated with the short course). Those with a slower response to therapy had instead a low rate of SVR (25% for patients becoming HCV-RNA negative at 12 weeks and 17% for those who cleared HCV-RNA only after 24 weeks). The pattern was seemingly different among patients treated for 48 weeks: SVR rates were 85, 93 and 67% for subjects clearing HCV-RNA at 4, 12 or 24 weeks, respectively. Thus low pretreatment viraemia associated to a precocious response to PEG IFN plus ribavirin identifies a subgroup of patients with genotype 1 in whom 24 weeks of treatment are sufficient to obtain the maximal SVR rate allowed by combination therapy. Optimization by avoiding overtreatment would thus become a reality in such cases. In fact, the registration of PEG IFN alfa2b has already been revised by EMEA to include this modality of use.
Issues arising during the phase of optimization of treatments are definitely more complex than the pure demonstration of safety and efficacy in registrative trials. Specifically, results generated by these trials in highly selected and motivated patients must be fine-tuned to fit into the complex array of real-life patients, who often have comorbidities or low compliance, and also keep account of demographic, social and financial constraints. It is of foremost importance, when interpreting the results of these studies, to make a clearcut distinction between evidence generated within RCTs by direct comparison of rigorously randomized groups and indirect inferences derived from the confrontation of non-randomized or ‘historical control’ groups, from subgroup analyses and from the application of a posteriori multivariate models or of mathematical situations. Only direct comparisons allow a reliable confrontation between groups which are fully comparable for all relevant features. At least two recent studies [15], [16] have addressed the issue of optimization, in both cases for the easy-to-treat genotypes 2 and 3, using an appropriate design.
The Zeuzem study on genotype 1 patients with low viral load unfortunately has a number of limitations which potentially detract from its applicability. It has a low internal validity, due to the intrinsic weakness of a design which allows the use of a historical control group, derived from another study, performed more than 5 years ago. This control group is in itself a very small subgroup distilled from a large cohort (11.9%, i.e. 38 out of 348 genotype 1 patients receiving PEG IFN alfa2b 1.5μg/kg weekly plus Ribavirin 800mg daily in the original Mann's study). Although selection modalities are not stated, it may be inferred that patients were included in the historical control group only if: (a) they had received enough ribavirin in relation to body weight to allow for post-hoc adjustment of dosing at ≥10.6mg daily; (b) treatment had been given as assigned for the entire 48 week period; (c) samples were available for testing at 4, 12 and 24 weeks. These requirements actually segregate a population of rather lean patients, with a body weight inferior to 75.5kg, with a high compliance to therapy and to follow-up, and with few or no treatment-related side effects forcing dose reduction or withdrawal. It comes as no surprise that in these ‘ideal’ subjects the SVR rate is 71%. By converse, it must be stressed that these patients were treated at a time when PEG IFNs were still experimental drugs: the degree of confidence of both the caregiver and the patient may well have been different from the current standard. Finally, the small size of subgroups in the EVR analysis (13 patients with EVR at 4 weeks, 15 at 12 weeks and 3 at 24 weeks) makes any comparison with the much larger 24 week group hard to substantiate.
Weight-based ribavirin was given over an extended range of choice (800–1400mg) in the intent to optimize the exposure to the drug. It is then odd to note that subjects on the higher doses of 1000–1200 tended to have more ribavirin-related adverse events than those on the lower dose. If a true optimization of ribavirin dosing is to be achieved, further studies taking into account individual variations in pharmacokinetics, possibly measuring plasma or whole blood levels are needed [17].
PEG IFN alfa2b was given at the standard recommended dosage of 1.5μg/kg weekly. While this dosage is clearly the most effective when given with low amounts of ribavirin (800mg), it is still debatable that such a dose is really needed to obtain response in patients with genotype 1. As a matter of fact, when PEG IFN alfa2b was used as monotherapy [3], 1.0μg/kg performed fractionally better than 1.5μg/kg. Recent results from an Italian multicenter trial in genotype 1 patients [18] show that an SVR of 41 can be reached by giving PEG IFN alfa2b approx. 1.0μg/kg weekly plus Ribavirin 1000–1200mg daily for 52 weeks. This response rate compares well with the 42% SVR reported by Manns [1] on 1.5μg/kg. In the Italian study patients who were HCV-RNA negative at 12 weeks had an ultimate SVR rate of 70%, thus confirming that EVR also applies to lower PEG IFN doses. Clearly, there is space for further optimization also in the reduction of the amount of IFN to be used.
Another matter of concern is the limited external validity, due to the modalities of inclusion within the study. A large number of cases (724) were screened for eligibility, but only 237 patients were enrolled. The low number of patients included at each site (on average 5.5 cases) represents a source of selection bias, since no data concerning the consecutivity of enrolment are given, and also a potential cause of heterogeneity in the actual handling of treatment.
It is not stated whether patients were admitted into the selection process before or after HCV-RNA quantification. If, as likely, quantification was one of the criteria to be assessed during screening, then an unknown proportion of the 454 who did not meet protocol criteria were left out because of an HCV-RNA value >600,000IU/ml. How was this tested? The issue may have major relevance in the context of a multicenter study, where 43 Centres have enrolled patients over a time span of 3 years. Since only a generic statement about the use of an rt-PCR is given by the Authors, it is possible that screening tests were actually done at each site with different methods and with a high potential for inconsistencies. Moreover, due to the spontaneous variations over time of HCV-RNA levels within a 0.5log range [19], it would have been worth assessing baseline HCV-RNA as a mean of values obtained at different points of observation in the months preceeding the start of therapy.
Definitely, the indications of this study cannot be extrapolated to subjects with advanced fibrosis or cirrhosis. Albeit individual data on the number of patients with cirrhosis are not given in Zeuzem's paper, the low mean Knodell score of 1.2 for fibrosis proves that advanced fibrosis was uncommon in the 24 weeks group. Consequently, as found by the Authors, it would be impossible to show upon univariate analysis any significant role of fibrosis on response in this cohort. In all megatrials [1], [2], [9] fibrosis has instead emerged as a significant predictor of resistance to the combination of PEG IFNs and ribavirin, although to a lesser degree than observed with non PEG IFNs. When fibrosis is assessed as a continuous variable [18], a clear cut inverse relationship with response emerges at all stages. It is thus very likely that, in the presence of more advanced liver disease, a short treatment schedule would not obtain adequate rates of SVR. Since viraemia tends to be lower when cirrhosis is more advanced, this issue may have practical relevance.
Notwithstanding all the methodological criticisms, Zeuzem and co-workers must be commended for pushing the issue of optimization beyond the conventional wisdom of genotype, with a large single-arm trial for also taking into consideration both quality and early assessment of viral drop. There is an evident need for studies with truly prospective recruitment and observation and a more articulate panel of options not only in terms of length but also of dosing of PEG IFN and ribavirin. Also, if important treatment decisions are to be made on viral loads, then standardization of HCV-RNA tests and their prompt availability become paramount.
At the present time, the strength of the evidence presented by Zeuzem and co-workers is in our opinion not sufficient to generalize the applicability of this approach to optimization. While further randomized trials are in progress, subjects with genotype 1, a low viral load and an early drop of HCV-RNA under therapy may be treated with this short schedule if they have modest or no fibrosis and hence are unlikely to progress significantly should HCV relapse. Those with more advanced fibrosis are probably still better served by the conventional, more troublesome schedule of 48 weeks.
References
- Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965
- Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982
- Hepatitis interventional therapy group, a randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34:395–403
- Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666–1672
- Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International hepatitis interventional therapy group (IHIT). Lancet. 1998;352:1426–1432
- Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group. N Engl J Med. 1998;339:1485–1492
- . Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645–652
- Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD)/ribavirin. J Hepatol. 2005;43:425–433
- Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–355
- HCV viraemia is more important than genotype as a predictor of response to interferon in Sicily (southern Italy). J Hepatol. 1996;25:583–590
- Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology. 2003;37:600–609
- Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy. J Viral Hepatol. 2005;12:465–472
- . Use of virologic assays in the diagnosis and management of hepatitis C virus infection. Clin Liver Dis. 2005;9:371–382
- Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viraemia. J Hepatol 2006; 44: 97–103.
- Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005;352:2609–2617
- Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129:522–527
- . Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia. J Viral Hepatol. 2004;11:84–87
- Peginterferon alfa-2b plus ribavirin for naive patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol. 2004;41:474–481
- Hepatitis C virus RNA profiles in chronically infected individuals: do they relate to disease activity?. Hepatology. 1999;29:585–589
PII: S0168-8278(05)00693-8
doi:10.1016/j.jhep.2005.11.002
© 2005 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
