REVIEW REVIEW
Predicting the Response to the Treatment of Hepatitis C Virus Infection David L. Thomas, M.D.
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.
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 riba-
virin 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 30 kg/m2
B44PR48
PR48
63 70
35 40
85
64
63
33
69 65
52 34
68 53
40 23
67 52
38 38
67 65 66
47 33 33
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.
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 47
Clinical Liver Disease, Vol. 1, No. 2, April 2012
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 ¼ 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.
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 Differences in the responses to peginterferon and ribavirin have been reported in patients from different ethnic groups:
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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
References 1. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355. 2. Derbala M, Amer A, Bener A, Lopez AC, Omar M, El Ghannam M. Pegylated interferon-alpha 2b-ribavirin combination in Egyptian patients with genotype 4 chronic hepatitis. J Viral Hepat 2005;12:380-385. 3. Legrand-Abravanel F, Sandres-Saune K, Barange K, Alric L, Moreau J, Desmorat P, et al. Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin. J Infect Dis 2004;189:1397-1400.
Thomas
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 IL28B 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. n CORRESPONDENCE David L. Thomas, MD., Johns Hopkins School of Medicine, Suite 437, 1830 Monument Street, Baltimore, MD 21205. E-mail:
[email protected] feron-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41: 1105-1109. 10. Labarga P, Soriano V, Caruz A, Poveda E, Di LF, Hernandez-Quero J, et al. Association between IL28B gene polymorphisms and plasma HCV-RNA levels in HIV/HCV-co-infected patients. AIDS 2011;25:761-766. 11. Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, Patel K, et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology 2010;139:821-827. 12. Jacobson IM, Catlett I, Marcellin P, Bzowej NH, Muir AT, Adda N, et al. Telaprevir substantially improves SVR rates across all IL28b genotypes in the advanced trial. J Hepatol 2011;54:S1369.
4. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124-134.
13. Poordad F, Bronowicki JP, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski M, et al. IL28b polymorphism predicts virological response in patients with chronic hepatitis C genotype 1 treated with boceprevir (BOC) combination therapy. J Hepatol 2011;54:S12.
5. Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, et al. Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatmentnaive chronic hepatitis C genotype 6. Hepatology 2010;52:1573-1580.
14. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-2271.
6. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206.
15. Rodriguez-Torres M, Jeffers LJ, Sheikh MY, Rossaro L, Ankoma-Sey V, Hamzeh FM, et al. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med 2009;360:257-267.
7. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-2416.
16. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461:798-801.
8. Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120-129.
17. Deltenre P, Louvet A, Lemoine M, Mourad A, Fartoux L, Moreno C, et al. Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis. J Hepatol 2011;55:1187-1194.
9. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated inter-
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18. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-450.
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