Predicting the response to the treatment of hepatitis C virus infection

Authors


  • Potential conflict of interest: Advisory Board: Merck; Clinical Research: Gilead Merck.

Abstract

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As long as the treatment of hepatitis C virus (HCV) infection is expensive and is associated with adverse events, patients and providers will need to know the likelihood of a response so that they can decide whether the benefits outweigh the risks. The factors that determine this likelihood are called pretreatment predictors of response, and they can be classified as viral or host determinants (Table 1). Although there are many clinically relevant responses that occur during and after treatment, the primary endpoint is a sustained virological response (SVR), which is defined as the suppression of HCV RNA below the level of detection at the end of treatment and 6 months afterward. SVR is widely regarded as a virological cure, and unless otherwise specified, it is synonymous with a response in this review. Although many interesting viral and host response predictors have been discovered, this review focuses on those widely available to medical providers. Finally, because treatment response predictors may differ as treatments for HCV differ, this review focuses on US Food and Drug Administration–approved treatments as of September 2011.

Table 1.. Determinants of the Response to HCV Treatment
Viral Determinants
 HCV genotype
 HCV viral load
Host Determinants
 IL-28B genotype
 Race
 Fibrosis stage
 Age
 Insulin resistance
 HIV coinfection
Table 2.. Determinants of the Response to HCV Protease Inhibitors, Peginterferon, and Ribavirin for the Treatment of Chronic HCV Genotype 1 Infections
DeterminantSVR (%)DeterminantSVR (%)
T12PR24-48PR48B44PR48PR48
  1. Abbreviations: B44PR48, boceprevir for 44 weeks and peginterferon and ribavirin for 48 weeks; PR48, peginterferon and ribavirin for 48 weeks; T12PR24-48, telaprevir for 12 weeks and peginterferon and ribavirin for 24 to 48 weeks.

Genotype  Genotype  
 1a7141 1a6335
 1b7948 1b7040
Viral load  Viral load  
 <800,000 IU/mL7870 ≤800,000 IU/mL8564
 ≥800,000 IU/mL7436 >800,000 IU/mL6333
Age  Age  
 ≤45 years8352 ≤40 years6952
 >45-65 years7038 >40 years6534
Race  Race  
 White7546 White6840
 Black6225 Black5323
Fibrosis  Fibrosis  
 0-27747 0-26738
 3-46233 3-45238
BMI  BMI  
 <25 kg/m28344 ≤25 kg/m26747
 ≥25-<30 kg/m26745 25-30 kg/m26533
 ≥30 kg/m27141 >30 kg/m26633
Abbreviations

B44PR48, boceprevir for 44 weeks and peginterferon and ribavirin for 48 weeks; BMI, body mass index; BOC, boceprevir; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IL-28B, interleukin-28B; PR48, peginterferon and ribavirin for 48 weeks; RGT, response-guided therapy; SVR, sustained virological response; T8PR, telaprevir for 8 weeks and peginterferon and ribavirin; T12PR, telaprevir for 12 weeks and peginterferon and ribavirin; T12PR24-48, telaprevir for 12 weeks and peginterferon and ribavirin for 24 to 48 weeks.

Viral Determinants

HCV is the most genetically diverse virus known to cause disease in man, and at least 6 distinct genetic groupings (genotypes) have been identified (a seventh genotype has also recently been provisionally characterized). HCV treatment responses vary with the genotype, with the highest SVR rates observed for genotype 2 and the lowest rates observed for genotypes 1 and 4. For example, when peginterferon and ribavirin were used at similar doses for 48 weeks, SVR was achieved by 52% of genotype 1–infected patients and by 80% of genotype 2/3–infected patients.1 An abbreviated treatment duration and a lower ribavirin dose reduced SVR rates for patients with HCV genotype 1 infections but not for patients with genotype 2 or 3 infections. Thus, subsequent clinical trials largely focused on either genotype 1 infections or genotype 2/3 infections. Additional smaller studies have suggested that similarly to genotype 1, genotype 4 is poorly responsive2; genotype 5 is similar to genotype 35; genotype 3 is less responsive than genotype 24; and similarly to genotype 2, genotype 6 is very responsive.5 With HCV protease inhibitors, higher SVR rates have been detected with genotype 1b versus genotype 1a6 (Table 2).

The amount of HCV detected in the blood before treatment (the baseline HCV viral load) may also determine the likelihood of a response to peginterferon and ribavirin.1, 4 The predictive value of the baseline viral load is lower for genotypes with higher SVR rates and is also lower with more potent treatments for the same genotype. In one study of patients with HCV genotype 3 infections who were treated with peginterferon alfa-2a and 800 mg of ribavirin for 24 weeks, SVR was achieved by 81%, 70%, and 59% when the pretreatment viral loads were ≤400,000, >400,000 to 800,000, and >800,000 IU/mL, respectively; the results for patients with genotype 2 (a more responsive genotype) were 82%, 79%, and 73%, respectively.4 For genotype 1–infected patients, the HCV viral load is less predictive of a response if HCV protease inhibitors are taken. For example, in a study of patients with HCV genotype 1 infections, patients treated with peginterferon, ribavirin, and telaprevir had high SVR rates despite their baseline HCV RNA levels: 78% at <800,000 IU/mL and 74% at ≥800,000 IU/mL. For patients who were randomized to peginterferon, ribavirin, and a placebo, the SVR rates were 70% and 36% in the respective viral load groups.7 In another study of patients with HCV genotype 1 infections who were treated with peginterferon, ribavirin, and boceprevir, the SVR rates were 76% to 85% for patients with HCV RNA levels < 800,000 IU/mL and 61% to 63% for patients with HCV RNA levels ≥800,000 IU/mL; for patients randomized to peginterferon, ribavirin, and a placebo, the SVR rates were 64% and 33% for the respective viral load groups.6

Host Determinants

Interestingly, the strongest host determinant of a response to peginterferon and ribavirin is the patient's DNA sequence near the gene for interleukin-28B (IL-28B), or lambda interferon 3. According to one commercially available test (the C versus T allele for rs12979860), the response rates of patients with a chronic HCV genotype 1 infection who were treated with peginterferon and ribavirin were 69%, 33%, and 27% for Caucasians with the CC, CT, and TT genotypes, respectively; for black patients, the SVR rates were 48%, 15%, and 13%, respectively.8 For Caucasians and Asian patients, the T versus G allele at position rs8099917 provides similar information.9 The IL-28B genotype is also predictive of treatment outcomes for patients with non-1 HCV genotypes and for human immunodeficiency virus (HIV)/HCV-coinfected patients.10, 11 However, the predictive value of the genetic test is diminished in persons treated with HCV protease inhibitors. Among Caucasian patients with the CC, CT, and TT genotypes who were taking telaprevir, peginterferon, and ribavirin, SVR was achieved by 90%, 71%, and 73%, respectively (Fig. 1).12 Among Caucasian patients with the CC, CT, and TT genotypes who were taking boceprevir, peginterferon, and ribavirin, SVR was achieved by 80%, 71%, and 59%, respectively (Fig. 2).13

Figure 1.

SVR rates with peginterferon and ribavirin are higher for genotype 1 patients with a favorable IL-28B genotype (blue bars). Differences between IL-28B genotypes decrease for patients also taking HCV protease inhibitors (red and green bars). CC, CT, and TT refer to the respective alleles at rs12979860.12 Abbreviations: PR48, peginterferon and ribavirin for 48 weeks; T8PR, telaprevir for 8 weeks and peginterferon and ribavirin; T12PR, telaprevir for 12 weeks and peginterferon and ribavirin.

Figure 2.

The IL-28B CC genotype predicts SVR with BOC, peginterferon, and ribavirin. The odds of SVR were calculated for the subset of serine protease inhibitor therapy 2 registration trial patients whose IL-28B and treatment outcome data were available. For example, even after adjustments for the other factors shown, patients with a CC genotype were more than 4 times more likely to achieve SVR. All factors in the figure are statistically significant (P = 0.002 for age, P < 0.001 for all other factors).6, 13 Abbreviations: BOC, boceprevir; PR48, peginterferon and ribavirin for 48 weeks; RGT, response-guided therapy.

Differences in the responses to peginterferon and ribavirin have been reported in patients from different ethnic groups: Asians have the highest response rates, Caucasians have intermediate response rates, and patients of Latino or African ancestry have the lowest response rates.14, 15 These differences are strongly correlated with differences in the frequencies of favorable IL-28B alleles, and they appear to persist with at least the first generation of HCV protease inhibitors.6, 7, 16

The liver disease stage is also a determinant of the response to peginterferon and ribavirin. SVR was achieved by 81%, 75%, and 62% of genotype 1–infected patients taking peginterferon, ribavirin, and telaprevir who had minimal fibrosis, portal fibrosis, or bridging fibrosis/cirrhosis, respectively.7 Likewise, SVR was achieved by 67% and 41% to 52% of genotype 1–infected patients taking peginterferon, ribavirin, and boceprevir who had minimal to moderate fibrosis or bridging fibrosis/cirrhosis, respectively.6 In comparison with patients without cirrhosis, patients with HCV genotype 2 or 3 infections and cirrhosis had 15% and 21% lower SVR rates, respectively.4

Persons with insulin resistance may also have lower SVR rates than younger individuals without insulin resistance. The predictive value of insulin resistance varies, perhaps to some extent because of correlated factors such as a higher body mass index (BMI), steatosis, male sex, and older age. In a recent meta-analysis of 2732 patients treated with peginterferon and ribavirin, the estimated SVR rates were 20% lower for persons with insulin resistance (as determined by the homoeostasis model assessment).17 A high BMI is related to insulin resistance and typically is also associated with a lower response to peginterferon and ribavirin. In the boceprevir registration trial, a low BMI was associated with SVR in the control arm but not in the boceprevir arms.6 However, in the telaprevir registration trial, a higher SVR was seen with a low BMI in the telaprevir arms but not in the control arms.7

An HIV coinfection diminishes the response to peginterferon and ribavirin for all HCV genotypes (and probably IL-28B host genotypes). The lower SVR rates can be largely explained by the higher HCV viral loads of HIV/HCV-coinfected patients because the SVR rates are similarly high for patients with baseline HCV RNA levels < 800,000 IU/mL.1, 18 Studies are ongoing to assess the response of HCV genotype 1/HIV-coinfected persons to HCV protease inhibitors, peginterferon, and ribavirin.

Summary

The response to HCV treatment varies according to both viral and host factors. Although the predictive value of each factor differs in various studies and with different HCV treatments, the HCV genotype, baseline viral load, age, IL-28B genotype, race, liver disease stage, and HIV coinfection status remain potentially important determinants of the likelihood of SVR. By using the results for all these markers, providers can provide patients relatively precise estimates of their odds of being cured with today's standard of care.

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