Clinical Professor of Medicine
Department of Hepatology
Director
NYU Hepatology Associates - Plainview
New York University
Plainview, New York
Maximizing sustained virologic response (SVR) rates (an undetectable HCV RNA level 24 weeks after discontinuation of therapy) is the primary goal of therapy for patients with hepatitis C virus (HCV). This endpoint depends on numerous factors (Table), and adherence to therapy is one of the few variables that can be influenced by the patient and/or the healthcare team by using a multidisciplinary approach. Despite the known importance of treatment adherence in achieving viral eradication, adherence continues to be suboptimal, a fact underscored in a recent study demonstrating that only approximately 60% of patients with HCV in the United States adhered to prescribed therapy.[1] The dawn of a new era of HCV treatment is upon us with the anticipated approval of 2 novel direct-acting antivirals (DAAs) in the latter half of 2011. The addition of a DAA to the current standard of care regimen (peginterferon and ribavirin) enhances SVR rates and diminishes length of treatment in many patients.[2-5] However, issues of adherence will likely become even more significant, as the incidence of adverse events may rise, dosing schedules will become more complex, dietary requirements may be needed, and pill burden will increase. Furthermore, the lack of adherence to DAAs may select for HCV drug resistance mutations, a potentially serious consequence not present with the current standard of care regimen.
Table. Factors Affecting SVR Rates
Adherence Affects Response Rates
Suboptimal drug exposure of ribavirin and/or interferon has been demonstrated to result in reduced SVR rates in numerous studies of both treatment-naive and treatment-experienced patients.[6-10] Genotype 1 patients who were unable to complete ≥ 80% of the prescribed doses of both peginterferon and ribavirin ≥ 80% of the time had a 34% SVR rate vs a 51% SVR rate in those who completed > 80% of both drugs > 80% of the time.[7] Consistent with these findings, a retrospective analysis of 188 HCV-infected Veteran Affairs patients found that adherence to ≥ 85% of prescribed peginterferon plus ribavirin positively correlated with degree of viral suppression and ability to achieve early virologic response (defined as a ≥ 2 log reduction from baseline or undetectable serum HCV RNA at Week 12 of therapy).[10]
Ribavirin Adherence
Several studies have shown that suboptimal ribavirin dosing and/or adherence leads to lower response rates. Indeed, studies have demonstrated that exposure to weight-based ribavirin vs fixed-dose ribavirin is associated with improved early virologic response and SVR rates.[11,12] In addition, a retrospective analysis of 5 clinical trials concluded that patients with genotype 1 HCV exposed to > 13 mg/kg/day of ribavirin had a 2.15-times greater chance of achieving an undetectable HCV RNA by Week 4 (rapid virologic response [RVR]) vs patients exposed to < 13 mg/kg/day of ribavirin (Capsule Summary).[13] Furthermore, genotype 1 patients not achieving RVR were statistically significantly less likely to achieve SVR when cumulative ribavirin dose exposure (due to dose reduction, premature cessation, or skipped doses) was < 60%.[6] In a study by Bronowicki and colleagues,[14] Patients with genotype 1 HCV who discontinued ribavirin after achieving an undetectable HCV RNA by Week 24 were significantly less likely to achieve an SVR vs patients who continued their ribavirin therapy (52.8% vs 68.2%, respectively; P = .004). Finally, dose reduction of ribavirin during the initial 12-20 weeks of therapy has been associated with diminished SVR rates in genotype 1 patients.[7,15,16]
Whereas cumulative ribavirin dose exposure was found not to influence RVR and SVR in genotype 2 patients,[17] the importance of maintaining adequate doses of ribavirin throughout the entire course of treatment was emphasized by Andriulli and colleagues[18] who found that patients with genotype 2/3 HCV had a significantly diminished SVR (54% vs 82%) when ribavirin was discontinued by Week 6 of treatment, even if RVR was achieved (Capsule Summary).
The primary role of ribavirin in HCV treatment is to reduce the likelihood of relapse. Indeed, in an evaluation of 984 genotype 1 HCV–infected patients treated with peginterferon alfa-2b plus ribavirin, the degree of ribavirin exposure was found to be inversely correlated with relapse rates. Only 11% of patients receiving ≥ 12 mg/kg/day of ribavirin relapsed compared with 60% of those receiving < 6 mg/kg/day.[19] In addition, only 4% of patients with an early virologic response in this trial relapsed when exposed to ribavirin doses > 12 mg/kg/day, and ribavirin exposure beyond Week 12 continued to affect relapse rates, demonstrating that ribavirin is inversely dose dependent correlated with relapse in patients with genotype 1 HCV responding to peginterferon plus ribavirin. This study demonstrated the importance of adhering to a dose of ≥ 12 mg/kg/day of ribavirin during the entire treatment period, especially in patients achieving an early virologic response.
Despite these findings, ribavirin adherence continues to be a challenge that appears to be more difficult to overcome than interferon adherence.[20-22] The effect of simplifying ribavirin pill burden was assessed in 2 studies comparing adherence rates in HCV-infected patients treated with fewer, higher-dose ribavirin tablets—a 400-mg or 600-mg ribavirin tablet available in a unit dose blister pack—vs the traditional 200-mg bottled ribavirin tablets. Results from an observational study of 92 patients with HCV from a single center found that patients taking peginterferon with the more compact formulation of ribavirin allowing a reduced pill burden (same total dose) experienced fewer adverse events, improved quality of life, better adherence to prescribed HCV therapy, and a trend toward higher SVR rates vs patients taking peginterferon plus the standard dosing of ribavirin.[23] In the multicenter Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) study, patients who received their ribavirin in the form of the higher-dose tablets provided in a unit dose blister pack were less likely to prematurely stop therapy and more likely to adhere to prescribed HCV treatment at Weeks 12 and 24 compared with patients taking traditional 200-mg ribavirin tablets.[24] Streamlining ribavirin dosing regimens by decreasing pill count may become an even more important factor contributing to enhanced adherence once DAAs become part of HCV therapy, further increasing the regimen pill burden.
Assessment of Adherence
Although there is no gold standard of adherence measurement, it is important for all clinicians to incorporate strategies into their practices to assess adherence to prescribed HCV medications and to differentiate nonadherent patients from those who are truly nonresponders. Adherence analysis by a combination of patient self-report and electronic monitoring of the 401 patients who participated in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (VIRAHEP-C) trial revealed that patient self-report overestimates compliance, that adherence wanes over time, and that patients are more likely to miss doses of ribavirin than peginterferon.[20] When pharmacy refill data during the initial 12 weeks of treatment was retrospectively evaluated in 188 predominantly HCV-monoinfected US veterans, adherence to peginterferon was found to be better than adherence to ribavirin—a finding consistent with other adherence studies.[10] A prospective, real-life, observational study of genotype 2 and 3 patients revealed that by 3 months of treatment, 20% of HCV patients self-reported missing 1 peginterferon injection whereas approximately 28% of patients self-reported missing 1200-mg ribavirin within the previous 4-week treatment period and that missed dosages of both agents increased at 6 months of treatment.[21] Of importance, this study also demonstrated that adherence at 6 months was better in those receiving patient therapeutic education during the initial 12 weeks of therapy compared with those not receiving patient education.
Suboptimal Adherence Identification and Management
In addition to reinforcing the importance of treatment adherence to patients, identification of individuals at increased risk for adverse events and aggressive management of adverse events are also necessary components of good clinical care that will enhance patient outcomes.
More than 20% of patients must decrease dose, temporarily discontinue, or prematurely stop ribavirin and/or peginterferon because of adverse events.[16,25,26] However, certain subsets of individuals may have more difficulty tolerating treatment compared with others. Mitra and colleagues[1] found that patients with advanced disease are less likely to be adherent to HCV therapy than those with early disease, a finding likely related to an increased susceptibility to adverse events.[27] A recent study showed that 61% of HCV/HIV-coinfected women and 48% of coinfected men experienced adverse events requiring dose modification of standard of care therapy.[28] Whereas traditionally believed to be poor candidates for HCV treatment because of an increased likelihood of nonadherence and susceptibility to psychiatric adverse events associated with treatment, injection drug users, including active drug users, have been found to be adherent to treatment with comparable SVR rates so long as psychosocial support is supplied.[29-31]
Hepatitis C virus is more common among people with psychiatric conditions compared with the general population,[32] and psychiatric illness, in particular depression, has been found to be a risk factor for HCV medication nonadherence. Development of depression while receiving therapy, which has been noted to occur in between 20% to 35% of patients,[25,26] may lead to discontinuation or decrease in dosage of medication with a resultant negative impact on outcome.[33,34] Pretreatment with antidepressants, specifically paroxetine, has been shown to reduce the severity of depression while receiving treatment in individuals displaying depressive symptoms at baseline.[35] The initiation of citalopram after the onset of interferon-induced depression controlled symptoms and enabled patients to complete the full course of standard-of-care treatment.[36] Therefore, to improve adherence, practitioners must evaluate all HCV-infected patients at baseline and during therapy for psychiatric symptoms and initiate antidepressants or antipsychotics promptly, as needed.
Anemia is an adverse effect of both interferon and ribavirin, with a decrease of hemoglobin of > 3 g/dL occurring in more than one half of patients receiving standard-of-care treatment.[37] Anemia often results in dose reduction or discontinuation, particularly of ribavirin, which may negatively affect outcome, especially in patients with genotype 1 HCV.[25] Reduction of the incidence and severity of treatment-induced anemia with erythropoietin has been shown to encourage adherence and to enable patients to remain on higher doses of ribavirin.[37,38] In a prospective, randomized, controlled trial evaluating the effect of erythropoietin on SVR, it was demonstrated that erythropoietin improved quality of life and improved SVR rates in some—but not all—patients with HCV.[8] Rapid virologic response rates did not improve significantly in HCV/HIV-coinfected patients preemptively given erythropoietin.[39] However, in HCV-infected patients achieving a > 2 log decline in HCV RNA after 4 weeks of therapy, SVR rates were significantly improved when anemia was managed with erythropoietin vs ribavirin dose reductions (81.8% vs 45.0%, respectively).[40] Therefore, treatment with erythropoietin should be considered in specific patients as a tool for enhancing medication adherence and improving outcomes, with an eye toward avoiding overcorrection that may result in thrombotic events.[41]
Conclusion
Although great excitement exists surrounding the future of HCV treatment, it must be emphasized that the increased complexity of treatment regimens, coupled with an associated rise in incidence of adverse events and the risk for development of drug resistance, will require even greater attention to adherence issues. Since adherence to prescribed HCV medication has been shown to be enhanced by a combination of patient education, patient motivation, reduced pill burden, and careful and prompt adverse effect management, clinicians should consider a multidisciplinary team approach to assess and enforce adherence and to optimize HCV patient care.
Melissa Palmer, MD, has disclosed that she has received grants for research support from Bristol-Myers Squibb, Gilead Sciences, and Three Rivers Pharmaceuticals; has served as a consultant for Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals; and has received fees for non-CME services from Genentech, Gilead Sciences, Merck, and Three Rivers Pharmaceuticals.
References
1. Mitra D, Davis KL, Beam C, Medjedovic J, Rustgi V. Treatment patterns and adherence among patients with chronic hepatitis C virus in a US managed care population. Value Health. 2010;13:479-486.
2. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292-1303.
3. Suzuki F, Akuta N, Suzuki Y, et al. Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks. Hepatol Res. 2009;39:1056-1063.
4. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;[Epub ahead of print].
5. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology. 2007;132:1270-1278.
6. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124-129.
7. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.
8. Shiffman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103-112.
9. Raptopoulou M, Tsantoulas D, Vafiadi I, et al. The effect of adherence to therapy on sustained response in daily or three times a week interferon alpha-2b plus ribavirin treatment of naive and nonresponder chronic hepatitis C patients. J Viral Hepat. 2005;12:91-95.
10. Lo Re V 3rd, Amorosa VK, Localio AR, et al. Adherence to hepatitis C virus therapy and early virologic outcomes. Clin Infect Dis. 2009;48:186-193.
11. Bain VG, Lee SS, Peltekian K, et al. Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alfa-2a plus ribavirin. Aliment Pharmacol Ther. 2008; 28:43-50.
12. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971-981.
13. Rodriguez-Torres M, Sulkowski M, Chung RT, Hamzeh FM, Jensen DM. Association of pre-treatment and on-treatment factors with rapid virologic response in HCV genotype 1 infected patients treated with peginterferon alfa-2a/ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 1305.
14. Bronowicki JP, Ouzan D, Asselah T, et al. Effect of ribavirin in genotype 1 patients with HCV responding to pegylated interferon alfa a plus ribavirin. Gastroenterology. 2006;131:1040-1048.
15. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.
16. Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol. 2004;3:5-10.
17. Inoue Y, Hiramatsu N, Oze T, et al. Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses. J Viral Hepat. 2010;17:336-344.
18. Andriulli A, Cursaro C, Cozzolongo R, et al. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to peg-interferon alfa-2a and ribavirin. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 234.
19. Hiramatsu N, Oze T, Yakushijin T, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586-594.
20. Smith SR, Wahed AS, Kelley SS, Conjeevaram HS, Robuck PR, Fried MW. Assessing the validity of self-reported medication adherence in hepatitis C treatment. Ann Pharmacother. 2007;41:1116-1123.
21. Cacoub P, Ouzan D, Melin P, et al. Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: a prospective, real-life, observational study. World J Gastroenterol. 2008;14:6195-6203.
22. Weiss JJ, Bhatti L, Dieterich DT, et al. Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin. Aliment Pharmacol Ther. 2008;28:289-293.
23. Palmer M. Improvement in treatment adherence in patients with chronic hepatitis C. Practical Gastroenterology. 2008;32:31-42.
24. Alam I, Stainbrook T, Cecil B, Kistler KD. Enhanced adherence to HCV therapy with higher dose ribavirin formulation: final analyses from the ADHERE registry. Aliment Pharmacol Ther. 2010;32:535-542.
25. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa 2b plus ribavirin compared with interferon alfa 2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965.
26. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
27. Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:350-355.
28. Bhattacharya D, Umbleja T, Carrat F, et al. Women experience higher rates of adverse events during hepatitis C virus therapy in HIV infection: a meta-analysis. J Acquir Immune Defic Syndr. 2010;[Epub ahead of print].
29. Robaeys G, Van Vlierberghe H, Matheï C, et al. Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes. Eur J Gastroenterol Hepatol. 2006;18:159-166.
30. Bruggmann P, Falcato L, Dober S, et al. Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients. J Viral Hepat. 2008;15:747-752.
31. Melin P, Chousterman M, Fontanges T, et al. Effectiveness of chronic hepatitis C treatment in drug users in routine clinical practice: results of a prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:1050-1057.
32. Brunette MF, Drake RE, Marsh BJ, et al. Responding to blood-borne infections among persons with severe mental illness. Psychiatr Serv. 2003;54:860-865.
33. Raison CL, Broadwell SD, Borisov AS, et al. Depressive symptoms and viral clearance in patients receiving interferon-a and ribavirin for hepatitis C. Brain Behav Immun. 2005:19:23-27.
34. Sylvestre D. Treating hepatitis C in active substance users. Clin Infect Dis. 2005;40(suppl 5):S321-S324.
35. Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther. 2007;25:1163-1174.
36. Kraus MR, Schäfer A, Schöttker K, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut. 2008;57:531-536.
37. Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.
38. Afdhal NH. Role of epoetin alfa in maintaining ribavirin dose. Gastroenterol Clin North Am. 2004;33(1 suppl):S25-S35.
39. Vispo E, Labarga P, Guardiola JM, et al. Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C. AIDS Res Hum Retroviruses. 2010;26:419-424.
40. Falasca K, Ucciferri C, Mancino P, Gorgoretti V, Pizzigallo E, Vecchiet J. Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response. J Med Virol. 2010;82:49-56.
41. Fandrey J, Dicato M. Examining the involvement of erythropoiesis-stimulating agents in tumor proliferation (erythropoietin receptors, receptor binding, signal transduction), angiogenesis, and venous thromboembolic events. Oncologist. 2009;14(suppl 1):34-42.
Source
No comments:
Post a Comment