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Original Research |

Pegylated Interferon-α2a With or Without Low-Dose Ribavirin for Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Receiving Hemodialysis: A Randomized Trial

Chen-Hua Liu, MD; Chung-Feng Huang, MD; Chun-Jen Liu, MD, PhD; Chia-Yen Dai, MD, PhD; Cheng-Chao Liang, MD, MS; Jee-Fu Huang, MD, PhD; Peir-Haur Hung, MD; Hung-Bin Tsai, MD; Meng-Kun Tsai, MD; Shih-I Chen, MD; Jou-Wei Lin, MD, PhD; Sheng-Shun Yang, MD, PhD; Tung-Hung Su, MD; Hung-Chih Yang, MD, PhD; Pei-Jer Chen, MD, PhD; Ding-Shinn Chen, MD; Wan-Long Chuang, MD, PhD; Ming-Lung Yu, MD, PhD; and Jia-Horng Kao, MD, PhD
[+] Article and Author Information

From National Taiwan University Hospital and College of Medicine and Far Easter Memorial Hospital, Taipei; Kaohsiung Medical University and Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung; Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi; Buddhist Tzu Chi General Hospital, Chiayi County; and Taichung Veterans General Hospital, Taichung, Taiwan.

Acknowledgment: The authors thank the nurses and patients involved in the study; Ching-Chuan Chen for central block randomization management; Hui-Ju Lin, Yu-Lin Tan, and Po-Chung Liu for clinical data management; Wan-Ting Yang for host genetic analyses; Yu-Sheng Chiu, PhD, for virology analyses; and the 4th Core Lab of National Taiwan University for instrumental support.

Grant Support: By the National Taiwan University Hospital and the National Center of Excellence for Clinical Trial and Research (NCTRC200721) and the National Science Council and Department of Health, Executive Yuan, Taiwan (NSC 100-2314-B-002-137-MY2).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0989.

Reproducible Research Statement: Study protocol and statistical code: Available from Dr. C.H. Liu (e-mail, jacque_liu@mail2000.com.tw). Data set: Not available.

Requests for Single Reprints: Jia-Horng Kao, MD, PhD, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan South Road, Taipei 10002, Taiwan; e-mail, kaojh@ntu.edu.tw.

Current Author Addresses: Drs. C.H. Liu, C.J. Liu, M.K. Tsai, T.H. Su, H.C. Yang, and D.S. Chen: National Taiwan University Hospital, Chung-Shan South Road, Taipei 10002, Taiwan.

Dr. C.F. Huang: Kaohsiung Medical University and Kaohsiung Municipal Ta-Tung Hospital, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.

Drs. C.Y. Dai, J.F. Huang, W.L. Chuang, and M.L. Yu: Kaohsiung Medical University, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.

Dr. C.C. Liang: Far Eastern Memorial Hospital, Nan-Ya South Road, Taipei 220, Taiwan.

Dr. P.H. Hung: Chiayi Christian Hospital, Jhong-Siao Road, Chia-Yi, 60002 Taiwan.

Dr. H.B. Tsai: Buddhist Tzu Chi General Hospital, Min-Sheng Road, Chiayi County 622, Taiwan.

Drs. S.I. Chen and J.W. Lin: National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin Road, Yun-Lin 640, Taiwan.

Dr. S.S. Yang: Taichung Veterans General Hospital, Taiwan Boulevard, Taichung, 40705, Taiwan.

Drs. P.J. Chen and J.H. Kao: National Taiwan University Hospital and College of Medicine, Chung-Shan South Road, Taipei 10002, Taiwan.

Author Contributions: Conception and design: C.H. Liu, C.J. Liu, C.Y. Dai, M.K. Tsai, J.W. Lin, D.S. Chen, M.L. Yu, J.H. Kao.

Analysis and interpretation of the data: C.H. Liu, C.J. Liu, C.C. Liang, J.F. Huang, J.W. Lin, D.S. Chen, M.L. Yu, J.H. Kao.

Drafting of the article: C.H. Liu, C.J. Liu, C.Y. Dai, J.W. Lin, M.L. Yu, J.H. Kao.

Critical revision of the article for important intellectual content: C.H. Liu, C.J. Liu, W.L. Chuang, M.L. Yu.

Final approval of the article: C.H. Liu, C.J. Liu, C.Y. Dai, P.H. Hung, J.W. Lin, H.C. Yang, W.L. Chuang, M.L. Yu, J.H. Kao.

Provision of study materials or patients: C.H. Liu, C.J. Liu, J.F. Huang, H.B. Tsai, M.K. Tsai, S.I. Chen, T.H. Su, S.S. Yang, H.C. Yang, P.J. Chen, W.L. Chuang, M.L. Yu, J.H. Kao.

Statistical expertise: C.H. Liu, J.W. Lin.

Obtaining of funding: C.H. Liu, C.J. Liu, M.L. Yu, J.H. Kao.

Administrative, technical, or logistic support: P.J. Chen, J.W. Lin, M.L. Yu, J.H. Kao.

Collection and assembly of data: C.H. Liu, C.F. Huang, C.J. Liu, C.Y. Dai, C.C. Liang, J.F. Huang, P.H. Hung, H.B. Tsai, W.L. Chuang, M.L. Yu, J.H. Kao.


Ann Intern Med. 2013;159(11):729-738. doi:10.7326/0003-4819-159-11-201312030-00005
Text Size: A A A

Background: Data are limited on the efficacy and safety of pegylated interferon plus ribavirin for patients with hepatitis C virus genotype 1 (HCV-1) receiving hemodialysis.

Objective: To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis.

Design: Open-label, randomized, controlled trial. (ClinicalTrials.gov: NCT00491244)

Setting: 8 centers in Taiwan.

Patients: 205 treatment-naive patients with HCV-1 receiving hemodialysis.

Intervention: 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102).

Measurements: Sustained virologic response rate and adverse event–related withdrawal rate.

Results: Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001). More patients receiving combination therapy had hemoglobin levels less than 8.5 g/dL than those receiving monotherapy (72% vs. 6%; risk difference, 66% [CI, 56% to 76%]; P < 0.001). Patients receiving combination therapy required a higher dosage (mean, 13 946 IU per week [SD, 6449] vs. 5833 IU per week [SD, 1169]; P = 0.006) and longer duration (mean, 29 weeks [SD, 9] vs. 18 weeks [SD, 7]; P = 0.004) of epoetin-β than patients receiving monotherapy. The adverse event–related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, −3% to 9%]).

Limitation: Open-label trial; results may not be generalizable to patients on peritoneal dialysis.

Conclusion: In treatment-naive patients with HCV-1 receiving hemodialysis, combination therapy with pegylated interferon plus low-dose ribavirin achieved a greater sustained virologic response rate than pegylated interferon monotherapy.

Primary Funding Source: National Center of Excellence for Clinical Trial and Research.

Figures

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Figure 1.

Study flow diagram.

HBV = hepatitis B virus; HCV = hepatitis C virus.

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Figure 2.

Change in hemoglobin levels in treated patients from baseline to the end of follow-up.

There were significant group differences for hemoglobin levels at week 4 of treatment (P < 0.001) and week 4 posttreatment follow-up (P < 0.001). Tx = treatment; FU = follow-up.

* The on-treatment hemoglobin levels for patients who prematurely discontinued treatment due to adverse events, no response, or viral breakthrough were assessed until the last on-treatment visit. The off-therapy hemoglobin levels for patients who were lost to complete follow-up were assessed until the last off-therapy visit.

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Appendix Figure.

Hemoglobin levels in treated patients from baseline to the end of follow-up.

There were significant group differences for hemoglobin levels at week 8 of treatment (P < 0.001) and week 4 posttreatment follow-up (P < 0.001). Tx = treatment; FU = follow-up.

* The on-treatment hemoglobin levels for patients who prematurely discontinued treatment due to adverse events, no response, or viral breakthrough were assessed until the last on-treatment visit. The off-therapy hemoglobin levels for patients who were lost to complete follow-up were assessed until the last off-therapy visit.

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Triple therapy for treatment of hepatitis C virus in hemodialysis patients is possible and efficient
Posted on December 17, 2013
Sara Lemoinne, MD Benoit Barrou, MD Dominique Thabut, MD
Marie Curie University
Conflict of Interest: None Declared
Cure of hepatitis C virus (HCV) infection is crucial in hemodialysis patients who are awaiting kidney transplantation. HCV infection is associated with decreased survival both before and after kidney transplantation (1). However, interferon treatment after transplantation is contraindicated because of a high risk of acute rejection. In the present issue, Liu and colleagues reported results of a randomized trial comparing the efficacity and safety of pegylated interferon plus low-dose ribavirin versus pegylated interferon monotherapy in 205 treatment-naïve HCV patients undergoing hemodialysis. The authors concluded that the virologic response was greater with the combination therapy than monotherapy. However, the rate of sustained virologic response with the combined therapy was only 64%. Protease inhibitors have significantly improved the viral response in patients with genotype 1 HCV infection, but no data are available for patients with end-stage renal disease (ESRD) (2). Recently, the pharmacokinetic properties of the protease inhibitor boceprevir were found similar in ESRD patients and healthy controls (3). A recent study found early rapid viral response in 3 of 4 patients on hemodialysis after 12 weeks of triple therapy with peginterferon alfa-2a, ribavirin and telaprevir (4). In our center, we have started to administer triple therapy with protease inhibitors to hemodialysis patients.
Here, we report on our experience by describing the first case of cured HCV infection with triple therapy with peginterferon, ribavirin and boceprevir in a kidney transplantation candidate on hemodialysis.
Case report
A 49-year-old male candidate for kidney transplantation undergoing hemodialysis for 17 years was referred because of chronic HCV infection (genotype 1a, IL28B:C/T) in August 2011. Liver biopsy disclosed advanced fibrosis. One year previously, he had received anti-viral treatment with adapted doses for hemodialysis (peginterferon alfa-2a, 180 µg/week, and ribavirin, 200 mg/day), which was stopped because of breakthrough at month 5. In October 2011, triple therapy was started with peginterferon alfa-2a, ribavirin and boceprevir (800 mg/8 hr). The baseline viral load was 5.73 log IU/ml. Four weeks later, HCV RNA levels were undetectable. The triple therapy was continued for 9 months, followed by peginterferon and ribavirin until October 2012. Adverse effects were asthenia and grade 3 anemia, which required an increased dose of erythropoetin and transfusion of one unit of blood. The patient achieved sustained virological response 24 weeks after the end of therapy. He is now a candidate for kidney transplantation and the HCV infection is cured.
Our positive results should encourage the use of such therapy for ESRD patients, especially those with advanced fibrosis who are awaiting kidney transplantation.
References
1. Scott DR, Wong JK, Spicer TS, Dent H, Mensah FK, McDonald S, et al. Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand. Transplantation. 2010;90(11):1165-71.
2. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207-17.
3. Treitel M, Marbury T, Preston RA, Triantafyllou I, Feely W, O'Mara E, et al. Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function. Clin Pharmacokinet. 2012;51(9):619-28.
4. Dumortier J, Guillaud O, Gagnieu MC, Janbon B, Juillard L, Morelon E, et al. Anti-viral triple therapy with telaprevir in haemodialysed HCV patients: Is it feasible? J Clin Virol. 2013;56(2):146-9.


Cart Before the Horse
Posted on January 30, 2014
David Padua, MD, Sammy Saab, MD, MPH
University of California at Los Angeles
Conflict of Interest: None Declared
We read with great interest the manuscript by Liu et al (1). The study adds to an increasing body of literature assessing the cost-effective studies in viral hepatitis, with over 90% of cost effective studies in viral hepatitis have shown favorable results (2). Hepatitis C is indeed a medical and public health concern. Not only is does it appear that the prevalence of hepatitis C has been underestimated, but hepatitis C is now responsible for more deaths in this country than HIV (3,4). Indeed, results of a recent pharmacoeconomic study by the Centers of Disease and Control Prevention suggest that screening of members of the baby-boomer generation to be cost-effective (5).
The current results of the study by Liu et al demonstrating that protease inhibitors are not cost-effective are refreshing (1). The study is timely as the hepatitis C protease inhibitors have been approved just within the past 12 months. However, this rapid publication may also highlight several deficiencies in basing cost effective studies on published effectiveness without clinical attribute. As it is understood, cost effective studies require reasonable data (published or assumed) on costs and efficacy. In their model, we did not find inference to the use of growth factors. Indeed, in the clinical trial using boceprevir, almost 50% of treated patients received erythropoietin (6,7). The use of these additional treatments will certainly add to the costs of treatment. The use of growth factors with boceprevir will likely become controversial with the recent data highlighting that growth factors do not necessarily result in improves sustained viral results (8). Additionally, transfusions and erythropoietin use in patients treated with telaprevir have been reported to be higher in a large observational study than that reported in the clinical trials (9).
Moreover, we found the authors baseline comparison using the IL28b genotype to be out of touch with current standard of care. The updated American Association for the Study of Liver Diseases (AASLD) guidelines recommend the antiviral therapy for hepatitis C genotype 1 should consist of a pegylated interferon, ribavirin, and a protease inhibitor (Class 1, Level A) (10). However, the authors are incorrect that the guidelines state that the IL28b may be used in the decision whether or not to incorporate protease inhibitors with the use of pegylated interferon and ribavirin. Rather, the AASLD guidelines suggest that IL28b genotype may provide information on the likelihood of achieving a sustained viral response and the shorter treatment duration (Class 2a, Level B). Consideration of a only using pegylated interferon and ribavirin in naïve patients without cirrhosis should be decided according to United Kingdom consensus guidelines only in the context of other parameters such as complete viral suppression after one month of dual therapy (10). The AASLD guidelines state that if this information affects a patient’s decision of whether or not to be treated, careful consideration should be taken as there is insufficient data to determine whether IL28b testing can appropriately risk stratify treatment regimens with or without protease inhibitors (11).
We urge caution on early introduction of pharmacoeconomic data before sufficient information is available on not only efficacy, but costs. It is important not to put the cart before the horse.


References
1. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C. A cost-effectiveness analysis. Ann Intern Med. 2012; 156:271-90.

2. Saab S, Choi YM, Rahal H, Li K, Tong J. Trends in Reporting Viral Hepatitis Cost-Effectiveness Study Results. Am J Managed 2012 (in review).

3. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011; 31:1090-101.

4. Ly KN, Xing J, Klevens M, Jiles RB, Ward JW, Holmberg SC. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-279.

5. Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012. 156:263-270.

6. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-217.

7. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkoski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

8. Poordad F, Lawitz EJ, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, et al. Randomized trial comparing ribavirin dose reduction versus erythropoietin for anemia management in previously untreated patients with chronic hepatitis C receiving boceprevir plus peginterferon/ribavirin. 47th Annual Meeting of the European Association for the Study of Liver Diseases. 2012. Abstract 1419.

9. Hezode C, Dorival C, Zoulim F, de Ledinghen V, Poynard T, Mathurin P, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. First results of the French Early Access Program in real-time setting. Global Antiviral Journal. HEP DART 2011; 7;Suppl 1:54.

10. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-44.

11. Ramachandran P, Fraser A, Agarwal K, Austin A, Brown A, Foster GR, et al. UK Consensus guidelines for the use of the protease inhibitors boceprevir and Telaprevir genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012; 35:647-62.

Author's Response
Posted on February 10, 2014
Chen-Hua Liu, MD, Jia-Horng Kao, MD, PhD
National Taiwan University Hospital
Conflict of Interest: Potential Conflict Jia-Horng Kao: consultant for Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche; on speaker’s bureau for Abbott, Roche, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Novartis.
In response
We appreciate Lemoinne et al.’s report on the successful retreatment by boceprevir-based triple therapy in one patient with hepatitis C virus (HCV) infection (genotype 1a, IL-28B: C/T) receiving hemodialysis who failed previous dual therapy, and their comments on the possibility of treating such patients with triple therapy. In line with our findings, their patient had a low probability to achieve sustained viral response (SVR) by dual therapy in terms of male sex, advanced hepatic fibrosis and unfavorable IL-28B genotype.
A previous small-scale study reported that telaprevir-based triple therapy had higher SVR rates than dual therapy in treatment-naïve HCV genotype 1 patients receiving hemodialysis. However, those who received triple therapy had more hematologic toxicity, skin rash, and dysgeusia (1). Data are limited with regard to previously treated HCV patients receiving hemodialysis, except for one study on those who relapsed to pegylated or standard interferon α-2a monotherapy (2). On the basis of Lemoinne et al.’s case report, the efficacy and safety of triple therapy were fair to retreat HCV genotype 1 patients who failed previous dual therapy. Compared with patients receiving dual therapy, the practicing physicians should be aware of the increased risks of severe anemia by telaprevir or boceprevir-based triple therapy, especially in those receiving hemodialysis (3). Furthermore, the universal triple therapy would be only cost-effective when the least-expensive protease inhibitor is used for patients with advanced fibrosis (4). Therefore, the value of telaprevir or boceprevir-based triple therapy in this special clinical setting needs to be confirmed by larger studies.
Recently, the newer generation of direct-acting antiviral agents (DAAs), either in interferon-containing or interferon-free regimens, shows excellent safety and efficacy to treat patients with HCV infection. Nevertheless, the pharmacokinetic profiles of these novel agents in patients receiving hemodialysis remain scanty (5). The optimized use of these DAAs in HCV patients receiving hemodialysis awaits further well-designed clinical studies.



References:
1. Basu PP, Siriki R, Shah NJ, Farhat S, Mittimanni K, Atluri S, et al. Telaprevir with adjusted dose of ribavirin in naïve CHC-G1: efficacy and treatment in CHC in hemodialysis population. TARGET-C (RCT). Presented at the 47th Annual Meeting of the European Association for the Study of the Liver, 26 April 2013, Amsterdam, the Netherlands. J Hepatol. 2013;58 (Suppl 1):S30-1.
2. Liu CH, Liang CC, Liu CJ, Tsai HB, Hung PH, Hsu SJ, et al. Pegylated interferon alfa-2a plus low dose ribavirin for the retreatment of dialysis chronic hepatitis C patients who relapsed from prior interferon monotherapy [Letter]. Gut. 2009;58:314-6. [PMID: 19136527]
3. Chou R, Hartung D, Rahman B, Wasson N, Cottrell EB, Fu R. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med. 2013;158:114-23. [PMID: 23437439]
4. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med. 2012;156:279-90. [PMID: 22351713]
5. Cornpropst MT, Denning JM, Clemons D, Marbury TC, Alcorn H, Smith WB, et al. The effect of renal impairment and end stage renal disease on the single dose pharmacokinetics of PSI-7977. Presented at the 46th Annual Meeting of the European Association for the Study of the Liver, 21 April 2012, Barcelona, Spain. J Hepatol. 2012;56 (Suppl 2):S433.
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Summary for Patients

Pegylated Interferon With or Without Ribavirin for Patients With Hepatitis C Receiving Hemodialysis

The full report is titled “Pegylated Interferon-α2a With or Without Low-Dose Ribavirin for Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Receiving Hemodialysis. A Randomized Trial.” It is in the 3 December 2013 issue of Annals of Internal Medicine (volume 159, pages 729-738). The authors are C.H. Liu, C.F. Huang, C.J. Liu, C.Y. Dai, C.C. Liang, J.F. Huang, P.H. Hung, H.B. Tsai, M.K. Tsai, S.I. Chen, J.W. Lin, S.S. Yang, T.H. Su, H.C. Yang, P.J. Chen, D.S. Chen, W.L. Chuang, M.L. Yu, and J.H. Kao.

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