NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 9 | NOVEMBER 2012 | 619

NEWS & VIEWSHEPATITIS

HCV virologic response—new nomenclature recommendationsStanislas Pol

As new therapeutics are emerging for the treatment of patients with HCV, the nomenclature for defining virologic response is becoming outdated, leading to inconsistencies and confusion. A recent paper has attempted to devise a new nomenclature that will be able to respond to future advances in HCV therapy.Pol, S. Nat. Rev. Gastroenterol. Hepatol. 9, 619–620 (2012); published online 28 August 2012; doi:10.1038/nrgastro.2012.164

Antiviral therapy can be considered in any patient with HCV.1 The patients who are typ-ically treated tend to be those who present during the acute phase and patients with chronic infection experiencing the major effects of disease progression—chronic hepatitis with necroinflammation and/or stage 2 fibrosis or extrahepatic disease (such as cryoglobulinaemic vasculitis or chronic fatigue). The current treatment for HCV is based on the historical use of standard interferon (from 1988 to 1995); the addition of riba virin, a nucleoside analogue with a twice daily oral intake (given as combination therapy from 1996 to 1998); and the intro-duction of PEG-IFN as a weekly subcutane-ous injection (again given in combination with ribavirin from 1998 to 2011).2 Referred to as ‘standard of care’, PEG-IFN and riba-virin combination therapy can result in a mean sustained virologic response (SVR) of 60%, corresponding to viral eradication, inactivation of necro inflammation and the remodelling of fibrosis (including reversal of early cirrhosis).3

An improved understanding of the viral lifecycle and the characterization of viral enzymes, which are potential drug targets, has facilitated the recent and rapid develop-ment of several new molecules in the past 5 years—the direct-acting antiviral agents. They specifically target HCV (NS3 or NS4A protease inhibitors, NS5B polymerase inhibitors, NS5A inhibitors and entry inhib-itors). In addition, non-HCV-specific anti-virals are also being developed (such as, new interferons, cyclophilin inhibitors, internal ribo somal entry site inhibitors, interfering mRNAs and therapeutic vaccines).

The first-generation protease inhibi-tors, approved in early-to-mid 2011

(depending on the regulatory agencies), are a thera peutic revolution. Using these new agents, the rate of SVR, especially in difficult-to-treat patients, is considerably increased. Telaprevir and boceprevir have demonstrated a 20–30% increase in SVR in patients infected with HCV genotype 1 (65–75% SVR for treatment-naive patients, 75–85% in previous relapsers, 55% in pre-vious partial responders and 30–40% in previous null responders).4–7 We are now entering a new field of antiviral therapies with interferon-including regimens, but also interferon-free regimens.8,9 Strikingly, the combinations of different oral antivirals for 12–24 weeks seems to be able to achieve SVR in most patients with HCV, including previous null responders,8 with an improved safety and tolerance.

The next hurdle will be to achieve effi-cient viral clearance in the most difficult-to-treat patients; namely, patients with advanced liver disease (for example, Child–Pugh class B or C cirrhosis) who have already undergone treatment, candidates

for liver transplantation, recipients of a liver or kidney transplant, patients who have previously had hepato cellular carci-noma and those undergoing dialysis or with haemoglobin diseases.

Given the diversity of treatment options that are expected in the coming years, physi cians will need help in their daily practice to identify appropriate therapies for their patients, monitor treatment efficacy and manage adverse events. Regular viro-logic monitoring is an important strategy to improve treatment potency and reduce the accumulation of resistance-associated variants that can be used in combination with ‘stopping rules’ (treatment is stopped in patients not responding to therapy). For this reason, I argue that a homogenous nomenclature for categorizing virologic response in clinical trials, as well as in the real-life setting, is needed. The current nomen clature to assess virologic response was devised when PEG-IFN was the stand-ard therapy. As new therapies have emerged, it has become clear that the current nomen-clature is insufficient to assess virologic response, with variations existing in the way terms are applied, which makes comparing different regimens difficult. To this end, a multipartner HCV drug development advi-sory group (including international experts representative of regulatory agencies, aca-demia, patient advocates and pharmaceu-tical companies) propose an intuitive and flexible nomenclature for defining viro-logic response.10 The findings of this paper will help to facilitate future adaptations of virologic response terms to account for the different thera peutic schedules and time points for virologic assessment or thresh-olds (for example, lower limit of detection

Box 1 | New nomenclature

■ RVR could be defined as W4UTND for no lead-in and LI4W–WUTND with a lead-in

■ Extended RVR could be defined as W4–12UTND

■ Very RVR could be defined as W2UTND

■ Complete early virologic response could be defined as W12UTND

■ End of treatment response could be defined as ETRTND

■ SVR12 could be defined as SVR12TND

■ SVR24 could be defined as SVR24TND

Abbreviations: ETR, end of treatment; LI, lead-in; RVR, rapid virologic response; SVR, sustained virologic response; TND, target not detected; U, unquantifiable; W, week.

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[LLOD] and lower limit of quantification [LLOQ]), according to the specifications of the assay used. Previously, such adapta-tions resulted in inconsistencies and con-fusion. The detection and quantification limits of virologic assays are different and the limits are changing as improvements are made, which does not simplify the decision- making process.

Standardization and clarification of nomenclature is needed. To achieve uni-formity, the panel recommends using the LLOQ as a reference value (rather than the LLOD that do not fall in the linear range of the assay). For values below the LLOQ, the HCV RNA target can be classified as being detected (TD) or not detected (TND). Viraemia should be unquantifi-able (U; W#UTND/TD) or quantifiable (Q; W#Q), where W# stands for weeks of treat-ment duration. W can be replaced by days of treatment duration (D), which is par-ticularly useful for the new oral antiviral combinations. For measuring quantifiable HCV RNA, the log10 decrease from base-line should be included and represented by W#Q [log10 decrease from baseline] (for example, W4Q [1.5] represents a 1.5 log10 decrease from baseline at week 4). A lead-in (LI) phase with PEG-IFN and ribavirin and its duration might be indicated in patients with unquanti fiable (LIW/D–W#UTD/TND) or quantifiable viraemia (LIW/D–W#Q [log10 decrease from baseline]). A learning curve will be necessary, and to familiarize physi-cians with the proposed nomenclature, the panel suggests that both the ‘old’ and new nomenclatures should be used simultane-ously, the rapid virologic response (RVR) being W4UTND and the extended RVR being W4–12UTND (Box 1).

Standardization of nomenclature for viro-logic response is critical for communication of clinical practice and the eventual estab-lishment of guidelines. Using the proposed nomenclature, it will also be possible to establish recommendations for stopping (or futility) rules, adding or switching rules and choosing treatment durations according to the early viral kinetics. These recommenda-tions would enable optimization of the SVR, decreased incidence of both viral resistance and adverse events, and reductions of the high cost of both treatment and manage-ment of adverse events. Indeed, in the near future, oral combination therapies will help us achieve >85% SVR in most patients. As such, the main limitations of combination therapy will be safety, costs, compliance, viral resistance and drug–drug interactions.

Université Paris Descartes, Institut Cochin Inserm Unit 1016, APHP, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. stanislas.pol@cch.aphp.fr

AcknowledgementsThe author would like to thank Dr Matthew Albert for his help in the discussion of the manuscript.

Competing interestsThe author declares associations with the following companies: BMS, Boehringer Ingelheim, Gilead, Janssen–Tibotec, Roche, Sanofi, MSD, Novartis and Vertex. See the article online for full details of the relationships.

1. European Association of the Study of the Liver. 2011 European Association of the Study of the Liver hepatitis C virus clinical practice guidelines. Liver Int. 32 (Suppl. 1), 2–8 (2012).

2. McHutchison, J. G. et al. Peginterferon α-2b or α-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580–593 (2009).

3. Mallet, V. et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann. Int. Med. 149, 399–403 (2008).

4. McHutchison, J. G. et al. Telaprevir for previously treated chronic HCV infection. N. Engl. J. Med. 362, 1292–1303 (2010).

5. Zeuzem, S. et al. Telaprevir for retreatment of HCV infection. N. Engl. J. Med. 364, 2417–2428 (2011).

6. Bacon, B. R. et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N. Engl. J. Med. 364, 1207–1217 (2011).

7. Jacobson, I. M. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364, 2405–2416 (2011).

8. Lok, A. S. et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N. Engl. J. Med. 366, 216–224 (2012).

9. Gane, E. J. et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376, 1467–1475 (2010).

10. Wedemeyer, H. et al. Recommendations for standardized nomenclature and definitions of viral response in trials of HCV investigational agents. Hepatology http://dx.doi.org/ 10.1002/hep.25888.

IBD

Is measuring bone age in children with Crohn’s disease useful?Thomas D. Walters

Impaired growth is common in children and adolescents with Crohn’s disease, but it can be difficult to interpret growth status accurately. Bone age is a useful measure of skeletal maturity, but should serial bone-age estimation be part of the routine care of children with Crohn’s disease?Walters, T. D. Nat. Rev. Gastroenterol. Hepatol. 9, 620–622 (2012); published online 25 September 2012; doi:10.1038/nrgastro.2012.181

Linear growth is commonly impaired in children and adolescents with Crohn’s disease. As such, the restitution and main-tenance of normal growth is frequently used as a marker of therapeutic success. The two variables most frequently used to monitor and assess linear growth are stature (attained height) and rate of growth (height velocity). However, determining whether either of these ostensibly simple meas-ures is ‘abnormal’ is not always straight-forward. A study by Gupta and colleagues1 has attempted to address the issue of monitoring growth.

Even in health, absolute linear growth velocity (measured in cm per year) varies with age and gender. To take this normal variation into account, large-scale popula-tion data have been amassed and a variety of reference standards for growth and develop ment are available. Using these

normative values, an individual child’s growth measure ments can be numerically represented as either a ‘centile’ or as an SD or ‘z-score’. In general, healthy children grow steadily along the same height centile and hence maintain the same z-score for height from early childhood through until adulthood (with some minimal deviation around puberty). If an individual child or adolescent deviates from their particular growth curve it is considered evidence of ‘abnormal’ growth. Gupta and colleagues1 argue that, as well as stature and height velocity, radiological determination of bone age should be included in the routine assess-ment of growth for children and adolescents with Crohn’s disease. The group contends that failure to consider skeletal maturation might lead to the inaccurate interpretation of a patient’s growth status, and potentially result in suboptimal disease management.

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