Journal of Viral Hepatitis, 2009, 16, 75–90
`
`doi:10.1111/j.1365-2893.2008.01012.x
`
`REVIEW
`Expert opinion on the treatment of patients with chronic
`hepatitis C
`S. Zeuzem,1 T. Berg,2 B. Moeller,3 H. Hinrichsen,4 S. Mauss,5 H. Wedemeyer,6 C. Sarrazin,1
`D. Hueppe,7 E. Zehnter8 and M. P. Manns6 1Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universita¨t,
`Frankfurt, Germany; 2Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charite´, Campus Virchow-Klinikum, Universita¨tsmedizin Berlin,
`Berlin, Germany; 3Hepatologische Schwerpunktpraxis, Berlin, Germany; 4Gemeinschaftspraxis, Kiel, Germany; 5Internistische Praxis, Du¨sseldorf,
`Germany; 6Medizinische Hochschule Hannover, Abt. Gastroenterologie und Hepatologie, Zentrum Innere Medizin, Hannover, Germany;
`7Gastroenterologische Gemeinschaftspraxis Herne, A¨ rztehaus am Evangelischen Krankenhaus Herne, Herne, Germany; and 8Internistische Praxis,
`Dortmund, Germany
`
`Received April 2008; accepted for publication May 2008
`
`OnlineOpen: This article is available free online at www.blackwell-synergy.com
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`for patients
`SUMMARY. The current preferred treatment
`with hepatitis C virus
`(HCV)
`is combination therapy
`consisting of pegylated interferon alfa and ribavirin (RBV)
`for 24–48 weeks. Although this approach appears to be
`highly effective for patients with HCV genotypes 2 or 3,
`who have a sustained virological
`response (SVR) of
`approximately 80%, the treatment algorithm is less effec-
`tive for patients with HCV genotype 1, as these patients
`have SVR rates of
`just 40–50%.
`In order to improve
`treatment outcomes,
`this article explores potential ap-
`proaches for the optimization of treatment for patients with
`HCV genotype 1: considering shorter treatment periods for
`patients with a rapid virological response (RVR), increasing
`treatment periods for slow responders, and increasing RBV
`dose are all suggestions. Results from clinical trials suggest
`that approximately 20% of the HCV genotype 1-infected
`
`population are slow responders, and around 15% of all
`HCV genotype-1 infected patients could benefit
`from a
`shorter treatment duration without compromising the SVR
`rate.
`Interest has also focused on whether
`treatment
`duration could be individualized in some patients with
`genotype 2 and 3 infection. Here all the findings from re-
`cent studies are translated into practical advice, to help
`practitioners make evidence-based treatment decisions in
`everyday clinical practice. Although there are areas where
`currently available data do not provide conclusive evidence
`to suggest amending treatment approaches, there is clearly
`potential
`for individualized treatment
`in all aspects of
`hepatitis treatment in the future.
`
`Keywords: hepatitis C, pegylated interferon alfa, ribavirin,
`treatment, virological response.
`
`INTRODUCTION
`
`Current treatment algorithms result in rates of sustained
`virological response (SVR) of 80% in patients infected with
`HCV genotypes 2 or 3, suggesting that some of the primary
`challenges in the management of chronic hepatitis C (CHC)
`have now been resolved. However, in patients infected with
`HCV genotype 1, the standard combination treatment of
`
`Abbreviations: ALT, alanine-aminotransferase; cEVR, complete early
`virologic response; CHC, chronic hepatitis C; EOT, end-of-treatment;
`HCV, hepatitis C virus; LVL, low-viral load; pEVR, partial early vir-
`ologic response; RBV, ribavirin; RVR, rapid virological response;
`SVR, sustained virological response.
`
`Correspondence: Prof. Dr med. Stefan Zeuzem, Medizinische Klinik
`I, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang
`Goethe-Universita¨t, Theodor-Stern-Kai 7, D-60590 Frankfurt,
`Germany. E-mail: zeuzem@em.uni-frankfurt.de
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`48 weeks of pegylated interferon alfa (peginterferon) and
`ribavirin (RBV) results in SVR rates of only 40–50% [1,2],
`with higher rates following 48 weeks rather than with
`24 weeks of
`treatment
`(51% vs 41%, respectively)
`[3].
`Emerging data suggest that treatment duration may be
`shortened or lengthened depending on baseline viral load
`and virological response at week 4 and ⁄ or week 12. This
`paper considers these results and their implications for
`treatment optimization and suggests how this latest research
`can be translated into everyday clinical practice.
`
`ISSUES UNDER CONSIDERATION
`
`Principal considerations for treatment of CHC include dose
`and duration of antiviral therapy (along with related costs),
`quantification of baseline HCV RNA levels, the definition of
`response during the early stages and at the end of treatment,
`as well as the duration of the post-treatment follow-up
`(cid:42)(cid:76)(cid:79)(cid:72)(cid:68)(cid:71)(cid:3)(cid:21)(cid:19)(cid:19)(cid:20)
`(cid:44)(cid:16)(cid:48)(cid:36)(cid:46)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:76)(cid:79)(cid:72)(cid:68)(cid:71)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:27)(cid:16)(cid:19)(cid:19)(cid:22)(cid:28)(cid:19)
`
`75
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`76
`
`S. Zeuzem et al.
`
`period. In addition, there remain a number of areas of
`uncertainty that have also to be taken into consideration,
`such as the variation in baseline viral load, monitoring time
`points and the Ôtime windowÕ within which monitoring
`needs to take place.
`
`Current treatment algorithm for treatment of patients with
`HCV
`
`Current treatment recommendations for patients chroni-
`cally infected with HCV are shown in Fig. 1 [4–6]. Briefly,
`patients with genotype 2 or 3 infection are more responsive
`to the current standard of care of peginterferon plus RBV
`than those with genotype 1 or genotype 4 infection. The
`rates of SVR for genotype 2 or 3 infection are similar in
`patients treated for 24 or 48 weeks; thus, for these patients
`24-week treatment is generally considered appropriate. For
`patients infected with HCV genotype 1, the recommended
`treatment duration is 48 weeks of peginterferon with RBV.
`While standard doses for peginterferon alfa-2a (180 lg, qw)
`and peginterferon alfa-2b (1.5 lg ⁄ kg, qw) are well estab-
`lished, different
`recommendations exist
`for RBV dose
`according to HCV genotype and type of peginterferon [7,8].
`It appears that lower doses of RBV are required for treat-
`ment of patients infected with HCV genotype 2 or 3 than
`for genotypes 1 or 4 [9,10]. For the standard duration of
`treatment of HCV genotype 1 and 4 infection, weight-based
`RBV doses of 800–1200 mg, qd, or up to 1400 mg for
`patients above 105 kg, are recommended, while no addi-
`tional benefit of RBV doses higher than 800 mg in HCV
`genotype 2 and 3 infection was observed in several studies
`[3,11]. Available data for patients infected with genotype 5
`or 6 are limited; therefore, combination treatment with
`1000 ⁄ 1200 mg, qd, RBV for 48 weeks is currently rec-
`ommended.
`
`Determination and monitoring of viral load
`
`The decision on whether to continue or stop therapy should
`primarily be based on the level of HCV RNA during treat-
`ment. Therefore, it is necessary to measure viral load accu-
`rately. Important aspects to consider in this respect are the
`natural fluctuations in viral load during infection, as well as
`intra-assay (within an individual
`test) and inter-assay
`(between different
`tests) variability. Currently available
`commercial assays vary considerably in their dynamic ran-
`ges of quantification (Table 1). Despite the introduction of
`international units per mL (IU ⁄ mL) for reporting viral load,
`discrepancies may occur when patients are monitored using
`different types of assay [14–19]. For example, rules for early
`discontinuation at week 12 and 24, as well as rules for
`determination of treatment duration [baseline viral
`load,
`RVR, complete early viral response (cEVR)], were established
`mainly with standard RT-PCR based assays, which have
`since been replaced by real-time PCR-based assays with
`higher sensitivity and broader dynamic range of linear HCV
`RNA quantification. The differences between commercial
`HCV RNA assays have been well documented in several
`studies [15–19], with the majority of studies showing an
`intra-assay variability of approx. 0.2 log. Generally, com-
`parisons between Amplicor Monitor and CAP ⁄ CTM yielded
`comparable results (±0.2 log), whereas comparisons be-
`tween bDNA and Abbott real-time HCV on the one hand and
`CAP ⁄ CTM on the other showed a difference of 0.5–0.7 log.
`Additionally, HCV RNA viral load decline assessed during
`antiviral therapy can give different results, regardless of the
`use of IUs. False-positive and false-negative results, as well as
`variations in the HCV RNA level of up to 2 log10 IU, have
`been observed, which may well have an impact on the
`management of patients, particularly if treatment decisions
`are made using a single HCV RNA assessment [15,16,19].
`
`Fig. 1 Overview of current treatment guidelines (based on references [4–6,12,13]).
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`

`

`Treatment of chronic hepatitis C
`
`77
`
`Table 1 Detection limits and range of linear quantification for HCV RNA tests [20]
`
`Test
`
`Detection limit
`(cut-off) IU ⁄ mL
`
`Dynamic range of linear
`quantification IU ⁄ mL
`
`Lower limit
`
`Upper limit
`
`Qualitative assays
`Versant qualitative assay (Siemens, Eschborn, Germany)
`Cobas Amplicor v2.0 (Roche, Mannheim, Germany)
`Quantitative assays
`Abbott Real Time
`Cobas TaqMan real-time PCR assay (Roche)
`Cobas Amplicor Monitor v2.0 (Roche)
`Versant HCV RNA 3.0 (Bayer)
`
`5–10
`50
`
`10
`10
`600
`615
`
`NA
`NA
`
`12
`43
`600
`615
`
`NA
`NA
`
`100 000 000
`69 000 000
`500 000
`7700 000
`
`Practitioners should be careful not to attach undue clinical
`significance to small changes (<0.5 log10) in serum HCV
`RNA level. The clinical relevance of serial HCV viral level
`measurements in a patient is dependent on continuous use
`of the specific quantitative assay employed in the initial
`determination of the viral level. This may imply repeated
`testing in some cases; but these extra costs may be justified if
`they affect treatment management decisions.
`
`GENOTYPE 1
`
`Week 12 stopping rule for patients with HCV genotype 1
`
`The current week 12 stopping rule recommends that
`patients without a ‡2 log10 drop in viral load compared to
`baseline (between 19% and 29% of patients with genotype 1
`infection) discontinue therapy since the likelihood of
`achieving SVR with continued treatment is small; the neg-
`ative predictive value is almost 100% [21,22]. Over-treat-
`ment of patients who have an extremely low chance of
`achieving SVR is thus avoided and valuable resources can be
`reserved for patients with a higher chance of treatment
`success [23]. Week 12 monitoring should be carried out as
`close as possible to the week 12 time point, ideally ±5 days,
`using a test with high sensitivity and wide dynamic range.
`Whether the 2 log10 drop represents the most accurate cut-
`off level for the decision on treatment termination or pro-
`ceeding remains to be determined in prospective clinical
`studies. It is likely that with greater use of more sensitive
`assays with a broader range of linear quantification (e.g.
`real-time PCR assays),
`this parameter may be
`re-
`fined ⁄ adjusted in the near future. It may also be the case
`that new drugs currently in development will require dif-
`ferent threshold levels and ⁄ or stopping rules based on their
`different modes of action, although this remains to be seen.
`
`Assessment at week 24 in patients with HCV genotype 1
`
`If, at week 12, HCV RNA remains detectable but the viral
`load has dropped by at least 2 log10 (i.e. 100-fold) from
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`baseline, treatment should be continued for the full 48-week
`course. However, if the patient remains HCV RNA positive at
`week 24, it is unlikely that an SVR will be achieved (negative
`predictive value 98–100%),
`[2,21,24], and, unless the
`patient is considered at high risk due to rapidly progressing
`fibrosis, treatment termination at week 24 can be consid-
`ered. Studies are ongoing to determine whether patients may
`derive some benefit
`from treatment with peginterferon
`monotherapy, despite a lack of virological response. These
`include the COPILOT study comparing colchicine with low-
`dose peginterferon alfa-2b [25,26], which showed both high
`rates of premature discontinuation of therapy and that
`maintenance therapy with peginterferon was associated
`with improved disease free survival almost exclusively in
`patients with portal hypertension, and the EPIC3 program
`with peginterferon alfa-2b [27]. Recent results from the
`HALT-C trial [28], which investigated the effect of treating
`non-responders with peginterferon alfa-2a and RBV con-
`cluded overall that long-term therapy with peginterferon did
`not reduce the rate of disease progression and so do not
`support maintenance therapy in patients with HCV and
`advanced hepatic fibrosis who are prior non-responders.
`Interestingly, a significant decline in clinical outcomes was
`observed in patients with chronic HCV and advanced fibrosis
`or cirrhosis who achieved a profound decline in HCV RNA,
`defined as >4 log and ⁄ or undetectable with subsequent
`breakthrough or relapse, suggesting that a small subgroup of
`patients may benefit [29]. Unless results of the ongoing
`studies provide additional guidance, continued treatment of
`patients cannot be recommended.
`
`Recommendations for optimizing treatment in patients
`with HCV genotype 1
`
`Shorter treatment for patients with a rapid virological response
`The current 48-week treatment duration, recommended for
`HCV genotype 1-infected patients, may potentially result in
`the over-treatment of some genotype 1-infected patients who
`are more likely to achieve SVR, i.e. patients with low viral
`load before treatment and rapid virological response (RVR)
`
`

`

`78
`
`S. Zeuzem et al.
`
`at week 4. Clearly it is desirable to expose patients to the
`shortest possible treatment duration – without compromis-
`ing efficacy – in order to minimize the likelihood of adverse
`events and reduce costs. Hadziyannis et al. found that more
`than one third of individuals with HCV genotype 1 who were
`randomized to 24 weeks of therapy with pegylated IFNa-2a
`plus RBV achieved SVR [3]. Moreover, patients infected with
`HCV genotype 1 who became HCV RNA-negative by week 4,
`i.e. patients with RVR, were more likely to achieve SVR than
`those who did not become HCV RNA negative until week 12
`[22]. A recent prospective trial demonstrated that patients
`with low baseline HCV RNA levels (£600 000 IU ⁄ mL) and
`an RVR achieve an SVR rate of up to 90% (Fig. 2) [30].
`Jensen et al. observed that almost a quarter (22.6%) of HCV
`genotype 1 patients treated with peginterferon plus RBV
`achieved RVR [31]. Of these patients, 89% showed SVR after
`treatment duration of only 24 weeks. Both pegylated inter-
`ferons have recently been approved in the EU for shortened
`treatment duration of 24 weeks for HCV genotype 1 patients
`(defined as <800 000 IU ⁄ mL
`with low-viral
`load (LVL)
`for peginterferon alfa-2a and <600 000 IU ⁄ mL for pegin-
`terferon alfa-2b) and RVR [7,8]. To assure accurate deter-
`mination of baseline viral
`load in cases with HCV RNA
`concentrations between 400 000 and 1 million IU ⁄ mL,
`physicians should consider performing two measurements
`using the same technique,
`from samples taken at least
`4 weeks apart. Whether 10 or 50 IU is the most appropriate
`cut-off for determining RVR remains unclear, however, and is
`under investigation. Recently, Sarrazin et al. compared clin-
`ical outcomes for large cohorts of patients whose serum
`samples were analysed using both the COBAS TaqManTM
`(detection limit approximately 10 IU ⁄ mL) and COBAS Am-
`plicorTM (detection limit <50 IU ⁄ mL) assays. In this study,
`RVR rates and subsequent SVR rates were similar when RVR
`
`was defined as undetectable of below 15 IU ⁄ mL by the CO-
`BAS TaqMan assay in comparison with undetectable
`(<50 IU ⁄ mL) by the COBAS Amplicor assay, implying that
`HCV RNA levels rapidly decline not only to below 50 IU ⁄ mL
`but also below 15 IU ⁄ mL in patients achieving an RVR [15].
`Interestingly, relapse rates were consistently lower in pa-
`tients with undetectable HCV RNA at week 4 by COBAS
`TaqManä compared with COBAS Amplicorä, although the
`full significance of this remains to be established [15].
`Patients should not be considered for shorter treatment
`duration if they have a baseline viral
`load above 600–
`800 000 IU ⁄ mL and ⁄ or have cirrhosis, are co-infected with
`HIV, or are immunosuppressed. Other factors influencing
`virological response that may also be considered include
`metabolic syndrome, insulin resistance and extensive stea-
`tosis. Zeuzem et al. demonstrated that the efficacy of pegin-
`terferon alfa-2a plus RBV is comparable between patients
`with genotype 1 infection and persistently normal alanine-
`aminotransferase (ALT) and those with elevated ALT levels
`[32]. However, SVR rates were significantly lower in those
`patients with persistently normal ALT treated for 24 weeks
`compared with 48 weeks (13% vs 40%, respectively), which
`also suggests that such patients may not be suitable candi-
`dates for shorter therapy. As this study of patients with
`persistently normal ALT did not include evaluation of RVR,
`it was not possible to identify a potential patient subgroup
`within this population (e.g. low viral load and ⁄ or RVR) who
`might benefit from shorter treatment.
`
`DETERMINING PRE-TREATMENT VIRAL LOADS
`AND DEFINING LOW VS HIGH-VIRAL LOADS
`
`The definition and differentiation between low and high viral
`loads is still under discussion. Historically, pre-treatment
`
`Fig. 2 Rapid virological response predicts
`sustained virological response in HCV-1
`infected patients with low baseline viral
`load (£ 600 000 IU ⁄ mL).
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`

`

`viral load was classified as ÔhighÕ or ÔlowÕ using a cut-off of
`2 · 106 copies ⁄ mL, based on data generated using con-
`ventional interferon-based regimens or pegylated interferon
`monotherapy [33,34]. When HCV RNA assays were stan-
`dardized, conversion of copies ⁄ mL to IU ⁄ mL according to the
`WHO standard gave varying results depending on the assay
`used; 800 000 IU ⁄ mL has been recommended as the deci-
`sion threshold for high versus low viraemia [35]. However,
`recent data suggest that a baseline level of 400 000 IU ⁄ mL
`is the most effective cut-off for a high or low probability to
`achieve SVR in genotype 1-infected patients [36,37]. This
`level was confirmed in a large Ôreal-lifeÕ experience study [38]
`and in a further study by Martinot-Peignoux and colleagues,
`with the caveat that it should be applied to treatment-naı¨ve
`patients only [39]. In a recent study, pre-treatment HCV-
`RNA levels of 250 000 IU ⁄ mL best discriminated between
`genotype 1-infected patients with or without SVR after
`24 weeks of therapy in patients with low pre-treatment viral
`load [37]. Whether a single cut-off level for pre-treatment
`viraemia is sufficient or whether several ranges of pre-
`treatment HCV RNA levels might allow for individualized
`treatment duration remains to be elucidated. Furthermore,
`cut-offs for low or high baseline HCV RNA concentration
`were established mainly on the basis of standard RT-PCR
`and bDNA assays and re-definition by the currently used
`real-time PCR-based assays is required. According to current
`data, treatment duration of 24 weeks in genotype-1 infected
`patients should be strongly considered for patients who
`achieve RVR and have a baseline viral
`load below
`800 000 IU ⁄ mL.
`
`DETERMINING RVR AT WEEK 4
`
`Patients who are considered for shortened treatment dura-
`tion must be tested at week 4 for RVR (i.e. no HCV RNA
`detectable) using a highly sensitive method (limit of detec-
`tion £50 IU ⁄ mL) [15]. The week 4 value should be mea-
`sured as close as possible to day 28 of therapy, i.e. between
`the fourth and fifth injection of peginterferon. Patients
`without assessment of RVR should not be considered as
`candidates for shortened therapy duration.
`Monitoring is an important feature in the management of
`CHC; not only to document treatment success, but also as an
`indicator of compliance and adherence. Patients with RVR at
`week 4 should be tested again at week 12 (±5 days).
`The probability that the PCR test is negative at week 4 but
`positive at week 12 is low; only 1 of 22 patients who
`experienced virological breakthrough prior to week 24 had
`an RVR [40].
`
`Optimizing response by reducing relapse rates in patients
`with HCV genotype 1
`
`A patient with virological relapse is one who achieved an
`end-of-treatment (EOT) response but who failed to achieve
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`Treatment of chronic hepatitis C
`
`79
`
`an SVR. Relapse has been reported to occur at similar rates
`for patients treated with peginterferon alfa-2a and -2b (18%
`and 19%, respectively) who were treated for 48 weeks
`according to the standard treatment algorithm [1,2]. The
`IDEAL study, which investigates response to peginterferon
`alfa-2a and two different doses of peginterferon alfa-2b with
`RBV in patients with genotype 1 CHC, is also addressing this
`issue [41]. Intensification of treatment is a possible approach
`to reduce the incidence of relapse. IDEAL is accepted as late-
`breaker at EASL 2008.
`
`INCREASED DOSE OF RIBAVIRIN
`
`Recent studies suggest that high-dose RBV in combination
`with pegylated interferon can improve response in genotype
`1-infected patients. Lindahl et al. used an individualized
`dosing regimen based largely on renal
`function,
`in an
`attempt to achieve >15 lmol ⁄ L steady-state RBV concen-
`tration in 10 treatment-naı¨ve patients [42]. After initial dose
`adjustments, the mean dose of RBV was 2540 mg, qd (range
`1600–3600 mg, qd) and the mean RBV concentration
`achieved was 14.7 lM (range 7.8–22.0 lm) at weeks
`24–48. Nine of 10 patients achieved SVR following treat-
`ment of up to 48 weeks duration, but with more frequent
`and severe side effects, in particular anaemia. All patients
`required erythropoietin at some time during treatment.
`A recent study by Fried et al. demonstrated an improve-
`ment in SVR in genotype 1-infected patients with body
`weight >85 kg treated with a higher dose of RBV, especially
`in conjunction with a higher dose of peginterferon [43].
`Patients treated with 270 lg peginterferon alfa-2a and
`1600 mg, qd, RBV showed an SVR of 47% compared with
`28% in patients treated with the standard dosing regimen.
`This improvement was driven mainly by a marked reduction
`in relapse in the high-dose group compared with the
`standard-dose group (19% vs 40%, respectively). However,
`the use of a higher dose regimen was associated with an
`increased rate of haematological adverse events. More
`recently, in a prospective, open-label, randomized, controlled
`pilot study comparing 48 weeks of treatment with pegin-
`terferon plus standard weight-based RBV with or without
`erythropoietin (groups 1 and 2), and peginterferon plus
`higher weight-based RBV plus erythropoietin (group 3), SVR
`was significantly greater (P < 0.05) in group 3 patients
`(49%) due to a significant decline in relapse rate [44].
`Overall, the results of these studies provide encouraging data
`regarding the possibility of optimizing treatment regimens
`for patients with more difficult to treat disease.
`
`EXTENDING TREATMENT DURATION FOR SLOW
`VIROLOGICAL RESPONDERS
`
`Evidence from three randomized clinical trials support the
`case for extending treatment duration beyond 48 weeks in
`HCV genotype 1 patients with a slow virological response,
`
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`

`80
`
`S. Zeuzem et al.
`
`i.e. HCV RNA > 50 IU ⁄ mL at week 12 but undetectable
`(<50 IU ⁄ mL) at week 24 [45–47]. Berg et al. randomized
`patients to 48 or 72 weeks of treatment with peginterferon
`alfa-2a (180 lg, qw) plus RBV (800 mg, qd) and analysed
`the resulting SVR and relapse rates [45]. Extended treatment
`of 72 weeks did not increase the SVR rate in the intent-
`to-treat population; which suggests that it is inappropriate to
`extend treatment for all genotype 1-infected patients. How-
`ever, the study demonstrated that identifying patients with
`and without virological response at week 12 using a sensi-
`tive molecular test (50 IU ⁄ mL) could facilitate the decision
`on therapy duration for each patient on an individual basis.
`Patients who remained HCV RNA positive at week 12 had
`significantly higher SVR rates when treated for 72 rather
`than 48 weeks (29% vs 17%; P = 0.04). The greatest benefit
`from extended treatment duration (72 weeks) was observed
`in patients with detectable HCV RNA, but with levels below
`6000 IU ⁄ mL, at week 12. The frequency and intensity of
`adverse events was similar in the 48- and 72-week treat-
`ment groups, suggesting that extended treatment can be
`manageable in terms of tolerability. Sanchez-Tapias et al.
`randomized
`patients
`without
`RVR
`(i.e.,
`HCV
`RNA > 50 IU ⁄ mL at week 4) to treatment with pegylated
`interferon alfa-2a (180 lg, qw) and RBV (800 mg, qd) for
`48 or 72 weeks [46]. Extending treatment to 72 weeks
`significantly increased the SVR rate compared with the
`standard 48 weeks of therapy (45% vs 32%, respectively;
`P = 0.01). In genotype 1-infected patients, this effect was
`particularly evident, with 44% of patients who received
`72 weeks of treatment achieving SVR compared with 28%
`of patients who were treated for 48 weeks (P = 0.003).
`The incidence of adverse events was similar between the
`two groups, although treatment discontinuation was
`significantly more frequent in the 72-week group (36% vs
`18%; P = 0.0004). A retrospective analysis of patients from
`the European-based trials,
`including that of Berg et al.,
`demonstrated that patients without RVR but achieving
`subsequent early viral response (EVR) (>2 log10 HCV RNA
`decrease), benefited from extending treatment duration and
`achieved a higher SVR rate (77% after 72 weeks vs 31%
`after 48 weeks [48].
`Pearlman et al. examined the effect of longer treatment
`duration with pegylated interferon alfa-2b plus weight-
`based RBV in patients infected with HCV genotype 1 who
`met EVR criteria at week 12 (>2 log10 drop in baseline
`HCV RNA), but who had detectable HCV RNA at week 12
`and became HCV RNA-negative at week 24 [47]. This
`group of ÔslowÕ viral responders was then treated for either
`48 or 72 weeks. Results showed a 39% SVR in the
`72-week arm compared with 18% SVR in the 48-week
`arm; treatment extension did not seem to result in an in-
`crease in dose reductions of RBV or discontinuations. Taken
`together, the available data suggest that longer duration of
`in ÔslowÕ
`therapy improves
`sustained response
`rates
`virological responders.
`
`Proportion of HCV genotype 1-infected patients who could
`be considered for shortened or extended therapy duration
`
`An extended treatment duration of 72 weeks can be con-
`sidered in ÔslowÕ virological responders, defined as patients
`who are HCV RNA positive at week 12 but become unde-
`tectable at week 24. These patients comprise approximately
`20% of the HCV genotype 1-infected population, a not
`insubstantial proportion [45]. Similarly, around 15% of all
`HCV genotype-1 infected patients could benefit
`from a
`shorter treatment duration without compromising the SVR
`rate; again constituting a clinically relevant proportion of
`patients [30]. A summary of
`the recommendations for
`optimizing treatment in patients with HCV genotype 1 is
`given in Fig. 3.
`
`GENOTYPES 2 AND 3
`
`Interest has also focused on whether treatment duration
`could be individualized in some patients with genotype 2 and
`3 infection; i.e. shortened due to the overall high rate of SVR
`(80%) achieved with the standard 24 weeks of treatment,
`or prolonged in slow responders.
`
`Recommendations for optimizing treatment in patients
`with HCV genotypes 2 and 3
`
`Shorter treatment for patients with a rapid virological response
`A number of studies have investigated whether it might be
`possible to reduce treatment duration in some patients
`with chronic HCV genotypes 2 or 3 infection based on
`RVR. Several small studies have demonstrated comparable
`SVR rates after 16 weeks and 24 weeks treatment
`in
`patients with either genotype 2 (Table 2) or 3 (Table 3)
`infection who achieve an RVR [49–52]. However, in the
`large-scale randomized, multinational ACCELERATE study,
`in which a lower dose of RBV was used, overall SVR rates
`were lower following 16 weeks of peginterferon plus RBV
`compared with 24 weeks treatment in genotype 2 and 3
`patients, although this difference only reached significance
`in genotype 2 patients [9]. Among the patients with an
`RVR, SVR rates were significantly higher in the 24-week
`group than in the 16-week group, both overall (85% vs
`79%, P < 0.001) and within each genotype group,
`although patients who achieved an RVR were more likely
`to achieve an SVR overall
`[9]. Overall,
`the significant
`difference seen in SVR rates was found to reflect a sig-
`nificantly higher relapse rate in the 16-week group (31%)
`compared with the 24-week group (18%; P < 0.001);
`shorter treatment duration was associated with a signifi-
`cantly higher risk of relapse in both genotype 2 and 3
`patients [9].
`There is some evidence to suggest that genotype 2 and 3
`may respond differently to treatment; overall SVR rates tend
`to be somewhat lower for genotype 3 patients who do not
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`

`

`(a)
`
`Treatment of chronic hepatitis C
`
`81
`
`(b)
`
`Genotype 1
`
`Determine viral load prior
`to treatment
`
`Tw o samples,
`4 we eks apar t
`
`Test for RVR at week 4
`
`Consider treating
`patients with RVR
`and LVL at baseline
`for 24 weeks
`
`Monitor
`
`Test for ETR at
`week 24
`
`Test for SVR at
`week 48
`
`Plan to treat patients
`without RVR for 48 weeks
`
`Test for EVR at week 12
`
`If HCV RNA
`undetectable,
`continue treatment
`to 48 week s
`
`Monitor
`
`If >2 log 10 re duction
`in HCV RNA,
`consider treating for
`72 week s
`
`If <2 log 10
`reduction,
`stop
`treatment
`
`If HCV RNA
`undetectable at
`week 24 consider
`treating for 72 week s
`
`If HCV RNA
`detectable at week
`24, stop
`treatment
`
`Test for ETR at
`week 48
`
`Monitor
`
`Test for SVR at
`week 72
`
`Test for ETR at
`week 72
`
`Test for SVR at
`week 96
`
`Fig. 3 (a) Proposed treatment algorithm for patients with HCV genotype 1 based on response at weeks 4 (RVR), 12 (EVR) and
`24. (b) Guidance for treatment and monitoring of response to peginterferon ⁄ RBV combination therapy in patients infected
`with HCV genotype 1. EVR, early viral response; RVR, rapid viral response; SVR, sustained viral response; PCR, polymerase
`chain reaction; ETR, end-of-treatment response.
`
`achieve an RVR compared with genotype 2 patients who do
`not achieve RVR, and also after shorter treatment duration
`in patients who do achieve RVR [9,50,51,53,54]. Whether
`genotype 3-infected individuals should not
`therefore be
`considered for shorter duration therapy requires further
`investigation.
`Baseline HCV RNA levels also influence SVR rates and
`patients with low pre-treatment serum HCV RNA levels and
`RVR have been reported to respond equally well to both 16
`and 24 weeks of therapy (SVR rates of 82–100% and 81–
`100%, respectively) [9,49,50,53]. It is possible, therefore,
`
`that these patients may be considered for shorter treatment
`duration.
`Genotype 2 and 3 infected patients with severe fibrosis are
`less likely to achieve either RVR or SVR, and to relapse more
`frequently following 12–14 weeks of antiviral
`therapy
`[9,49,51,53]. Andriulli et al. found that patients with low
`pre-treatment ALT levels were also found to relapse more
`frequently following shorter treatment duration (14% after
`12–14 weeks vs 2% after 24 weeks; P = 0.04) [51]. These
`findings suggest that patients with severe fibrosis or normal
`pre-treatment ALT levels are most likely unsuitable candi-
`
`Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Publishing Ltd
`
`

`

`82
`
`S. Zeuzem et al.
`
`Table 2 Overview of short-term treatment versus standard (24-week) treatment in patients (pts) with HCV genotype 2
`infection
`
`Duration
`(weeks)
`
`14*
`12*
`16
`16
`16
`14*
`
`Ref
`
`54
`à
`50
`51
`à
`53
`à
`9
`55
`
`Ribavirin
`dose
`(mg ⁄ day)
`
`800–1400
`1000–1200
`800–1200
`800–1400
`800
`800–1400
`
`SVR in pts
`with RVR
`following
`shorter
`duration
`therapy (%)
`
`91
`87
`95
`100
`78
`93
`
`SVR in pts
`with RVR
`following
`standard
`duration
`therapy (%)
`N ⁄ A
`89
`95
`98
`85
`97
`
`SVR in RVR-pts with
`low vs high
`baseline viraemia
`following shorter
`duration therapy
`
` 
`92% vs 88%*
`N ⁄ A
`100% vs 93%*§
`No data
`No data
`100% vs 90%**
`
`Relapse rate
`following shorter
`vs standard
`duration in RVR-pts
`10% vs N ⁄ A
`9% vs N ⁄ A
`N ⁄ A
`0% vs 2%
`No data
`7% vs 3%
`
`*Included only patients with RVR.
`à
`Patients randomized before treatment.
`HCV RNA £ 600 000 IU ⁄ mL vs >600 000 IU ⁄ mL.
` 
`§HCV RNA £ 800 000 IU ⁄ mL vs >800 000 IU ⁄ mL.
`**HCV RNA £ 400 000 IU ⁄ mL vs > 400 000 IU ⁄ mL.
`
`Table 3 Overview of short-term treatment versus standard (24-week) treatment in patients (pts) with HCV genotype 3
`infection
`
`Ref
`
`54
`5