Sofosbuvir Plus Ledispasvir for Recurrent Hepatitis C in Liver Transplant Recipients

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1 ORIGINAL ARTICLE Sofosbuvir Plus Ledispasvir for Recurrent Hepatitis C in Liver Transplant Recipients Ryan M. Kwok, 1 Joseph Ahn, 2 Thomas D. Schiano, 3 Helen S. Te, 4 Darryn R. Potosky, 5 Amber Tierney, 6 Rohit Satoskar, 1 Suzanne Robertazzi, 1 Colleen Rodigas, 1 Michelle Lee Sang, 1 Joshua Wiegel, 2 Neal Patel, 3 Janet Gripshover, 5 Mohamed A. Hassan, 6 Andrea Branch, 3 and Coleman I. Smith 1 1 Medstar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC; 2 Oregon Health and Science University, Portland, OR; 3 Division of Liver Diseases and Recanati-Miller Transplant Institute, Mount Sinai Medical Center, New York, NY; 4 Center for Liver Diseases, Department of Medicine, The University of Chicago Medical Center, Chicago, IL; 5 Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; and 6 University of Minnesota Medical School, Minneapolis, MN Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is associated with worse outcomes. The combination of ledipasvir (LDV) and sofosbuvir (SOF) has been approved for HCV treatment after LT, but there are limited data on the effectiveness and safety of LDV/SOF in the real-world setting. This multicenter study is the largest report to date on the effectiveness and safety of LDV/SOF in the post-lt setting. A total of 204 patients (72% male, 68% Caucasian, 66% genotype [GT] 1a, 21% METAVIR F3-F4, 49% treatment-experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virological response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients, and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. In conclusion, SOF and LDV with or without RBV for 8, 12, or 24 weeks in post-lt patients was effective and safe with a high SVR12 rate across a spectrum of GTs and stages of fibrosis. Liver Transplantation AASLD. Received June 3, 2016; accepted August 8, SEE EDITORIAL ON PAGE 1463 Chronic hepatitis C virus (HCV) is a major global health issue with greater than 185 million affected Abbreviations: AE, adverse event; ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; DAA, direct-acting antiviral; egfr, estimated glomerular filtration rate; EOT, end of treatment; FDA, US Food and Drug Administration; GT, genotype; Hb, hemoglobin; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; LDV, ledipasvir; LT, liver transplantation; NS5A, nonstructural protein 5A; RBV, ribavirin; SAE, serious adverse event; SD, standard deviation; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; SVR12, sustained virological response rate 12 weeks after completion of therapy; ULN, upper limit of normal ORIGINAL ARTICLE worldwide. (1) HCV is a leading indication for liver transplantation (LT) due to its progressive risk of cirrhosis and hepatocellular carcinoma (HCC). Without HCV eradication prior to LT, recurrent HCV infection in the graft is nearly universal, (2) leading to graft loss in up to 60% and death in 50% of LT recipients, with mortality estimates as high as 60% 1 year after the initial decompensation. (2) When compared with non- HCV LT recipients, HCV LT recipients have a 23% increased risk of death and a 30% increased risk of graft failure. (3) Until recently, options for HCV treatment after LT were limited due to low efficacy and concerns regarding safety. Historically, post-lt HCV regimens used interferon (IFN) and ribavirin (RBV). These treatments were fraught with significant side effects as well as low sustained virological response (SVR) rates ranging from 25% to 33% even after weeks of therapy. (4,5) Introduced in 2011, direct-acting antiviral

2 LIVER TRANSPLANTATION, Vol. 22, No. 11, 2016 (DAA) protease inhibitors boceprevir and telaprevir modestly improved sustained virological response rate 12 weeks after completion of therapy (SVR12) rates to approximately 60%, when used in conjunction with pegylated IFN and RBV. (6) Since 2013, all-oral, IFNfree DAA agents, consisting of various combinations of NS5B (nonstructural protein 5B) polymerase inhibitors, NS3/4 (nonstructural proteins 3/4) protease inhibitors, and nonstructural protein 5A (NS5A) inhibitors, with or without RBV, have transformed the landscape of the hepatitis C treatment. In 2014, the combination of sofosbuvir (SOF; a nucleoside NS5B polymerase inhibitor) and ledipasvir (LDV; an NS5A inhibitor) was approved by the US Food and Drug Administration (FDA) for treatment of genotype (GT) 1 chronic HCV in non-lt patients. (7-9) In a registry study, Charlton et al. (10) demonstrated the efficacy and safety of either 12 or 24 weeks of LDV/ SOF and RBV in 229 GT 1 and GT 4 post-lt patients. SVR12 in patients with METAVIR score F0- F3 or compensated cirrhosis (Child-Turcotte-Pugh [CTP] A) patients was 95%-98%. Patients with decompensated cirrhosis (CTP B and C) had an SVR12 rate of 60%-88%. Six (100%) patients with fibrosing Address reprint requests to Ryan M. Kwok, M.D., Division of Gastroenterology and Hepatology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD Telephone: ; FAX: ; ryan.m.kwok.mil@mail.mil Thomas D. Schiano: Gilead Sciences research support, advisory board; Merck research support, advisory board; Intercept research support; Alexion advisory board; BMS advisory board. Helen S. Te: Gilead Sciences research support; Abbvie research support; Conatus research support; BMS advisory board; Intercept advisory board. Rohit Satoskar: Gilead Sciences speaker bureau, advisory board, research support; Merck research support. Suzanne Robertazzi: Gilead Sciences advisory board. Colleen Rodigas: Gilead Sciences advisory board. Janet Gripshover: Gilead Sciences speaker bureau, advisory board; Abbvie speaker bureau, advisory board; Merck speaker bureau; BMS speaker bureau, advisory board. Coleman I. Smith: Gilead Sciences speaker bureau, advisory board, research support; Abbvie speaker bureau, advisory board, research support; Merck advisory board, research support; Janssen speaker bureau, advisory board, research support speaker; BMS speaker bureau, advisory board, research support. Ryan M. Kwok, Joseph Ahn, Darryn R. Potosky, Amber Tierney, Michelle Lee Sang, Joshua Wiegel, Neal Patel, Mohamed A. Hassan, and Andrea Branch have no conflict of interests to report. Copyright VC 2016 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt cholestatic hepatitis experienced SVR12. Subsequently, the FDA approved LDV/SOF with RBV for 12 weeks for GT 1 and 4 post-lt patients. Despite these promising trial results, data on the real-world effectiveness and safety of these medications are limited. We report the results of our multicenter experience using LDV/SOF, with or without RBV, in the treatment of HCV recurrence after LT. Patients and Methods STUDY PATIENTS AND DESIGN LT patients with virologically confirmed, recurrent HCV who received treatment with LDV/SOF at 6 centers were enrolled in the study: Medstar Georgetown University Hospital, Washington, DC; The University of Chicago Medicine, Chicago, IL; Oregon Health and Science University Hospital, Portland, OR; University of Minnesota Medical Center, Minneapolis, MN; University of Maryland Medical Center, Baltimore, MD; and Mount Sinai Medical Center, New York, NY. Data examining the effectiveness and safety of the treatment were obtained and a priori approval was obtained by the institutional review board at each institution. Data were retrospectively obtained from each patient, and the protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the respective institutional review board. No donor organs were obtained from executed prisoners or other institutionalized persons. The treatment regimen included orally administered LDV 90 mg/sof 400 mg, with or without RBV (400 mg to 1200 mg per day), for 8, 12, or 24 weeks. Decisions regarding the duration of treatment, the use of RBV, and dose adjustments were made at the discretion of the treating provider. Immunosuppressive therapy was continued and adjusted per individual institutional protocol at the discretion of the treating provider. Patients were followed from October 2014 to January EFFECTIVENESS ASSESSMENTS Serum HCV RNA levels were quantified with a lower limit of quantification of 15 IU/mL. Hepatitis C RNA levels were measured prior to treatment, at variable time points throughout treatment, at the end of treatment (EOT), and variably within the 12 weeks ORIGINAL ARTICLE 1537

3 LIVER TRANSPLANTATION, November 2016 Characteristic TABLE 1. Baseline Demographic and Clinical Characteristics for Patients With SVR12 Data Value (n 5 162) Age, years Sex, male 116 (71) Race Caucasian 110 (68) African American 25 (15) Hispanic 14 (9) Asian 7 (4) Other 6 (4) Duration from LT (days) at start of treatment HCV GT 1a 112 (69) 1b 38 (23) 1 6 (4) 2 1 (1) 3 1 (1) 4 3 (2) 1 and 6 1 (1) Simultaneous renal transplant 15 (9) History of previous treatment None 82 (50) IFN 5 (3) Peg-IFN and RBV 14 (9) Peg-IFN and RBV with first-generation protease inhibitors 40 (25) Peg-IFN and RBV with SOF 2 (1) SOF plus SMV 10 (6) Other regimen 9 (6) METAVIR fibrosis stage* F0-F2 110 (68) F3-F4 33 (20) Unknown 19 (12) Immunosuppression Tacrolimus 136 (84) Cyclosporine 7 (4) Antimetabolite (mycophenolate mofetil, 51 (31) azathioprine) Mammalian target of rapamycin inhibitors 11 (7) (sirolimus, everolimus) Prednisone 16 (10) HCV RNA >6,000,000 IU/mL 37 (23) Baseline creatinine at treatment initiation Creatinine >2 mg/dl 7 (4) Creatinine >1.5 mg/dl 42 (26) NOTE: Data are given as mean 6 SD or n (%). serious adverse events (SAEs), graft dysfunction, and graft and patient survival were recorded. Results BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS A total of 204 LT recipients from 6 centers with documented recurrent HCV GTs 1, 3, 4, or 6 were treated with SOF/LDV with or without RBV for 8, 12, or 24 weeks. Demographic and clinical data are summarized in Table 1. To date, 79% (n 5 162) have had an SVR12 assessment. Of the patients achieving SVR12, 28% (n 5 45) were treated with LDV/SOF with RBV and of these 87% (n 5 39) were treated for 12 weeks. The remaining 13% (n 5 6) of patients treated with RBV were treated for 24 weeks. Of the SVR12 patients, 72% (n 5 117) were treated with SOF/LDV without RBV; 6% (n 5 7) of these patients were treated for 8 weeks, 59% (n 5 69) were treated for 12 weeks, and 35% (n 5 41) were treated for 24 weeks. VIROLOGICAL RESPONSE An EOT response of 99% (n 5 143/145) and SVR12 of 96% (n 5 156/162) was observed. Several patients achieving SVR12 did not have EOT response data available. Thus, we report an overall higher number of SVR12 patients versus EOT. Among patients treated with LDV/SOF with RBV, there was a 100% EOT and 98% SVR12 response. Those treated with LDV/ SOF without RBV had a 98% EOT and 96% SVR12 response. A comparison of SVR12 in patients treated with or without RBV is illustrated in Figs. 1 and 2. following the completion of therapy. The primary endpoint was the proportion of patients achieving undetectable HCV RNA SVR12. The secondary endpoint was the proportion of patients achieving undetectable HCV RNA at the EOT. SAFETY ASSESSMENTS Safety data were collected prior to initiation of medications, during treatment, and up to 12 weeks after the completion of treatment. Adverse events (AEs), IMMUNOSUPPRESSION Table 1 summarizes the immunosuppressive medication regimens. Immunosuppression was adjusted during treatment in 32% (n 5 65) of patients, with 72% (n 5 47/65) requiring a dose increase and 28% (n 5 18/65) requiring a dose reduction. After treatment completion, 16% (n 5 26) required an immunosuppression adjustment, with 77% (n 5 20/26) requiring a dose increase and 23% (n 5 6/26) requiring a dose reduction ORIGINAL ARTICLE

4 LIVER TRANSPLANTATION, Vol. 22, No. 11, 2016 FIG. 1. Sustained virological response rates (SVR12) among treatment groups. FIG. 2. SVR12 by treatment regimen, duration, and GT. ORIGINAL ARTICLE 1539

5 LIVER TRANSPLANTATION, November 2016 Event TABLE 2. AEs and Laboratory Abnormalities GRAFT LOSS/REJECTION Patients With Event (n 5 204) Any AE 65 (32) Any AE leading to discontinuation 4 (2) SAE Death 4 (2) Acute kidney injury 3 (1) Hyponatremia 1 (<1) Hyperkalemia 1 (<1) Encephalopathy 2 (1) Pancreatitis 1 (<1) Pneumonia 1 (<1) Bacteremia 1 (<1) Peritonitis 1 (<1) Pericarditis/Endocarditis 2 (1) Common AE Constitutional (fatigue, weight loss) 40 (20) Pulmonary (SOB [shortness of breath], cough) 4 (2) Cardiac (chest pain) 3 (1) Gastrointestinal (nausea, vomiting, 6 (3) diarrhea, abdominal pain) Musculoskeletal (joint or muscle pains) 2 (1) Neurological (headaches) 16 (8) Skin (rash) 5 (2) Psychiatric symptoms 1 (<1) Grade 3-4 chemical or hematologic abnormalities 18 (9) Hb <8 g/dl (RBV group) 3 (1) Hb <8 g/dl (non-rbv group) 7 (3) Total bilirubin >3 mg/dl 7 (3) Creatinine >3 mg/dl 2 (1) Baseline creatinine at treatment initiation mg/dl Creatinine >2 mg/dl 8 (4) ALT > 5 3 ULN 2 (1) Amylase and/or lipase >3 3 ULN 0 (0) NOTE: Data are given as mean 6 SD or n (%). One episode of mild biopsy-proven rejection (rejection activity index 5 4) occurred during treatment week 8 in 1 patient. An increase in tacrolimus resulted in normalization of liver enzymes and SVR12 was achieved. No graft losses occurred during HCV treatment. AEs/SAFETY was safe and well tolerated as shown by the safety data in Table 2. There were 4 deaths in this cohort (Table 3), none of which were assessed to be related to LDV/SOF. All patients had completed HCV treatment and achieved EOT response but died prior to collection of SVR12 laboratory tests. Four patients discontinued therapy prior to completion due to AEs (Table 4), and 1 patient discontinued due to loss of insurance coverage. Seven treatment failures were reported (Table 5). Four patients had undetectable HCV RNA either while on treatment, at EOT, or relapsed after achieving SVR12. Among these, 1 was attributed to nonadherence whereas the others had significant comorbidities such as human immunodeficiency virus (HIV), HCC, or simultaneous liver and kidney transplantation, which may have contributed to the reduction of treatment effectiveness. Discussion To date, this study of 204 participants is the largest published, multicenter, real-world experience with LDV/SOF with or without RBV in post-lt patients. We observed a remarkable overall EOT response of 99% and SVR12 rate of 96%, which are comparable to previously reported rates in clinical trials. 10 In addition to excellent overall effectiveness in this real-world setting, this study includes the largest RBV-free cohort reported to date in the post-lt setting. This group demonstrated a 98% EOT and 98% SVR12 rates, which is similar to those treated with RBV. Pungapapong et al. similarly concluded that the addition of RBV did not appear to increase virologic responsiveness in 25 GT 1 LT recipients treated with 12 weeks of SMV and SOF. 11 TABLE 3. Cause of Death Patient Characteristics Years Posttransplant GT METAVIR Fibrosis Stage Regimen Completion of EOT Virological Response* Cause of Death 63-year-old male 9 years 1b 2 SOF/LDV plus RBV 12 weeks Yes Undetectable HCV RNA Respiratory failure; new dx (diagnosis) of lung cancer 61-year-old male 10 years 1b 3 SOF/LDV plus Yes Undetectable HCV RNA Presumed sepsis RBV 12 weeks 64-year-old male 8 years 4 4 SOF/LDV 24 weeks Yes Undetectable HCV RNA Persistent Mitral Valve Endocarditis 73-year-old male 6 years 1a 2 SOF/LDV 12 weeks Yes Undetectable HCV RNA Cerebrovascular accident *SVR12 HCV RNA is not available. Liver kidney recipient ORIGINAL ARTICLE

6 LIVER TRANSPLANTATION, Vol. 22, No. 11, 2016 TABLE 4. Premature Discontinuation Patient Characteristics GT HCV RNA, IU/mL METAVIR Fibrosis Stage Planned Regimen Completed Weeks of Reason for Discontinuation Response Achieved 65-year-old male 1a SOF/LDV plus RBV for 24 weeks 47-year-old male 1b SOF/LDV for 12 weeks 67-year-old male 1a SOF/LDV for 12 weeks 73-year-old male 1a SOF/LDV plus RBV for 12 weeks 61-year-old female 1a SOF/LDV for 24 weeks 18 Recurrent major depressive symptoms leading to nonadherence SVR12 11 Elevated bilirubin and ALT which SVR12 normalized after discontinuation* 8 Intolerable neurologic SVR12 symptoms including headaches 8 Patient did not feel well Not available 16 Loss of insurance coverage EOT, No SVR12 data available * was discontinued and normalized after an elevation in ALT was noted. The patient was ultimately found to have a biliary stricture requiring stenting and has had progressive normalization of liver enzymes. The combination of LDV/SOF was well tolerated with a low rate of AEs. Two percent (n 5 5) of patients stopped medications prematurely due to AEs. This rate is similar to previously reported discontinuation rates with other DAA regimens. (12,13) Of these patients, 4 achieved undetectable EOT HCV RNA and 3 achieved SVR12 as well. Four deaths occurred after the completion of therapy and were deemed to be unrelated to LDV/SOF therapy (Table 3). No episodes of hepatic decompensation were observed during treatment. There was 1 occurrence of a mild, acute cellular rejection episode that responded to an increase in immunosuppression. Notably, this patient achieved SVR12. Significant laboratory abnormalities were seen in a small percentage of patients (9%), nearly half of which were due to anemia. Interestingly, the percentage of patients with hemoglobin (Hb) < 8 g/dl was similar between treatment regimens regardless of the use of RBV. Two patients who had pretreatment baseline creatinine levels > 2.5 mg/dl developed elevated creatinine levels > 3 mg/dl during treatment, supporting prior findings 10 that LDV/SOF has no clinically meaningful impact on creatinine clearance. However, data for the use of LDV/SOF are limited in patients with an estimated glomerular filtration rate (egfr) < 30 ml/ minute; thus, its use in patients with renal insufficiency is not recommended. (14) Although egfr was not TABLE 5. Failures Patient Characteristics GT Pretreatment HCV RNA, IU/mL Previous METAVIR Fibrosis Stage Regimen Comments 55-year-old male 1a na ıve 0 SOF/LDV 12 weeks HIV positive* 61-year-old male 1a SIM/SOF 12 weeks 0 SOF/LDV 12 weeks Worsening HCC 58-year-old male 1b na ıve 2 SOF/LDV 8 weeks Nonadherence 59-year-old female na ıve 4 SOF/LDV 12 weeks Simultaneous renal transplant with renal-related complications 64-year-old male na ıve 4 SOF/LDV 24 weeks GT 3 patients are historically more difficult to treat. SOF/ LDV is not currently recommended for GT 3 post-lt patients 57-year-old female 1 and na ıve 0 SOF/LDV 12 weeks Two GTs potentially more difficult to treat 62-year-old male 1b SOF/RBV 12 weeks 2 SOF/LDV 24 weeks Resistance *Patient achieved SVR12; however, he had positive HCV RNA at week 26. The patient s HIV was well controlled on antiretroviral therapy. No evidence of reinfection or other contributing factors were readily identifiable. Nonadherence was ascribed after failure to pick up the last refill of medications. The patient received 8 weeks of a 12-week planned course and was lost to follow-up. Patient was treated with 24 weeks of LDV/SOF without RBV and was ultimately found to have resistance to both LDV/SOF and ombitasvir/paritaprevir/ritonavir with dasabuvir. Further testing revealed drug resistance to NS5A (LDV and ombitasvir) with associated mutations to Y93H (an amino acid substitution [tyrosine to histidine at position 93] in the NS5a protein gene) detected. ORIGINAL ARTICLE 1541

7 LIVER TRANSPLANTATION, November 2016 recorded, 42 patients with baseline creatinine levels >1.5 mg/dl were treated with 79% (33/42) achieving SVR12. Because of the need for frequent monitoring and hematologic abnormalities associated with RBV, the appeal of a RBV-free regimen is apparent. Our data are promising for the prospect of a RBV-free regimen with near equal SVR12 rates when compared with a RBVcontaining regimen (96% versus 98%). On the basis of these findings, the necessity of RBV in treatment success in the post-lt setting appears to be unresolved. These findings warrant larger, prospective studies. Similarly appealing, 6 of the 7 (86%) patients who were treated with 8 weeks of LDV/SOF achieved SVR12. The single patient who failed treatment was determined to be noncompliant and received only 8 weeks of a 12-week planned course. SVR12 data were not available because he was lost to follow-up and was considered a treatment failure. Among the patients receiving 8 weeks of LDV/ SOF, 1 patient was treatment experienced and had cirrhosis, and 1 patient had a HCV viral load >6 million IU/mL. Both patients achieved SVR12. At least 3 patients received only 8 of 12 weeks of the treatment planned because of insurance issues, intolerance, and nonadherence. For the remaining patients, treatment regimen and duration were made at the discretion of the treating providers with reasons cited relating to relatively low viral load and favorable GTs. In our study, the majority of treatment failures were associated with difficult-to-treat GTs, significant comorbidities, and nonadherence. One patient had a mixed GT (GTs 1 and 6) in which the current recommendations are for either awaiting a pangenotypic regimen or treating to maximize efficacy against each GT represented. (14) The other patient had GT 3 which has historically been challenging to treat (15) and for which current guidelines do not recommend treatment with LDV/ SOF. 13 Three patients had significant comorbidities which may have contributed to treatment failure, including HIV coinfection, progressive HCC, and renal insufficiency after a combined liver and kidney transplant. Concern for traumatic brain injury or substance abuse was raised in the case of the participant with nonadherence with medications. One case of drug resistance to both LDV/SOF and ombitasvir/paritaprevir/ritonavir with dasabuvir was observed. Further testing revealed drug resistance to NS5As (LDV and ombitasvir) with polypmorphisms of Y93H detected. This is assumed to be treatment emergent because the patient had only been previously treated with SOF/RBV. However, no pretreatment resistance testing was performed. Several limitations must be considered when interpreting this report. Because of the real-world nature of this study, there is considerable heterogeneity in the treatment regimen, including length of treatment, use of RBV, and time from LT for HCV treatment initiation. Baseline characteristics including the degree of fibrosis, hepatic decompensation, and previous treatment experience also varied widely. Given the low numbers of treatment failures and relapse, conclusions regarding factors leading to treatment failures are difficult to make. Although prior investigators have shown a clear decrement in SVR12 rates with decompensated cirrhosis (CTP Class B and C) (13) and advanced fibrosis, 10 no such association can be made from this study. In summary, LDV/SOF, with or without RBV, for 8, 12, or 24 weeks demonstrated an SVR12 rate of 96% in LT patients with recurrent HCV infection across a spectrum of GTs. This regimen was well tolerated with a small rate of SAEs or complications. response to a RBV-free regimen was excellent and was similar to those treated with RBV. Furthermore, no difference was seen in SVR12 rates between these groups based on the length of treatment. In conclusion, the combination of LDV/SOF with or without RBV appears to be effective and safe for the treatment of recurrent HCV in post-lt patients, in the real-world setting. Further studies to refine the optimal patient population and treatment regimen should be considered. Acknowledgements: We thank Mr. Alfred Wang (Rockville, MD) for providing support with information technology and Dr. Manish Singla (Walter Reed National Military Medical Center, Bethesda, MD) for providing support with generating the graphs. We thank Dr. Mary Kwok (Walter Reed National Military Medical Center, Bethesda, MD) for providing support during this study. REFERENCES 1) Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. 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