Lost in translation?<i>IL28B</i>'s discovery and the journey back to the patient
Authors: Paul J. Clark, Andrew J. Muir
Journal: Hepatology (2012)

See Reviews on Pages 361, 367 and 373 "There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know.'' United States Secretary of Defense Donald Rumsfeld "Medicine is a science of uncertainty and an art of probability." William Osler The discovery that variation near the IL28B gene is strongly associated with treatment response to peginterferon and ribavirin (PEG/RBV) for chronic hepatitis C virus (HCV) infection was significant in many respects.1-4 These studies were predicated on the hypothesis that a genetic factor may explain differences in sustained viral response (SVR), more specifically in the North American setting from the observation that African American patients had markedly lower SVR rates.5, 6 These robust and well-validated findings were delivered via genome-wide association studies (GWAS) using high-coverage GWAS chips and assessing well-characterized patient cohorts. At first pass, this information suggested a means to improve prediction of response to poorly tolerated PEG/RBV regimens. Perhaps more broadly, it restored early faith that pharmacogenomics may resolve clinical uncertainties and deliver the promise of more personalized medicine. This faith had been rattled after an early history of idiosyncratic cohort-specific associations using candidate gene testing technology. DAA, direct-acting antiviral; GWAS, genome-wide association studies; HCV, hepatitis C virus; IFN, interferon; ISG, interferon stimulated gene; PEG, peginterferon; RAV, resistance-associated variant; RBV, ribavirin; RCT, randomized control trial; SVR, sustained viral response. Now, over 2 years on from the IL28B discovery, have these hopes been realized? What more do we know of the biology underlying this genetic association? Has information regarding IL28B transformed into knowledge that influences clinical understanding? Are there data to support clinical decision making? And importantly, is IL28B clinically relevant, as direct-acting antiviral (DAA)-inclusive regimens offer increasingly efficacious treatment for all patients? These issues are considered in a series of minireviews in this edition of HEPATOLOGY.7-9 The initial GWAS discoveries established association but not causation, which is very infrequently determined in GWAS. In fact, despite the widespread adoption of IL28B into the nomenclature, the IL28B gene remains only guilty by association, implicated by its proximity to the discovery variants and biological plausibility as a type III interferon (type III IFN, or IFN lambda I-III, including IL28A/B and IL29), rather than established functional linkage to a genetic variant.10-12 Urban and Goldstein consider the state of the basic science of IL28B, charting the genetic and biological progress, and the continuing substantial gaps in what we know. Perhaps the first of these basic gaps is the identification of the causal variant(s), or the genetic sequence(s), in which variation in code results either directly or indirectly in altered protein structure and/or function to explain the phenotype. The most promising putative functional variant to be studied to date has been rs8103142 (Lys70Arg missense variant); however, after exposure to a variant-determined recombinant IFN lambda, no difference in viral replication or gene expression was noted in a Huh 7.5 hepatocyte cell culture hosting a replicon model.1, 10 Residual genetic associations with SVR remain after adjustment for IL28B, suggesting other loci may provide additional genetic contribution to variability in treatment response, and these remain to be determined. IL28B's association has generated further interest in the biology of type III IFN and its potential as a therapeutic agent. Exploring associations with gene expression of type III IFNs and interferon stimulated genes (ISGs) has provided variable results dependent on the tissue studied (whether whole blood, peripheral blood mononuclear cells, or liver tissue).1, 2 More consistent association has been observed between increased intrahepatic ISG induction and the poor response IL28B genotype, although again causation is not established, and ISG upregulation may indeed be independent of IL28B genotype.13-15 Recent data using models of infection in both primary human hepatocytes and chimpanzees support an important role for type III IFN in response to HCV.13 Although exogenous type III IFN is tolerable and has antiviral efficacy as a treatment,14 a significant functional role for type III IFN may be indirect, either through altering innate responses (e.g., type I INF) or through the adaptive immune system. The adaptive immune system plays an important role in HCV infection and clearance, although clearance is not dependent on T-cell–specific responses and anti-HCV antibody.18-21 Cytokines are a functional bridge between these systems, and cytokines such as CXCL-10 (or IP-10) may potentially act as more direct serum biomarkers of host-viral interaction and SVR prediction.22-24 IL28B genotype-based differences are apparent in natural killer cell activation, another important functional bridge between adaptive and innate immune system response in HCV infection and clearance.16, 22, 23 Defining the complex interaction of host genotype, adaptive and innate immune systems, and effects on and from HCV itself mandates a systems biology approach. For many clinicians, the most pressing questions relate to the use of IL28B to better direct treatment decisions for patients. Integrating host IL28B with clinical factors and on-treatment viral responses is a key theme of the review by Lai and Afdhal, focusing on treatment with PEG/RBV in the absence of DAA. These clinical questions are especially relevant in those parts of the world where DAAs are not yet available or where costs may be prohibitive. They review the retrospective data available on treatment response to PEG/RBV, which demonstrate IL28B as the key pretreatment predictor of response, potentially enhanced by additional biomarkers such as IP-10. Ultimately, IL28B improves viral kinetics, and thus not surprisingly, actual on-treatment viral responses provide the clinical trump card of response prediction for PEG/RBV regimens.24, 25 The authors identify the lack of prospective, randomized, control trial (RCT) data as a major barrier to establishing IL28B's clinical utility as a decision tool for PEG/RBV. The likelihood of large-scale RCTs prospectively assessing IL28B genotype-based PEG/RBV treatment algorithms is negligible. Evidence-based medicine requires managing one's best with the available evidence rather than necessarily managing with the best evidence (e.g., RCT data). In its absence, we seek to improve patient care by working with what we know (our "known knowns") to surmise as best we can, that which we do not know (the "known unknowns"). With this in mind, based on retrospective data, the authors suggest some practical treatment algorithms, integrating IL28B with other clinical predictors to manage the clinical uncertainty of PEG/RBV treatment. One common element is that for patients with the poor-response IL28B allele who do not achieve on-treatment milestones, thresholds for futility should be set conservatively, given that the poor odds of SVR with PEG/RBV may be significantly improved with more efficacious DAA alternatives. Although the details of these algorithms are likely to stimulate debate, they reflect a deeper reality of pharmacogenomics: knowing more does not necessarily make decisions simpler. Such algorithms reflect the complexity of trying to personalize medicine. Despite some hopes to the contrary, IL28B's significant association values have not smoothly translated into a sufficiently sensitive specific test with high positive predictive value, which when used in isolation reliably predicts outcomes for an individual patient. Such hopes were perhaps unrealistic. In this respect, IL28B is not dissimilar to other factors in the clinical assessment of an individual patient—neither a high HCV viral load or significant hepatic fibrosis preclude the chance of SVR. To paraphrase Osler, IL28B may aid in the "science of uncertainty," but for any individual we are still left with the "art of probability.". To improve the latter requires simultaneous consideration of multiple pretreatment and on-treatment factors for an individual. In this setting we need to develop bioinformatics at the bedside, with computer-based multivariable algorithms generating probabilities and confidence intervals, not just to make better decisions but to make it easier to make better decisions. This complexity is set to grow as treatments expand with nonstandardized on-treatment milestones, differing durations, and regimens of different DAAs, with eventually differing regimens of combination DAAs, including IFN-free regimens.26 Thompson and McHutchison consider the potential roles of IL28B in the era of DAA-inclusive treatment regimens for HCV. They recognize that through more efficacious viral targeting in DAA therapy, host factors such as IL28B or fibrosis may become less significant. Thus, the IL28B response gap for patients with poor response IL28B genotypes is narrowed by addition of DAAs. However, for patients with good response IL28B genotype, the efficacy gains in adding DAA to PEG/RBV are more marginal than for patients with poor response IL28B genotype, raising the important discussion about whether IL28B can be used to trade off efficacy and expense in health care settings where treatment must be rationalized. As treatment efficacy continues to improve, better tolerability and reduced treatment duration will inevitably become more highly prioritized therapeutic objectives. Importantly, again the data to support this come from retrospective subanalyses, in this case of boceprevir and telaprevir phase III data. With improved viral kinetics, good response IL28B genotype patients have reduced risk for development of resistance-associated variants (RAVs), and thus may be considered prime candidates for reduced duration regimens, or possibly for IFN-free regimens with PEG/RBV rescue in the event of DAA nonresponse. Recent preliminary data from the INFORM-1 (INterferon-Free regimen fOR the Management of HCV) trial support this, suggesting that patients with the good response IL28B have improved viral kinetics even with IFN-free regimens (in this case nucleoside polymerase inhibitor mericitabine and protease inhibitor danoprevir).27 These preliminary retrospective data are fascinating from both a biological perspective as well as the clinical opportunities they suggest, but underline the need for better quality data. Appropriately designed prospective RCTs will be the key to unraveling the future role for IL28B in designing the more personalized DAA regimens of the future. IL28B represents both the pitfalls and promise of genomics in medicine. Our capacity to extract ever-growing data from the human genome is currently well in advance of our capacity to generate useful insight from it. Many more clinical and biological questions are raised than answered by the IL28B genetic association. Much of the promise of IL28B lies in unraveling related biological pathways—genetic, functional and viral—to better understand disease mechanisms.28 Defining genetic contribution to a phenotype typically requires a large number of variants, with each individual variant having potentially very modest contribution.29 IL28B is relatively unique in this respect, with few GWAS discoveries rivaling its significance as a well-validated genetic signal explaining much of the population-based variance in treatment response to PEG/RBV. Nonetheless, as these reviews indicate, inferring population-based observations and translating them to individual decision-making provides much of the challenge and opportunity in genomics, more specifically for patients with HCV. In the journey of research from clinical observation to scientific discovery, the ultimate destination should always be to return to the patient.30 Translation of scientific discovery is not an event but a process. For IL28B, this dynamic translational process has been productive and promising. These reviews provide evidence of what we know of IL28B, and greater a sense of what we know we do not know, emphasizing the need for further basic and prospective clinical research. HCV's dynamic therapeutic environment contributes to the pool of "unknown unknowns" regarding IL28B's future role. Clearly, from IL28B's discovery, the return journey to the patient has only just begun.