Outcomes of HCV treatment: Who does well and who does not?
Journal
Journal of Gastroenterology and Hepatology (Australia)
Journal Volume
25
Journal Issue
5
Pages
846-848
Date Issued
2010
Author(s)
Hsu C.-S.
Abstract
Chronic hepatitis C virus (HCV) infection is an important etiology of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, affecting more than 170 million people worldwide.1 Combination therapy with pegylated interferon (PEG-IFN) plus weight-based ribavirin (RBA) is the current standard of care for the treatment of chronic hepatitis C (CHC), with an overall sustained virologic response (SVR) rate of 70–90% in Asian patients compared with 50–80% in Caucasian patients.2, 3 However, combination therapy is costly and causes substantial adverse events, and thus efforts to search for factors facilitating individualized therapy are important to avoid unnecessary treatment and minimize serious adverse effects.4 In our clinical practice, several baseline and on-treatment factors have been used to predict sustained virologic response (SVR) in CHC patients. They are viral factors, including genotype and early viral kinetics, host factors including ethnicity, metabolic factors, histological factors, type and duration of therapeutic regimens.4-6 Among these factors, some are correctable, easily adjusted and monitored clinically, whereas others are not. In this issue of the Journal of Gastroenterology and Hepatology, factors associated with virologic relapse after the achievement of end of treatment virologic response (ETVR) and improvement of liver stiffness (LS) (a kind of noninvasive measurement regarding the extent of liver fibrosis) are identified and discussed.7, 8 In regard to HCV treatment, on-treatment virologic responses are useful for the prediction of SVR; the terms given relate to their timing relative to treatment duration. According to the update guidelines of 2009 American Association for the Study Liver Diseases (AASLD),9 undetectable serum HCV RNA at week 4 of treatment is defined as rapid virologic response (RVR), and this predicts a high likelihood of achieving an SVR. Early virologic response (EVR) is defined as a ≥2 log reduction or complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level. Failure to achieve EVR is the most accurate predictor of not achieving SVR. Undetectable virus at the end of therapy is referred to as end-of-treatment virologic response (ETVR), which does not accurately predict SVR but is necessary for it to occur. Virologic breakthrough refers to the reappearance of HCV RNA while still on therapy, and virologic relapse is the reappearance of HCV RNA in serum after treatment is discontinued after ETVR is achieved. Previous studies have shown that weight-based ribavirin is more effective than a fixed dose of ribavirin in inducing SVR, and a suboptimal dose of ribavirin is an important cause of virologic relapse; thus, weight-based ribavirin is recommended to reduce the virologic relapse rate.10 In the paper by Shin et al. factors associated with virologic relapse are explored in a cohort of Korean CHC patients who received PEG-IFN plus RBA treatment (weight-based dose for HCV genotype 1 patients and fixed dose for genotype 2 or 3 patients) and achieved ETVR. Baseline factors between patients with and without SVR were compared and analyzed. They found that risk factors for relapse were age older than 50 years and, in genotype 1 cases, higher baseline HCV RNA level (≥2 000 000 IU/mL), while lower adherence to PEG-IFN (<80%) was important in genotype 2 or 3 patients. These findings not only confirm the importance of compliance and adherence to treatment, but also suggest that genotype 1 patients older than 50 years and with higher baseline HCV RNA level (≥2 000 000 IU/mL), have a lower chance of treatment success. The authors speculated that such cases may benefit from longer treatment duration than currently recommended. However, several issues are worthy of discussion. First, early viral kinetic parameters, such as RVR and EVR have been documented to be the most important factors predictive of therapeutic response in CHC patients treated with combination therapy. However, such viral kinetic data are lacking in most patients in this study. Second, Basso et al.11 indicated that only alanine aminotransferase (ALT) elevation in the later course of antiviral therapy of HCV RNA-negative patients was associated with virologic relapse, whereas pretreatment demographic (age, gender), clinical (ALT levels, histological grade and stage, body mass index) and viral (load, genotype) parameters failed to correlate with this phenomenon. It is known that older age, higher baseline viral load, and poor adherence to therapy are predictors of SVR. Thus the present results reported here are not surprising and cannot be simply interpreted as factors required for the implementation of prolonged therapy. In regard to measures to reduce virologic relapse rate after achieving ETVR, whether patients with risk factors for virologic relapse can benefit from extended combination therapy remains largely unknown. Moreover, in addition to the consideration of prolonged therapy, other measures such as incremental dose of ribavirin, adoption of a ribavirin analog, add-on novel STAT-C agents, assurance of adherence, and improvement of insulin resistance may also be used to reduce virologic relapse in CHC patients. However, further studies are needed to prove their usefulness. In the meantime, the severity of hepatic fibrosis is an important prognostic factor of chronic HCV infection, and histologic assessment of hepatic fibrosis by liver biopsy is the current gold standard; however, liver biopsy is associated with patient discomfort, risk of serious complications, less acceptance by patients, and its accuracy may be affected by sampling variability as well as inter-observer variability. Thus, several noninvasive methods in assessing liver fibrosis have been introduced.12, 13 Among these noninvasive methods, transient elastography has been increasingly recognized as a highly reproducible technique in assessing liver stiffness (LS) with good correlation to the histologic data. Transient elastography is shown to be clinically helpful in terms of predicting changes of liver histology, which is feasible for serial follow-up, and it avoids discomfort as well as serious complications. For these reasons, there has been a high acceptance level by patients. The paper by Wang et al. in this issue of JGH studied factors associated with the improvement of hepatic fibrosis after IFN-based therapy for CHC, as assessed via serial measurements of LS. Changes of LS were observed over an interval of at least 38 weeks, and the key finding was that LS decreased significantly in patients with SVR. In addition, the authors found that a lower initial LS value, higher body mass index, longer interval between the end of treatment and initial LS measurement, as well as advanced hepatic fibrosis before therapy may slow the rapidity of LS improvement in patients with SVR. Although these findings are clinically useful, several points need to be clarified. First, an earlier histology-based study of Japanese CHC patients demonstrated that the changes of hepatic fibrosis was −0.28 ± 0.03 units/year (regression) in patients with SVR, 0.02 ± 0.02 units/year in patients without SVR (P < 0.001), and 0.10 ± 0.02 units/year in untreated patients;14 these rates of change are less than the changes of LS observed by Wang et al. Second, transient elastography is not a reliable instrument to detect the presence of advanced fibrosis or cirrhosis in patients with active hepatitis, at least for hepatitis B, and there exists a positive correlation between serum aminotransferase level and LS value at the onset of acute viral hepatitis (r = 0.53, P = 0.02 and r = 0.51, P = 0.03 for alanine aminotransferase and aspartate aminotransferase, respectively).15 In addition, chronic hepatitis B patients with the same fibrosis stages but higher ALT levels tend to have higher LS values, and the diagnostic performance for low-stage hepatic fibrosis was seriously affected at elevated serum ALT levels.16 Accordingly, it is suggested that LS should be assessed after the normalization of serum ALT levels, and different LS cutoff values and algorithms derived for normal and elevated serum ALT levels in chronic hepatitis B patients have been proposed.17 Whether similar ALT-based algorithms should be considered in CHC patients awaits additional studies. Recently, the substitution of amino acids 70 and/or 91 in the core region of HCV genome (HCV-CR) has been shown to be a negative predictor associated with SVR in Japanese HCV genotype 1 patients, and a risk factor for the development of hepatocellular carcinoma.18 In addition, several independent genome-wide association studies (GWAS) from different parts of the world have identified strong associations of single nucleotide polymorphisms (SNPs) in the interleukin-28B (IL28B) region with therapeutic response to combination therapy in HCV-infected individuals.19 These genetic polymorphisms may explain approximately half of the difference in response rates between patients of African-Americans, European ancestry, and Asian ancestry.19 Taking these lines of novel evidence together, further studies should evaluate the clinical impact of amino acid substitution patterns in HCV-CR as well as genetic polymorphisms in IL28B on virologic relapse or the rapidity of LS improvement in CHC patients treated with PEG-IFN plus RBA. To this end, much needs to be done in the start of a new decade to better understand the outcomes of HCV treatment and foresee who does well and who does not.
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; interferon; interleukin 28; peginterferon; ribavirin; virus RNA; antivirus agent; virus RNA; interleukin 28B; peginterferon; ribavirin; accuracy; amino acid substitution; analytic method; antiviral therapy; cancer risk; chronic hepatitis; drug dosage form comparison; drug efficacy; editorial; genetic association; genetic polymorphism; genotype; hepatitis C; human; immunotherapy; insulin resistance; liver biopsy; liver fibrosis; liver stiffness; patient compliance; predictor variable; priority journal; recurrence risk; risk assessment; single nucleotide polymorphism; treatment duration; treatment outcome; treatment response; virus hepatitis; virus load; blood; complication; drug combination; drug effects; genetics; Hepacivirus; Hepatitis C, Chronic; liver; liver cirrhosis; pathology; patient selection; recurrent disease; risk factor; severity of illness index; time; virology; age; algorithm; aminotransferase blood level; antiviral therapy; Asian; body mass; chronic hepatitis B; chronic hepatitis C; clinical practice; Editorial; elastography; ethnicity; gold standard; health care quality; Hepatitis C virus genotype 1; liver histology; personalized medicine; prognosis; Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver; Liver Cirrhosis; Patient Selection; Recurrence; Risk Assessment; Risk Factors; RNA, Viral; Severity of Illness Index; Time Factors; Treatment Outcome; Viral Load
Publisher
Blackwell Publishing
Type
editorial