Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Review
Predictors of hepatitis C treatment response: what’s new? Expert Rev. Anti Infect. Ther. 12(2), 183–191 (2014)
Louise Berry*1 and Will Irving2 1 Department of Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK 2 NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, NG7 2UH, UK *Author for correspondence: [email protected]
Hepatitis C virus infection is a growing, global health problem, with mortality expected to reach a peak in the next ten years in many western countries. A number of host and viral factors have been established as useful predictors of treatment response in the context of interferon and ribavirin. Several new markers have recently been identified that improve our understanding of treatment response. The addition of protease inhibitors to treatment regimens has highlighted the importance of viral kinetics on-treatment in predicting response to treatment. Many new classes of direct acting anti-virals are currently being developed and expected to be clinically available in the near future. Current predictors of treatment response will be redefined in the context of interferon free regimens. KEYWORDS: direct-acting antivirals . hepatitis C virus . IL-28B . interferon . predictors . ribavirin . sustained virological response
Since its identification in 1989, hepatitis C has been recognized as a growing health problem. WHO estimates that globally, 150 million people are chronically infected with HCV and that each year 350,000 people die of HCVrelated liver diseases [1]. About 75–85% of newly infected persons develop chronic infection which can progress asymptomatically for many years. Untreated, 60–70% of infected people will develop chronic liver disease, up to 30% will develop cirrhosis and 5% per year will develop decompensated liver disease or hepatocellular carcinoma [2,3]. Twenty-five percent of liver-related deaths globally are attributable to hepatitis C. It is expected that hepatitis C-related morbidity and mortality will reach its peak in the USA in the next 10 years [4]. Given that most of those infected are unaware of their diagnosis, the CDC recently recommended screening for HCV in all persons born between 1945 and 1965 [5]. In the past decade, interferon and ribavirin has been the mainstay of treatment for patients with hepatitis C. The aim of treatment is to achieve a sustained virological response (SVR), that is, undetectable viral RNA in the blood 6 months after the treatment has been completed. Standard of care has consisted of weekly subcutaneous injections of pegylatedinterferon and oral weight-based ribavirin (PR) www.expert-reviews.com
10.1586/14787210.2014.874283
for 24 weeks in genotypes (G) 2 and 3 or 48 weeks in G1, 4, 5 and 6. SVR rates for standard of care are 40–54% in G1 and 65–82% in G2/3 [6]. In 2011, two new drugs, boceprevir (BOC) and telaprevir (TVR) were approved by the US FDA and the EMA for use in HCV G1-infected patients. These new drugs are NS3/4A protease inhibitors (PIs), acting directly on the virus’s replicative ability. Used with PR, these PIs have increased SVR rates to 67–75% in previously untreated patients and 41–52% in previous nonresponders [7–10]. Currently, an array of new direct-acting antivirals (DAAs), targeting various points of the HCV life cycle, are undergoing Phase II and III trials. All-oral combinations of DAAs and ribavirin are expected to become available over the next 5 years for treatment of hepatitis C, and offer the hope of high cure rates for difficult-to-treat patients without the side effects associated with interferon-based regimens. In this context, the relative importance and relevance of current predictors of response is likely to change. At present, there are numerous factors including viral (e.g., genotype, viral load), host (e.g., fibrosis, immune factors) and treatmentrelated factors that determine treatment response. Their relative contribution varies
2014 Informa UK Ltd
ISSN 1478-7210
183
Review
Berry & Irving
Table 1. Classification of pre-treatment factors into viral factors and host factors.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Pre-treatment factors Viral
Host
Genotype (2/6 > 3/5 > 1 > 4) Subtype (1b > 1a) Baseline viral load Resistance mutations
IL-28B genotype Other immune factors: HLA-C, NK-KIR and IP-10 Cirrhosis Coinfection (HIV, hepatitis B) Race Alcohol consumption Diabetes Age Obesity Previous treatment response
On-treatment factors
G3 [15]. Recent trial results have found sofosbuvir, a potent NS5B polymerase inhibitor, to be highly effective when combined with PR, with SVR rates greater than 89% in G1, 2, 4, 5 and 6, but much lower in G3 patients [16,17]. Subtype
RVR Vitamin D supplementation Adherence
RVR: Rapid virological response.
between patients, and knowledge of these can help determine the best treatment regimen and duration for individual patients. They can be used in pre-treatment counseling to explain the likelihood of SVR and treatment duration for that patient, and deciding whether to defer treatment until newer regimens, with higher cure rates and fewer side effects, are available. This review will cover the viral, host and treatment-related predictors of response focusing on those that are most relevant in clinical practice and how these may be of relevance in the future. Pre-treatment predictors of response
Many pre-treatment predictors of response have been well defined in the context of dual therapy with PR. They can now help to determine which patients can expect a good response from dual therapy and identify those who would fare better with triple therapy including a PI. Pre-treatment factors can be classified into viral factors and host factors as summarized in TABLE 1.
G1 has two common subtypes: 1a and 1b. In the context of triple therapy including DAAs, 1a has been associated with higher rates of viral breakthrough, and clearly has a lower barrier to resistance, for example, requiring only one nucleotide substitution at position 155 to develop resistance to PIs, whereas 1b requires two [18]. Likewise, polymorphisms within the NS5A gene which may compromise response to NS5A inhibitors, are more common in subtype 1a than 1b [19]. Baseline viral load
Low baseline HCV RNA viral load is a positive predictor of SVR. This is particularly true for G1, which is less sensitive to interferon therapy. Various cut-offs have been used to discriminate between low and high viral load. One study used 400,000 IU/ml in treatment-naı¨ve G1 patients; SVR rates were 67 and 37% in those with low and high viral loads, respectively [20]. This cut-off was not found to be useful for treatmentexperienced patients. Elsewhere, a baseline of 78% SVR, with 24 weeks dual therapy alone [22,23]. In the SPRINT-2 study of BOC/PR, patients with a low baseline viral load (2 log at week 12; Partial responders: HCV RNA still detectable at week 24; Responder-relapsers: HCV RNA became undetectable during treatment but reappeared after treatment ended.
In the RESPOND-2 trial, SVR rates in the BOC-containing arms were higher in the previous relapsers (75 and 69%) than the partial responders (52 and 40%). In the PR arm, rates were 29 and 7% for relapsers and partial responders, respectively [9]. The REALIZE trial also included non-responders in their analysis. SVR rates in the TVR arms were 83–88% for previous relapsers (vs 24% in the control group), 54–59% for prior partial responders (vs 15% in control group) and 29–33% in null responders (vs 5% for controls) [10]. A sub-analysis of the REALIZE study evaluated the impact of IL-28B polymorphisms on SVR in TVR-treated, HCV G1-infected patients with prior PR treatment failure. IL-28B genotype data were available for 80% of the 662 patients randomized between treatment arms. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with TVR-based treatment were comparable across IL-28B genotypes. IL-28B genotype did not significantly affect SVR (two-step multivariate analyses; p > 0.16 in pairwise comparison among CC, TT and CT). Prior response category did have significant predictive impact on SVR. Thus in treatment-experienced G1 patients, with well-defined treatment response, IL-28 genotyping is of limited utility [45]. In summary, a number of host and viral baseline parameters have been identified which exert a strong influence on treatment outcome. Efforts have been made to integrate these indicators into a model that can predict a patient’s likely response to treatment. Of note, the Prometheus index, which incorporates IL-28B variants, HCV RNA level, HCV genotype and liver fibrosis, has been used to predict response to PR therapy. It was found to be most useful for patients coinfected with HCV and HIV [46]. Further refinement of such tools with the inclusion of other variables such as IP-10 and anti-E1E2 may strengthen their predictive ability. In resource-limited settings, this could assist the clinician to identify those patients who could expect a good chance of response to PR+/-PI therapy and those who should wait for newer antivirals. On-treatment predictors of SVR Virological response
Virological response in the first 4 weeks of treatment bears a critical influence on whether SVR is achieved. Early viral response is likely determined by a number of viral and host factors, of which IL-28B is just one. Several studies have shown that an undetectable viral load at 4 weeks, or RVR is the strongest predictor of SVR with PR therapy [22,23]. Retrospective analysis of IDEAL trial data shows that IL-28B genotype loses its predictive value when RVR is included in the analysis. Another study illustrated how in RVR patients, there was no www.expert-reviews.com
Review
significant difference in SVR or relapse rates after 24 or 48 weeks by IL-28B type [47]. Similar results have been described in the PI triple therapybased trials. The BOC-based trials SPRINT-2 and RESPOND used a lead-in of 4 weeks PR therapy prior to inclusion of BOC. IL-28B genotype strongly predicted lead-in response (OR 15.8). However, when interferon responsiveness, defined as a >1 log10 decline in HCV viral load at week 4 was added to the multivariable logistic regression model, IL-28B genotype was no longer a significant predictor of SVR [48]. Thus, RVR is a reflection of known and unknown predictors of early viral kinetics and cannot be replaced by IL-28B. Responsiveness to therapy at key time-points provides the basis of response-guided therapy (RGT), which may identify those patients with an increased likelihood of achieving SVR, who may therefore be eligible for shortened treatment. Monitoring viral load also serves to identify those patients who are so unlikely to achieve SVR that further treatment is futile, in other words, stopping rules. Data from the TVR ADVANCE and ILLUMINATE trials show that none of those patients with HCV RNA levels >1000 IU/ml at week 4 of triple therapy achieved SVR and therefore in those circumstances, all treatment should be stopped [8,49]. Similarly for BOC regimens, an RNA level >100 IU/ml at week 12 has been established as a futility rule based on which treatment should be stopped. Strict adherence to these stopping rules will lead to the reduction of unnecessary costs and side effects associated with treatment, and decrease the emergence of viral resistance, without compromising the chances of individual patients achieving SVR [9,50]. Vitamin D supplementation
There has been growing interest in vitamin D’s immunomodulatory role in the context of HCV infection. Vitamin D has been shown to have an anti-inflammatory role by downregulating Toll-like receptor expression, which reduces the production of several inflammatory factors including CXCL10 and TNF-a [51]. These have been implicated in promoting HCV replication. A study has found that lower levels of vitamin D were independently associated with severe fibrosis (Metavir score F3–F4) by multivariate logistic analysis. In addition, vitamin D levels were an independent factor for lack of SVR (OR: 1.039; 95% CI: 1.002–1.077) [52]. In addition, a Swiss study of chronic hepatitis C patients found that vitamin D receptor polymorphisms influence response to PR-based therapy and exert an additive genetic predisposition to low 25-OH vitamin D serum levels [53]. Several studies of vitamin D supplementation during PR treatment have shown increased SVR rate in the supplemented group. One study of 72 treatment-naı¨ve G1 patients using 2000 IU/day of vitamin D3 observed a significant difference in SVR rates of 86% of patients receiving supplementation and 42% in controls (p < 0.001). In a second study involving patients with G2/3, 19/20 (95%) patients with vitamin D supplementation and 23/30 (77%) controls were HCV RNA 187
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Review
Berry & Irving
negative 24 weeks after treatment (
Review
Predictors of hepatitis C treatment response: what’s new? Expert Rev. Anti Infect. Ther. 12(2), 183–191 (2014)
Louise Berry*1 and Will Irving2 1 Department of Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK 2 NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, NG7 2UH, UK *Author for correspondence: [email protected]
Hepatitis C virus infection is a growing, global health problem, with mortality expected to reach a peak in the next ten years in many western countries. A number of host and viral factors have been established as useful predictors of treatment response in the context of interferon and ribavirin. Several new markers have recently been identified that improve our understanding of treatment response. The addition of protease inhibitors to treatment regimens has highlighted the importance of viral kinetics on-treatment in predicting response to treatment. Many new classes of direct acting anti-virals are currently being developed and expected to be clinically available in the near future. Current predictors of treatment response will be redefined in the context of interferon free regimens. KEYWORDS: direct-acting antivirals . hepatitis C virus . IL-28B . interferon . predictors . ribavirin . sustained virological response
Since its identification in 1989, hepatitis C has been recognized as a growing health problem. WHO estimates that globally, 150 million people are chronically infected with HCV and that each year 350,000 people die of HCVrelated liver diseases [1]. About 75–85% of newly infected persons develop chronic infection which can progress asymptomatically for many years. Untreated, 60–70% of infected people will develop chronic liver disease, up to 30% will develop cirrhosis and 5% per year will develop decompensated liver disease or hepatocellular carcinoma [2,3]. Twenty-five percent of liver-related deaths globally are attributable to hepatitis C. It is expected that hepatitis C-related morbidity and mortality will reach its peak in the USA in the next 10 years [4]. Given that most of those infected are unaware of their diagnosis, the CDC recently recommended screening for HCV in all persons born between 1945 and 1965 [5]. In the past decade, interferon and ribavirin has been the mainstay of treatment for patients with hepatitis C. The aim of treatment is to achieve a sustained virological response (SVR), that is, undetectable viral RNA in the blood 6 months after the treatment has been completed. Standard of care has consisted of weekly subcutaneous injections of pegylatedinterferon and oral weight-based ribavirin (PR) www.expert-reviews.com
10.1586/14787210.2014.874283
for 24 weeks in genotypes (G) 2 and 3 or 48 weeks in G1, 4, 5 and 6. SVR rates for standard of care are 40–54% in G1 and 65–82% in G2/3 [6]. In 2011, two new drugs, boceprevir (BOC) and telaprevir (TVR) were approved by the US FDA and the EMA for use in HCV G1-infected patients. These new drugs are NS3/4A protease inhibitors (PIs), acting directly on the virus’s replicative ability. Used with PR, these PIs have increased SVR rates to 67–75% in previously untreated patients and 41–52% in previous nonresponders [7–10]. Currently, an array of new direct-acting antivirals (DAAs), targeting various points of the HCV life cycle, are undergoing Phase II and III trials. All-oral combinations of DAAs and ribavirin are expected to become available over the next 5 years for treatment of hepatitis C, and offer the hope of high cure rates for difficult-to-treat patients without the side effects associated with interferon-based regimens. In this context, the relative importance and relevance of current predictors of response is likely to change. At present, there are numerous factors including viral (e.g., genotype, viral load), host (e.g., fibrosis, immune factors) and treatmentrelated factors that determine treatment response. Their relative contribution varies
2014 Informa UK Ltd
ISSN 1478-7210
183
Review
Berry & Irving
Table 1. Classification of pre-treatment factors into viral factors and host factors.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Pre-treatment factors Viral
Host
Genotype (2/6 > 3/5 > 1 > 4) Subtype (1b > 1a) Baseline viral load Resistance mutations
IL-28B genotype Other immune factors: HLA-C, NK-KIR and IP-10 Cirrhosis Coinfection (HIV, hepatitis B) Race Alcohol consumption Diabetes Age Obesity Previous treatment response
On-treatment factors
G3 [15]. Recent trial results have found sofosbuvir, a potent NS5B polymerase inhibitor, to be highly effective when combined with PR, with SVR rates greater than 89% in G1, 2, 4, 5 and 6, but much lower in G3 patients [16,17]. Subtype
RVR Vitamin D supplementation Adherence
RVR: Rapid virological response.
between patients, and knowledge of these can help determine the best treatment regimen and duration for individual patients. They can be used in pre-treatment counseling to explain the likelihood of SVR and treatment duration for that patient, and deciding whether to defer treatment until newer regimens, with higher cure rates and fewer side effects, are available. This review will cover the viral, host and treatment-related predictors of response focusing on those that are most relevant in clinical practice and how these may be of relevance in the future. Pre-treatment predictors of response
Many pre-treatment predictors of response have been well defined in the context of dual therapy with PR. They can now help to determine which patients can expect a good response from dual therapy and identify those who would fare better with triple therapy including a PI. Pre-treatment factors can be classified into viral factors and host factors as summarized in TABLE 1.
G1 has two common subtypes: 1a and 1b. In the context of triple therapy including DAAs, 1a has been associated with higher rates of viral breakthrough, and clearly has a lower barrier to resistance, for example, requiring only one nucleotide substitution at position 155 to develop resistance to PIs, whereas 1b requires two [18]. Likewise, polymorphisms within the NS5A gene which may compromise response to NS5A inhibitors, are more common in subtype 1a than 1b [19]. Baseline viral load
Low baseline HCV RNA viral load is a positive predictor of SVR. This is particularly true for G1, which is less sensitive to interferon therapy. Various cut-offs have been used to discriminate between low and high viral load. One study used 400,000 IU/ml in treatment-naı¨ve G1 patients; SVR rates were 67 and 37% in those with low and high viral loads, respectively [20]. This cut-off was not found to be useful for treatmentexperienced patients. Elsewhere, a baseline of 78% SVR, with 24 weeks dual therapy alone [22,23]. In the SPRINT-2 study of BOC/PR, patients with a low baseline viral load (2 log at week 12; Partial responders: HCV RNA still detectable at week 24; Responder-relapsers: HCV RNA became undetectable during treatment but reappeared after treatment ended.
In the RESPOND-2 trial, SVR rates in the BOC-containing arms were higher in the previous relapsers (75 and 69%) than the partial responders (52 and 40%). In the PR arm, rates were 29 and 7% for relapsers and partial responders, respectively [9]. The REALIZE trial also included non-responders in their analysis. SVR rates in the TVR arms were 83–88% for previous relapsers (vs 24% in the control group), 54–59% for prior partial responders (vs 15% in control group) and 29–33% in null responders (vs 5% for controls) [10]. A sub-analysis of the REALIZE study evaluated the impact of IL-28B polymorphisms on SVR in TVR-treated, HCV G1-infected patients with prior PR treatment failure. IL-28B genotype data were available for 80% of the 662 patients randomized between treatment arms. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with TVR-based treatment were comparable across IL-28B genotypes. IL-28B genotype did not significantly affect SVR (two-step multivariate analyses; p > 0.16 in pairwise comparison among CC, TT and CT). Prior response category did have significant predictive impact on SVR. Thus in treatment-experienced G1 patients, with well-defined treatment response, IL-28 genotyping is of limited utility [45]. In summary, a number of host and viral baseline parameters have been identified which exert a strong influence on treatment outcome. Efforts have been made to integrate these indicators into a model that can predict a patient’s likely response to treatment. Of note, the Prometheus index, which incorporates IL-28B variants, HCV RNA level, HCV genotype and liver fibrosis, has been used to predict response to PR therapy. It was found to be most useful for patients coinfected with HCV and HIV [46]. Further refinement of such tools with the inclusion of other variables such as IP-10 and anti-E1E2 may strengthen their predictive ability. In resource-limited settings, this could assist the clinician to identify those patients who could expect a good chance of response to PR+/-PI therapy and those who should wait for newer antivirals. On-treatment predictors of SVR Virological response
Virological response in the first 4 weeks of treatment bears a critical influence on whether SVR is achieved. Early viral response is likely determined by a number of viral and host factors, of which IL-28B is just one. Several studies have shown that an undetectable viral load at 4 weeks, or RVR is the strongest predictor of SVR with PR therapy [22,23]. Retrospective analysis of IDEAL trial data shows that IL-28B genotype loses its predictive value when RVR is included in the analysis. Another study illustrated how in RVR patients, there was no www.expert-reviews.com
Review
significant difference in SVR or relapse rates after 24 or 48 weeks by IL-28B type [47]. Similar results have been described in the PI triple therapybased trials. The BOC-based trials SPRINT-2 and RESPOND used a lead-in of 4 weeks PR therapy prior to inclusion of BOC. IL-28B genotype strongly predicted lead-in response (OR 15.8). However, when interferon responsiveness, defined as a >1 log10 decline in HCV viral load at week 4 was added to the multivariable logistic regression model, IL-28B genotype was no longer a significant predictor of SVR [48]. Thus, RVR is a reflection of known and unknown predictors of early viral kinetics and cannot be replaced by IL-28B. Responsiveness to therapy at key time-points provides the basis of response-guided therapy (RGT), which may identify those patients with an increased likelihood of achieving SVR, who may therefore be eligible for shortened treatment. Monitoring viral load also serves to identify those patients who are so unlikely to achieve SVR that further treatment is futile, in other words, stopping rules. Data from the TVR ADVANCE and ILLUMINATE trials show that none of those patients with HCV RNA levels >1000 IU/ml at week 4 of triple therapy achieved SVR and therefore in those circumstances, all treatment should be stopped [8,49]. Similarly for BOC regimens, an RNA level >100 IU/ml at week 12 has been established as a futility rule based on which treatment should be stopped. Strict adherence to these stopping rules will lead to the reduction of unnecessary costs and side effects associated with treatment, and decrease the emergence of viral resistance, without compromising the chances of individual patients achieving SVR [9,50]. Vitamin D supplementation
There has been growing interest in vitamin D’s immunomodulatory role in the context of HCV infection. Vitamin D has been shown to have an anti-inflammatory role by downregulating Toll-like receptor expression, which reduces the production of several inflammatory factors including CXCL10 and TNF-a [51]. These have been implicated in promoting HCV replication. A study has found that lower levels of vitamin D were independently associated with severe fibrosis (Metavir score F3–F4) by multivariate logistic analysis. In addition, vitamin D levels were an independent factor for lack of SVR (OR: 1.039; 95% CI: 1.002–1.077) [52]. In addition, a Swiss study of chronic hepatitis C patients found that vitamin D receptor polymorphisms influence response to PR-based therapy and exert an additive genetic predisposition to low 25-OH vitamin D serum levels [53]. Several studies of vitamin D supplementation during PR treatment have shown increased SVR rate in the supplemented group. One study of 72 treatment-naı¨ve G1 patients using 2000 IU/day of vitamin D3 observed a significant difference in SVR rates of 86% of patients receiving supplementation and 42% in controls (p < 0.001). In a second study involving patients with G2/3, 19/20 (95%) patients with vitamin D supplementation and 23/30 (77%) controls were HCV RNA 187
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Review
Berry & Irving
negative 24 weeks after treatment (
