The Medical Letter. on Drugs and Therapeutics. Volume 59 October 9, Mavyret and Vosevi Two New Combinations for Chronic HCV Infection...

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1 The Medical Letter on Drugs and Therapeutics Volume 59 ISSUE ISSUE No Volume 56 IN THIS ISSUE Mavyret and Vosevi Two New Combinations for Chronic HCV Infection...p 166 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc. publications are protected by U.S. and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with U.S. and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter on Drugs and Therapeutics Volume 59 Take CME Exams Mavyret and Vosevi Two New Combinations for Chronic HCV Infection The FDA has approved Mavyret (Abbvie) and Vosevi (Gilead), two new fixed-dose combinations of direct-acting antiviral (DAA) drugs, for treatment of chronic hepatitis C virus (HCV) infection caused by any of the six major HCV genotypes in patients without cirrhosis or with compensated cirrhosis. Both are approved for use in treatment-experienced patients. Mavyret is also approved for treatmentnaive patients. HCV GENOTYPES HCV genotype 1 accounts for about 75% of HCV infections in the US, genotypes 2 and 3 account for about 20-25% of infections, genotype 4 for about 6%, and genotypes 5 and 6 for 1%. Genotype testing is recommended to determine the optimal treatment regimen. TREATMENT OPTIONS FOR DAA-EXPERIENCED PATIENTS Treatment of chronic HCV infection with DAAs results in sustained virologic response Table 1. Treatment Options for DAA-Experienced Patients 1 Previously Regimen Failed DAA 2 Genotype Ledipasvir/sofosbuvir (Harvoni) Sofosbuvir 1 ± RBV NS3/4A PI 1 Sofosbuvir/velpatasvir (Epclusa) Sofosbuvir 1b, 2 NS3/4A PI 1 Elbasvir/grazoprevir (Zepatier) NS3/4A PI 1 + RBV Sofosbuvir/velpatasvir/ NS5A inhibitor 1, 3, 4, 5, 6 voxilaprevir (Vosevi) Sofosbuvir 1a, 3, 4, 5, 6 ± RBV NS3/4A PI 3, 4, 5, 6 Glecaprevir/pibrentasvir NS5A inhibitor 1 (Mavyret) Sofosbuvir 1, 2 NS3/4A PI 1 DAA=Direct-acting antiretroviral; HCV=hepatitis C virus; PI=protease inhibitor; RBV=ribavirin 1. Adapted from HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Available at Accessed September 28, With or without peginterferon/ribavirin or ribavirin. Patients without cirrhosis or with compensated cirrhosis. (SVR) rates of >90% in treatment-naive patients and in those previously treated with peginterferon/ ribavirin. Treatment options are limited for patients who do not respond to a DAA-based regimen. The choice of drugs depends on the patient's HCV genotype, the regimen(s) tried previously, and the presence or absence of cirrhosis; testing for resistance-associated substitutions should be considered. 1 Pronunciation Key Glecaprevir : glek a' pre vir Mavyret: mav' ih reht Pibrentasvir : pi brent' as vir MAVYRET Mavyret contains two new drugs: glecaprevir, an HCV NS3/4A protease inhibitor, and pibrentasvir, an NS5A inhibitor. Clinical Studies Approval of Mavyret was based on the results of clinical trials of 8-16 weeks duration in treatment-naive and -experienced HCV-infected patients without cirrhosis or with compensated cirrhosis, only a few of which have been published. 2-4 The results are summarized in Table 2. In addition to the trials listed in Table 2, 104 treatment-naive and -experienced patients with chronic HCV infection (genotypes 1-6) and stage 4 or 5 chronic kidney disease, without cirrhosis or with compensated cirrhosis, received Mavyret for 12 weeks in an unpublished, open-label, single-arm trial (EXPEDITION-4; sum marized in the package insert). The overall sustained virologic response rate at 12 weeks after the end of treatment (SVR12) was 98%. No dosage adjustments were necessary during the trial. Adverse Effects The most common adverse effects of Mavyret in clinical trials were headache (13%), fatigue (11%), and nausea (8%). The labels of all DAA drugs used for treatment of HCV infection include a boxed warning about a risk of hepatitis B virus reactivation associated with their use. 5 Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org 166

3 Table 2. Mavyret Clinical Trials SVR12 Trial Genotype (n) Duration Rate 1 Treatment-Naive or PRS-Experienced without Cirrhosis ENDURANCE-1 1 (n=351) 8 weeks 99% SURVEYOR-2, 2 (n=197) 8 weeks 98% parts 2 and 4 4 (n=46) 8 weeks 93% 5 (n=2) 8 weeks 100% 6 (n=10) 8 weeks 100% ENDURANCE-4 5 (n=27) 12 weeks 100% and SURVEYOR-1 6 (n=30) 12 weeks 100% Treatment-Naive or PRS-Experienced with Compensated Cirrhosis EXPEDITION-1 1, 2, 4, 5, 6 (n=146) 12 weeks 99% 2 Treatment-Naive without Cirrhosis ENDURANCE (n=157) 8 weeks 95% 3 (n=233) 12 weeks 95% Treatment-Naive or PRS-Experienced without Cirrhosis or with Compensated Cirrhosis SURVEYOR-2, 3 (n=40) 12 weeks 98% part (n=69) 16 weeks 96% NS3/4A PI-Experienced 5 without Cirrhosis or with Compensated Cirrhosis MAGELLAN-1 1 (n=25) 12 weeks 92% NS5A Inhibitor-Experienced 6 without Cirrhosis or with Compensated Cirrhosis MAGELLAN-1 1 (n=17) 16 weeks 94% PI=protease inhibitor; PRS=prior treatment experience with regimens containing interferon, peginterferon, ribavirin and/or sofosbuvir without an NS3/4A protease inhibitor or NS5A inhibitor; SVR12=sustained virologic response (HCV RNA <15 IU/mL) at 12 weeks after the end of treatment 1. Based on results summarized in the package insert. 2. SVR12 rates were 99% for genotype 1 and 100% for genotypes 2, 4, 5 and ENDURANCE-3 also included 115 patients who received daclatasvir+ sofosbuvir for 12 weeks as an active control. The SVR12 rate in this group was 97%. 4. In SURVEYOR-2, part 3, patients treated for 12 weeks were treatmentnaive with compensated cirrhosis and those treated for 16 weeks were PRS-experienced without cirrhosis or with compensated cirrhosis. 5. Included patients previously treated with sofosbuvir plus simeprevir, or simeprevir, boceprevir, or telaprevir plus peginterferon/ribavirin. 6. Included patients previously treated with ledipasvir plus sofosbuvir or daclatasvir plus peginterferon/ribavirin. Pregnancy and Lactation No adequate studies in pregnant women are available. In animal studies, no adverse developmental outcomes were observed at exposures greater than those achieved in humans at recommended doses. Both drugs were present in breast milk after administration to lactating rodents; no effects on the growth or development of the nursing pups were observed. Drug Interactions Both glecaprevir and pibrentasvir inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs) 1B1 and 1B3. The drugs are also weak inhibitors of CYP1A2 and 3A, and uridine glucuronosyltransferase (UGT) 1A1. Glecaprevir and pibrentasvir are both P-gp and BCRP substrates and Table 3. Some Mavyret Drug Interactions: Drug(s) (Effect) Coadministration Contraindicated Atazanavir (increased Mavyret concentrations; increased risk of ALT elevations) Rifampin (decreased Mavyret Coadministration Not Recommended Carbamazepine, efavirenz, St. John s wort (decreased Mavyret Darunavir, lopinavir, ritonavir (increased Mavyret Ethinyl estradiol (increased risk of ALT elevations) Atorvastatin, lovastatin, simvastatin (increased statin Cyclosporine in doses >100 mg/day (increased Mavyret Dosage Adjustment of Interacting Drug Recommended Digoxin (increased digoxin Dabigatran (increased dabigatran Fluvastatin, pitavastatin, pravastatin, rosuvastatin (increased statin glecaprevir is a substrate of OATPs 1B1 and 1B3. Inhibitors of these transporters may increase plasma concentrations of Mavyret. Inducers of P-gp may decrease Mavyret concentrations. 6 Some potentially significant drug interactions with Mavyret are listed in Table 3. VOSEVI Vosevi contains three drugs, the NS5B nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir, which are the two components of the FDA-approved combination Epclusa, and a new HCV NS3/4A protease inhibitor voxilaprevir. Pronunciation Key Sofosbuvir : soe fos' bue vir Vosevi: vo sev' ee Velpatasvir : vel pat' as vir Voxilaprevir : vox" i la' pre vir Clinical Studies Approval of Vosevi was based on the results of two 12-week clinical trials (POLARIS-1 and POLARIS-4) in patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who had previously failed treatment with a DAAcontaining regimen. 7 The results are summarized in Table 4. In addition to the trials listed in Table 4, Vosevi was compared to Epclusa (sofosbuvir/velpatasvir) in two open-label trials (POLARIS-2 and POLARIS-3) in patients who had not been previously treated with a DAA-containing regimen. In POLARIS-2, patients with chronic HCV infection (genotypes 1-6), without cirrhosis or with compensated cirrhosis, were randomized to treatment with either Vosevi for 8 167

4 Table 4. Vosevi Clinical Trials 1 Trial Genotype (n) Duration SVR12 Rate NS5A-Inhibitor Experienced 2,3 POLARIS-1 Any (n=263) 12 weeks 96% 1 (overall; n=150) 4 97% 1a (n=101) 96% 1b (n=45) 100% 2 (n=5) 100% 3 (n=78) 95% 4 (n=22) 91% 5 (n=1) 100% 6 (n=6) 100% DAA-Experienced without an NS5A Inhibitor 2,5 POLARIS-4 6 Any (n=182) 12 weeks 98% 1a (n=54) 98% 1b (n=24) 96% 2 (n=31) 100% 3 (n=54) 96% 4 (n=19) 100% DAA=direct-acting antiviral; SVR 12=sustained virologic response (HCV RNA <15 IU/mL) at 12 weeks after the end of treatment 1. M Bourlière et al. N Engl J Med 2017; 376: Without cirrhosis or with compensated cirrhosis. 3. NS5A inhibitors included ledipasvir, daclatasvir, ombitasvir, relpatasvir, or elbasvir. 4. Includes 4 subjects with genotype 1 subtypes other than 1a or 1b, all of whom achieved SVR Most prior regimens contained sofosbuvir ± peginterferon/ribavirin or ribavirin and/or ± an NS3/4a protease inhibitor (boceprevir, simeprevir, or telaprevir). 6. POLARIS-4 included an active control group of patients with genotypes 1-3 that received Epclusa (sofosbuvir/velpatasvir); SVR12 rates with Vosevi were superior to those with Epclusa only in patients with genotypes 1a or 3. weeks (n=501) or Epclusa for 12 weeks (n=440). Genotype 3-infected patients with compensated cirrhosis were excluded from POLARIS-2 and instead enrolled in POLARIS-3, a separate trial comparing the same two treatment groups. In POLARIS-2, SVR12 rates were the same or lower with Vosevi compared to Epclusa for all HCV genotypes, and the overall SVR12 rate after 8 weeks of Vosevi (95%) was not sufficient to establish noninferiority with 12 weeks of Epclusa (98%). In POLARIS-3, the SVR12 rate was 96% in both treatment groups. 8 Vosevi is not FDA-approved for 8 weeks of use or for use in patients not previously treated with a DAA-based regimen. Adverse Effects The most common adverse effects of Vosevi in clinical trials were headache (21%), fatigue (17%), nausea (13%), and diarrhea (13%). The labels of all DAA drugs used for treatment of HCV infection include a boxed warning about a risk of hepatitis B virus reactivation associated with their use. 5 Pregnancy and Lactation No adequate studies in pregnant women are available. In animal studies, no adverse developmental outcomes were observed at exposures greater than those achieved in humans at recommended doses. Table 5. Some Vosevi Drug Interactions: Drug(s) (Effect) Coadministration Contraindicated Rifampin (decreased and/or increased Vosevi Coadministration Not Recommended Amiodarone (serious symptomatic bradycardia reported) Atazanavir, lopinavir, OATP inhibitors such as cyclosporine (increased voxilaprevir P-gp and CYP2B6, 2C8 or 3A4 inducers such as St. John s wort and carbamazepine (decreased Vosevi BCRP substrates such as methotrexate (increased concentrations of BCRP substrates) Rosuvastatin, pitavastatin (increased statin Monitoring Recommended Dabigatran clinical effects (increased dabigatran Digoxin therapeutic concentrations (increased digoxin Tenofovir disoproxil fumarate adverse effects (increased tenofovir DF Dosage Adjustment of Interacting Drug Recommended Pravastatin, atorvastatin, fluvastatin, lovastatin, simvastatin (increased statin Antacids, H2-receptor antagonists, proton-pump inhibitors (decreased velpatasvir All three drugs were present in breast milk after administration to lactating rodents; no effects on the growth or development of the nursing pups were observed. Drug Interactions Some potentially significant drug interactions with Vosevi are listed in Table 5. Sofosbuvir, velpatasvir and voxilaprevir are substrates of P-gp and BCRP. Voxilaprevir is also a substrate of OATPs 1B1 and 1B3. Velpatasvir and voxilaprevir are inhibitors of P-gp, BCRP, and OATP. Velpatasvir is metabolized by CYP2B6, 2C8, and 3A4, and voxilaprevir primarily by CYP3A4. Inducers of P-gp and/or moderate or strong inducers of CYP2B6, 2C8, or 3A4 may significantly decrease plasma concentrations of Vosevi. Inhibitors of P-gp, BCRP, OATP, or CYP2B6, 2C8, or 3A4 may increase concentrations of one or more components of Vosevi. 6 Absorption of velpatasvir decreases as gastric ph increases. CONCLUSION Both glecaprevir/pibrentasvir (Mavyret) and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) are effective for treatment of hepatitis C virus (HCV) infection caused by all of the six major HCV genotypes and have produced sustained virologic responses in treatment-experienced patients who failed treatment with a direct-acting antiviralbased regimen. Mavyret is also FDA-approved for treatment-naive patients and for a treatment duration of only 8 weeks in treatment-naive and -experienced patients without cirrhosis. 168

5 Table 6. Some Oral Regimens for HCV Infection Approved Number of Brand Name Formulation Usual Dosage Genotypes Tabs/Day Cost 1 Epclusa (Gilead) 400/100 mg sofosbuvir/ 1 tab once/d x 12 wks 2, $74,760 velpatasvir tabs Harvoni (Gilead) 90/400 mg ledipasvir/ 1 tab once/d x 12 wks 3,5 1, 4, 5, ,500 sofosbuvir tabs Mavyret (Abbvie) 100/40 mg glecaprevir/pibrentasvir 3 tabs once/d x 8 wks 6, ,400 9 Technivie (Abbvie) 12.5/75/50 mg ombitasvir/ 2 tabs qam x 12 wks 10, ,653 paritaprevir/ritonavir tabs Viekira Pak (Abbvie) 12.5/75/50 mg ombitasvir/ 2 ombitasvir/paritaprevir/ritonavir ,319 paritaprevir/ritonavir tabs tabs qam and 1 dasabuvir mg dasabuvir tabs tab bid x 12 wks 11,12 Viekira XR (Abbvie) 200/8.33/50/33.33 mg dasabuvir/ 3 tabs once/d x 12 wks 11, ,319 ombitasvir/paritaprevir/ritonavir extended-release tabs Vosevi (Gilead) 400/100/100 mg sofosbuvir/ 1 tab once/d x 12 wks 3, ,760 velpatasvir/voxilaprevir tabs Zepatier (Merck) 50/100 mg elbasvir/ 1 tab once/d x 12 wks 11,15 1, ,600 grazoprevir tabs 1. Approximate WAC for 12 weeks treatment. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. September 5, Reprinted with permission by First Databank, Inc. All rights reserved Patients with decompensated cirrhosis should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day ( 75 kg). 3. Not recommended for use in patients with severe renal impairment (egfr <30 ml/min/1.73 m2) or end-stage renal disease. 4. Patients requiring ribavirin would also take 4-7 tablets or capsules of ribavirin 200 mg/day in two divided doses with food. A 12-week supply of ribavirin for a 70-kg patient costs about $ An 8-week regimen may be considered for treatment-naive genotype 1 patients without cirrhosis with baseline HCV RNA <6 million IU/mL. A 24-week regimen is recommended for treatment-experienced genotype 1 patients with compensated cirrhosis. Genotype 1 patients with decompensated cirrhosis and genotype 1 or 4 post-liver-transplant patients without cirrhosis or with compensated cirrhosis should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/ day ( 75 kg). 6. Eight weeks for patients who are treatment-naive with genotypes 1-6 without cirrhosis or PRS-experienced (prior treatment with regimens containing interferon, peginterferon, ribavirin and/or sofosbuvir without an NS3/4A protease inhibitor or NS5A inhibitor) with genotypes 1, 2, 4, 5, or 6 without cirrhosis; 12 weeks for patients who are treatment-naive with genotypes 1-6 with compensated cirrhosis, PRS-experienced with genotypes 1, 2, 4, 5 or 6 with compensated cirrhosis, or genotype 1 previously treated with an NS3/4A PI (but not an NS5A inhibitor) without cirrhosis or with compensated cirrhosis; 16 weeks for patients with genotype 1 previously treated with an NS5A inhibitor (but not an NS3/4A PI) or genotype 3 who are PRS-experienced without cirrhosis or with compensated cirrhosis. 7. Not recommended in patients with moderate hepatic impairment. Contraindicated in patients with severe hepatic impairment. 8. FDA-approved for treatment-naive and -experienced patients with genotypes 1-6 previously treated with peginterferon, ribavirin, and/or sofosbuvir, and for treatment-experienced patients with genotype 1 previously treated with an NS5A inhibitor or an NS3/4A protease inhibitor, but not both. 9. Cost for 8 weeks of treatment. 10. Technivie is used in combination with ribavirin 1000 mg/day (<75 kg) or 1200 mg/day ( 75 kg). Technivie alone may be considered in treatment-naive patients who cannot tolerate ribavirin. 11. Contraindicated for use in patients with moderate or severe hepatic impairment weeks for patients with HCV genotype 1a and compensated cirrhosis (12 weeks may be considered in this population based on prior treatment history). All patients with genotype 1a should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day ( 75 kg). 13. Not recommended for use in patients with moderate or severe hepatic impairment. 14. FDA-approved for patients with genotypes 1-6 previously treated with an NS5A inhibitor and for patients with genotypes 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. 15. Patients with genotype 1a with baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93 should also take ribavirin and should be treated for 16 weeks. Genotype 1a or 1b patients previously treated with peginterferon, ribavirin, and an NS3/4A protease inhibitor should also take ribavirin, but can be treated for 12 weeks. Genotype 4 patients previously treated with peginterferon and ribavirin should also take ribavirin and should be treated for 16 weeks. The recommended dosage of ribavirin for those with CrCl >50 ml/min is: <66 kg = 800 mg/day, kg = 1000 mg/day, kg = 1200 mg/day, >105 kg = 1400 mg/day. 1. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Available at Accessed September 28, F Poordad et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017; 66: PY Kwo et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 2017; 67: X Forns et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, openlabel, multicenter phase 3 trial. Lancet Infect Dis 2017; 17: In Brief: Hepatitis B reactivation with direct-acting antiviral drugs for hepatitis C. Med Lett Drugs Ther 2016; 58: Inhibitors and inducers of CYP enzymes and p-glycoprotein. Med Lett Drugs Ther 2017 September 18 (epub). Available at: medicalletter.org/downloads/cyp_pgp_tables.pdf. Accessed September 28, M Bourlière et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376: IM Jacobson et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology 2017; 153:

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