February 2015 FAQs

What are the new recommendations for direct-acting antivirals for treatment of hepatitis C virus?

Introduction

Treatment of hepatitis C virus (HCV) infection has changed dramatically in the past few years, and even the past few months, with the explosion of potentially curative treatment regimens on the market.¹ In order to keep abreast of the emerging data, the American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) created an online guideline that is continually updated and available atwww.hcvguidelines.org. A need for continually-updated guidelines arrived with the approval of additional direct-acting antivirals, including sofosbuvir, simeprevir, and combination agents: ledipasvir/sofosbuvir (Harvoni), and paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak). The AASLD/IDSA guidelines provide direction for clinicians regarding how to incorporate the new direct-acting antivirals and combination products into patients’ treatment regimens, as well as recommendations for screening, special populations, and how to re-treat patients who have failed prior therapy.

Recently approved direct-acting antivirals and combination products

Prior to the 2014 AASLD/IDSA guidelines, boceprevir and telaprevir were the only direct-acting antivirals that were approved for use and recommended as components of standard of care regimens with pegylated interferon and ribavirin.² However, telaprevir has been removed from the market due to development of more favorable agents.³ Boceprevir is administered multiple times per day and is known to have high levels of resistance, numerous drug interactions, and multiple adverse events.⁴ In contrast, the newer direct-acting antivirals and combination products are administered once to twice daily and have better safety profiles. New clinical trials have shown promising efficacy and safety data for the new agents in the treatment of HCV, and they have been incorporated into the AASLD/IDSA guidelines.¹Boceprevir is no longer recommended by the AASLD/IDSA as part of the standard of care regimens for treatment of HCV. The new direct-acting antivirals are discussed below, with a focus on the combination agents, followed by a brief review of the new guidelines.

Ledipasvir/sofosbuvir (Harvoni)

Harvoni is a combination of 2 direct-acting antivirals, ledipasvir 90 mg and sofosbuvir 400 mg, taken once daily.⁵ The AASLD/IDSA guidelines recommend ledipasvir/sofosbuvir for genotypes 1a, 1b, 4, and 6.¹ Two phase 3 multicenter, open-label, randomized clinical trials, ION-1 and ION-3, led to the recommendation of ledipasvir/sofosbuvir for genotype 1.^6,7 ION-1 randomized 865 previously untreated patients with HCV genotype 1 into 1 of 4 treatment groups: ledipasvir/sofosbuvir with or without ribavirin, given for either 12 or 24 weeks.⁶ ION-3 randomized 647 previously untreated patients with HCV genotype 1 into 1 of 3 treatment groups, ledipasvir/sofosbuvir for 8 weeks or 12 weeks, or ledipasvir/sofosbuvir and ribavirin for 8 weeks.⁷ The primary outcome for both trials was a sustained virologic response (SVR) 12 weeks post-treatment.^6,7 Both trials compared the study groups to a historical control SVR of 60%, taken from phase 3 boceprevir and telaprevir trials. All treatment regimens in ION-1 had at least 97% of patients achieve an SVR, demonstrating ledipasvir/sofosbuvir is superior to the historical control of 60% (p<0.001).⁶ The presence of ribavirin or duration of treatment did not significantly affect the percentage of patients achieving an SVR. ION-3 demonstrated that all 3 treatment regimens were superior to the historical control of 60% (p< 0.001).⁷Although the initial rates of SVR were similar among the 8- and 12-week treatment regimens, the AASLD/IDSA does not recommend shortening the treatment duration of ledipasvir/sofosbuvir to 8 weeks due to concern for greater risk of relapse.¹

Paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak)

The Viekira Pak is a 4-drug combination regimen.⁸ It includes a combination tablet consisting of 75 mg of paritaprevir, 50 mg of ritonavir, and 12.5 mg of ombitasvir, packaged with two 250 mg dasabuvir tablets. The dosing regimen is 2 combination tablets in the morning along with 1 dasabuvir tablet, followed by 1 dasabuvir tablet in the evening. Five trials, SAPPHIRE-I, TURQUOISE-II, PEARL-I, PEARL-III, and PEARL-IV led to the recommendation of the 4-drug combination for genotypes 1a, 1b, and 4.^1,9-12 All of the studies assessed interferon-free regimens and some of the trial arms assessed the 4-drug combination with ribavirin. It was determined that patients with genotype 1a and patients with genotype 1b with cirrhosis derive a greater benefit from the 4-drug combination when used concomitantly with ribavirin.

PEARL-III and IV assessed the addition of ribavirin to the 4-drug combination in patients with genotype 1b and 1a.¹² PEARL-III included 419 patients with genotype 1b and PEARL-IV included 305 patients with genotype 1a. Patients were treatment-naïve and did not have cirrhosis. The interventions were the same among the 2 trials; all patients received the 4-drug combination for 12 weeks and were randomized to also receive either ribavirin or placebo. The primary endpoint was SVR at 12 weeks, and it was compared to a historical control of telaprevir, pegylated interferon, and ribavirin. The historical SVR rate was 72% for patients with genotype 1a and 80% for patients with 1b. In the PEARL-III trial, 99.5% of patients receiving the 4-drug combination and ribavirin achieved an SVR, as compared to 99% of patients receiving the 4-drug combination and ribavirin placebo. Both groups were noninferior and superior in comparison to the historical control, and the group receiving placebo was noninferior to the group receiving ribavirin. Therefore, ribavirin is not necessary for an effective regimen and is not recommended to use with the 4-drug combination for genotype 1b. However, the TURQUOISE-II trial showed lower SVR rates for patients with genotype 1b and cirrhosis, so ribavirin is recommended for use with the 4-drug combination for this patient population.¹⁰ TURQUOISE-III is being conducted in order to investigate if ribavirin is necessary for this patient population. ¹ PEARL-IV demonstrated that the 4-drug combination, with or without ribavirin, was noninferior and superior to the historical control, but noninferiority was not achieved when comparing the group who did not receive ribavirin to the group who did.¹² Therefore, for patients with genotype 1a, ribavirin is recommended in combination with the 4-drug combination.

Sofosbuvir (Sovaldi)

Just prior to the approval of the combination agents, Harvoni and the Viekira Pak, sofosbuvir in combination with older agents (ribavirin and pegylated interferon) was recommended for initial treatment of patients with all HCV genotypes.¹ FISSION, POSITRON, and VALENCE led to the recommendation of the interferon-free regimen of sofosbuvir and ribavirin for genotype 2, and NEUTRINO led to the recommendation of sofosbuvir, ribavirin and pegylated interferon for genotype 5.^13-15 Genotype 5 is the only genotype for which a first-line recommendation for initial therapy with an interferon-free regimen does not exist.¹

Simeprevir (Olysio)

Simeprevir, a new direct-acting antiviral, was approved around the same time as sofosbuvir.¹Since the addition of the combination agents, simeprevir is used less frequently. COSMOS, a trial studying the efficacy of sofosbuvir and simeprevir with or without ribavirin, led to the recommendation of a regimen containing sofosbuvir and simeprevir for genotypes 1a or 1b infection and cirrhosis, for both treatment-naïve patients or those who were previously non-responsive to treatment with pegylated interferon and ribavirin.¹⁶ Simeprevir is only recommended as first-line treatment for genotypes 1a and 1b by the AASLD/IDSA guidelines.¹

Treatment regimens

The AASLD/IDSA guidelines were recently updated in December of 2014 to include the new combination products.¹ The first-line recommendations for treatment-naïve patients from the AASLD/IDSA are summarized in the Table. Treatment considerations need to be made for patient-specific factors, including genotype, extent of liver disease, ability to tolerate treatment, concomitant medications, concomitant disease states (including co-infection with HIV), treatment experience, and possibility for liver transplantation or history of liver transplantation. A summary of the treatment recommendation are summarized in the Table.

Medication costs

A major disadvantage of the new direct-acting antivirals and combination products is the cost.^23‑25 For a 12-week course of treatment, the cost of Harvoni is approximately $94,500, the Viekira Pak (without ribavirin) is approximately $83,300, and sofosbuvir is approximately $84,000. Currently the AASLD/IDSA do not take cost into account for their recommendations.¹ The AASLD/IDSA guidelines are available on a website that is continually updated, so it is likely that cost will be addressed with the emergence of pharmacoeconomic data.

Safety

Historically, HCV treatment regimens have been associated with a high risk for adverse events.¹ Most of the significant adverse events were related to the use of pegylated interferon and ribavirin. Many of the new HCV regimens do not include pegylated interferon, and some do not include ribavirin. While this is an improvement for the safety of HCV treatment regimens, there are still some drawbacks to the new combination products. The Viekira Pak contains the protease inhibitor ritonavir, and therefore has many cytochrome P450-mediated drug-drug interactions.⁸ Patients with HCV may have other infections that need to be managed, such as HIV. Many HIV medications are either contraindicated or listed as a drug-drug interactions in the Vikeira Pak package insert. This poses a problem for clinicians trying to manage multiple disease states.

Another concern for the new direct-acting antivirals and the combination products is the lack of information. The only adverse effects and interactions listed were discovered through the clinical trials. It is reasonable to assume that as more patients are exposed to these drugs, the information on drug-drug interactions and adverse effects will increase.

Conclusion 
The new HCV guidelines have provided support for the use of the newer direct-acting antivirals and combination products in clinical practice. The AASLD/IDSA guidelines are especially helpful in that they are web-based and continually updated. Due to the approval of new agents and plethora of clinical trials being conducted, it is important to refer to the website for the most recent recommendations. The most important change from previous HCV treatment guidelines is the inclusion of the newer direct-acting antivirals and combination products as first-line treatment recommendations, as well as the recommendation to no longer use boceprevir and telaprevir as part of first-line regimens. Virologic cure, short duration of treatment, and all-oral regimens make the combination agents and sofosbuvir and simeprevir welcomed additions to the treatment options for patients with HCV.

Table. AASLD/IDSA recommendations for hepatitis c virus treatment regimens for initial therapy.^1,6,7,9-22

^a “See text for further detail on length of treatment”¹

^b Add weight-based RBV for patients with cirrhosis¹

Abbreviations: AASLD, American Association for the Study of Liver Diseases; IDSA, Infectious Disease Society of America; LED, ledipasvir; SOF, sofosbuvir; PAR, paritaprevir; RIT, ritonavir; OMB, ombitasvir; DAS, dasabuvir; RBV, ribavirin; SMV, simeprevir; IFN, interferon.

References

1. Recommendations for testing, managing, and treating hepatitis C, third edition. American Association for the Study of Liver Diseases and Infectious Diseases Society of America website. hcvguidelines.org. Updated July 11, 2014. Accessed January 23, 2015.

2. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. 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(4):1433-1444.

3. Vertex Pharmaceuticals discontinues Incivek. Canadian Treatment Action Council website.http://www.ctac.ca/multimedia-press/treatmentaccessnews/vertex-pharmaceuticals-discontinues-incivek . Accessed January 19, 2015.

4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2014. http://clinicalpharmacology-ip.com/default.aspx. Accessed October 29, 2014.

5. Harvoni [package insert]. Foster City, CA; Gilead Sciences, Inc; 2014.

6. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898.

7. Kowdley K, Gordon S, Reddy R, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.

8. Viekira Pak [package insert]. North Chicago, IL: AbbVie Inc; 2014.

9. Feld J, Kowdley K, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594-1603.

10. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepaticis C with cirrhosis. N Engl J Med. 2014;370(21):1973-1982.

11. Pol S, Reddy R, Hezode C, et al. Interferon-Free Regimens of Ombitasvir and ABT-450/r With or Without Ribavirin in Patients With HCV Genotype 4 Infection: PEARL-I Study Results. Presented at: 65th Annual Meeting of the American Association for the Study of Liver Diseases; November 7-11, 2014; Boston, MA.http://www.natap.org/2014/AASLD/AASLD_82.htm. Accessed January 14, 2015.

12. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(21):1983-1992.

13. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.

14. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.

15. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993-2001.

16. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384(9956):1756-1765.

17. Ruane PJ, Ain D, Meshrekey R, et al. Sofosbuvir plus ribavirin, an interferon-free regimen, in the treatment of treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection [Abstract P1243]. 49th Annual Meeting of the European Association for the Study of the Liver. April 9-13, 2014; London, United Kingdom.

18. Esmat G. Sofosbuvir plus Ribavirin in the Treatment of Egyptian Patients with Chronic Genotype 4 HCV Infection. ePOSTER presented at: AASLD Live Learning; November 9, 2014.http://liverlearning.aasld.org/aasld/2014/thelivermeeting/61005/doctor.gamal.esmatsofosbuvir.
plus.ribavirin.in.the.treatment.of.egyptian.html Accessed January 14, 2015.  

19. Molina JM, Orkin C, Iser DM, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotypes 1, 2, 3 and 4 infection in patients co-infected with HIV (PHOTON-2). Oral abstract session presented at: AIDS 2014 20^th International AIDS Conference; July 20-25, 2014; Melbourne, Australia. http://pag.aids2014.org/Abstracts.aspx?AID=11072. Accessed January 14, 2015.

20. Kapoor R, Kohli A, Sidharthan S, et al. Treatment of Hepatitis C Genotype 4 with Ledipasvir and Sofosbuvir for 12 weeks: Results of the SYNERGY Trial. Presented at: 65th Annual Meeting of the American Association for the Study of Liver Diseases; November 7-11, 2014; Boston, MA. http://www.natap.org/2014/AASLD/AASLD_76.htm. Accessed January 14, 2015.

21. Kohler JJ, Nettles JH, Ablard F, et al. Approaches to hepatitis C treatment and cure using NS5A inhibitors. Infect Drug Resist. 2014;7:41-56.

22. Wong KA, Worth A, Martin R, et al. Characterization of Hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother. 2013;57(12):6333-6340.

23. Ledipasvir-Sofosbuvir (Harvoni). Hep C Online.http://www.hepatitisc.uw.edu/page/treatment/drugs/ledipasvir-sofosbuvir . Accessed January 16, 2015.

24. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak). Hep C Online.http://www.hepatitisc.uw.edu/page/treatment/drugs/3d. Accessed January 16, 2015.

25. Sofosbuvir (Sovaldi). Hep C Online.http://www.hepatitisc.uw.edu/page/treatment/drugs/sofosbuvir-drug. Accessed January 16, 2015.

Prepared by:

Kendall Buchmiller

PharmD Candidate, 2016

College of Pharmacy

University of Illinois at Chicago

February 2015

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What is the Evidence for Use of Inhaled Epoprostenol?

Epoprostenol

Epoprostenol is a naturally occurring prostacyclin analogue that causes direct vasodilation of the pulmonary and systemic arterial vascular beds while also inhibiting platelet aggregation.¹The intravenous form of epoprostenol is Food and Drug Administration approved for patients with pulmonary hypertension. A prostacyclin analogue such as epoprostenol helps to relieve the symptoms of pulmonary hypertension through vasodilation of the pulmonary vasculature and decreased strain on the right ventricle. This medication is effective through the intravenous route, but there may be unwanted systemic vasodilation leading to hypotension. In order to avoid this detrimental effect, local delivery of epoprostenol to the pulmonary vasculature through inhalation has been hypothesized and studied. Two areas of increasing interest for the use of inhaled epoprostenol include the treatment of pulmonary hypertension in cardiac surgery patients and treatment of patients with acute respiratory distress syndrome (ARDS).

Inhaled epoprostenol post-cardiac surgery

Pulmonary hypertension is associated with increased rates of morbidity and mortality in patients undergoing cardiac surgery.² The cause of pulmonary hypertension is hypothesized to be multifactorial, but there seems to be some consensus that it may be caused by baseline disease process which is exacerbated by cardiopulmonary bypass damage to the pulmonary endothelium.^3,4 This damage to the endothelium may also lead to further loss of vasodilator function and increasing pulmonary resistance. In order to reverse this selective hypertension, it is essential to deliver vasoactive agents directly to the site of action (ie, the pulmonary vasculature).

Several studies have looked at the administration of inhaled epoprostenol for the treatment of pulmonary hypertension after cardiac surgery. ^2,3,5,6 The goal of these studies was to evaluate if this method of administration was effective at lowering pulmonary pressure after discontinuation of cardiopulmonary bypass. According to these studies, the use of inhaled epoprostenol was effective at lowering the pulmonary pressure after surgery (see Table 1).Other effects noticed in the study by Fattouch et al were a decreased amount of vasopressor agent and less time on cardiopulmonary bypass support associated with the use of inhaled epoprostenol.² However, one important drug effect that must be addressed is the increased bleeding rate seen in Groves et al which corresponds to the platelet inhibitory function of epoprostenol.³ Patients were noticed to have increased bleeding immediately after surgery; however, this effect soon returned to baseline (25 minutes) after study drug discontinuation. Table 1 summarizes available studies evaluating inhaled epoprostenol for pulmonary hypertension in cardiac surgery patients.

Table 1. Inhaled epoprostenol post-cardiac surgery.^2,3,5,6

Abbreviations: CI, cardiac index; CPB, cardiopulmonary bypass; CT, cardiothoracic; DB, double-blind; ICU, intensive care unit; IV, intravenous; LVAD, left ventricle assist device; mPAP, mean pulmonary arterial pressure; OL, open label; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PC, placebo controlled, PVR, pulmonary vascular resistance; RCT, randomized controlled trial; RR, retrospective review; RV, right ventricle; sPAP, systolic pulmonary arterial pressure.

Inhaled epoprostenol in ARDS

ARDS is characterized by rapidly developing severe dyspnea, hypoxemia, and diffuse pulmonary infiltrates, which eventually leads to respiratory failure. ⁷ This syndrome was first described over 20 years ago at the American-European Consensus Conference, and treatment modalities have since been developed. Due to the complexity of ARDS, many traditional treatment options are supportive care including adequate oxygenation with mechanical ventilation, minimization of pulmonary edema with diuresis, and antibiotics for infections. Unfortunately, the mortality rate from ARDS still approaches 40% to 50%; thus, the investigation for new treatment options continues.⁸

Inhaled epoprostenol is a treatment option that is being evaluated with increased interest due to the successful use of the intravenous form in pulmonary hypertension. The goal in ARDS is to decrease pulmonary pressure to improve oxygenation while maintaining systemic blood pressure to minimize any further ischemic damage.⁹ Siobal et al evaluated multiple clinical studies to determine the effect of inhaled vasodilator therapy in ARDS.¹⁰ According to their findings, inhaled epoprostenol may be effective to help with oxygenation in the acute phase of this life-threatening disease. However, since there was no mortality benefit with either inhaled nitric oxide or inhaled epoprostenol, the authors recommend discontinuation of treatment if a short trial does not convey a physiologic benefit. Table 2 summarizes 2 studies evaluating inhaled epoprostenol use in ARDS.

Table 2. Inhaled epoprostenol in ARDS.^9,11

Abbreviations: ARDS, acute respiratory distress syndrome; RR, retrospective review.

Administration of inhaled epoprostenol

Table 3 describes the preparation of a compounded epoprostenol product from several of the studies for nebulized administration.^2,5,6 The concentration of active compound in the solution ranged from 15 mcg/mL to 20 mcg/mL prior to administration. The commercially available products are now supplied with their own diluent that should be used to reconstitute the product prior to further dilution.^12,13

Table 3. Inhaled epoprostenol preparation.^2,5,6

Stability data of the epoprostenol solution is not mentioned in any of the above studies.^2,5,6However, Siobal et al addressed stability in their clinical review.¹⁰ They mention that epoprostenol requires reconstitution in the included diluent in order to maintain stability and when this diluent is used the solution is stable for 8 hours at room temperature or 48 hours if refrigerated.^10,13 Epoprostenol is also light sensitive and should be protected from light due to possible decomposition. Table 4 describes the dosing strategy for inhaled epoprostenol in multiple studies evaluating its use in ARDS and pulmonary hypertension post-cardiac surgery.

Table 4. Inhaled epoprostenol dosing.^3,5,6,9-11

Multiple studies have addressed the dosing strategy for inhaled epoprostenol in either of these 2 conditions. The dose varies among the studies, but there does seem to be a consensus that the maximum dose is 50 ng/kg/min.^3,9,10 Studies have started at lower doses and titrated up to the maximum dose of 50 ng/kg/min or initiated treatment at the maximum dose and down titrated based on clinical response. There may also be some further questions regarding the weight to use for dose calculation in obese patients. Siobal recommend dosing inhaled epoprostenol based on predicted body weight which is equivalent to ideal body weight .^10,14 This accounts for the estimated lung size of these patients rather than their actual body mass.

Further administration details were provided in some inhaled epoprostenol studies. Table 5 summarizes this information.

Table 5. Inhaled epoprostenol administration.^2,3,5,6

Conclusion

The use of inhaled epoprostenol in ARDS and pulmonary hypertension after cardiac surgery may have some benefit for certain patients. Studies have suggested that there is evidence of decreased pulmonary pressures and increased oxygenation in patients that respond to therapy. However, not every patient will respond to this therapy and a response should be assessed following initiation of treatment to determine actual benefit to the patient. Local administration does seem to limit systemic hypotension related to intravenous delivery of the medication, but the significance of this effect is unknown. Overall, the use of inhaled epoprostenol needs to be assessed in a larger trial in order to clarify if there are any improvements regarding morbidity or mortality in these patient populations.

References:

1. Attridge RL, Moote R, Levine DJ. Pulmonary arterial hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9^th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811465. Accessed December 18, 2014.

2. Fattouch K, Sbraga F, Sampognaro R, et al. Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, double-blind study. J Cardiovasc Med. 2006;7(2):119-123.

3. Groves DS, Blum FE, Huffmyer JL, et al. Effects of early inhaled epoprostenol therapy on pulmonary artery pressure and blood loss during LVAD placement. J Cardiothorac Vasc Anesth. 2014;28(3):652-660.

4. Denault A, Deschamps A, Tardif J-C, Lambert J, Perrault L. Pulmonary hypertension in cardiac surgery. Curr Cardiol Rev. 2010;6(1):1-14.

5. Haché M, Denault A, Bélisle S, et al. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc Surg. 2003;125(3):642-649.

6. De Wet CJ, Affleck DG, Jacobsohn E, et al. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart failure, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004;127(4):1058-1067.

7. Collins SR, Blank RS. Approaches to refractory hypoxemia in acute respiratory distress syndrome: current understanding, evidence, and debate. Respir Care. 2011;56(10):1573-1582.

8. Puri N, Dellinger RP. Inhaled nitric oxide and inhaled prostacyclin in acute respiratory distress syndrome: what is the evidence? Crit Care Clin. 2011;27(3):561-587.

9. Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. Ann Pharmacother. 2013;47(6):790-796.

10. Siobal MS, Hess DR. Are inhaled vasodilators useful in acute lung injury and acute respiratory distress syndrome? Respir Care. 2010;55(2):144-157.

11. Camamo JM, McCoy RH, Erstad BL. Retrospective evaluation of inhaled prostaglandins in patients with acute respiratory distress syndrome. Pharmacotherapy. 2005;25(2):184-190.

12. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomas Reuters (Healthcare), Inc; 2014. http://www.thomsonhc.com/hcs/librarian. Accessed December 20, 2014.

13. Flolan [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

14. NHLBI ARDS Network. Predicted body weight calculator. http://www.ardsnet.org/node/77460. Accessed December 26, 2014.

Prepared by:

Kyle Gordon, PharmD

PGY1 Pharmacy Resident

College of Pharmacy

University of Illinois at Chicago

February 2015

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What vaccines should be administered to adult, splenectomized, patients?

Introduction: the spleen

The spleen is an organ that is about the size of a fist and can become enlarged by infection.¹Six percent of the body’s cardiac output goes to the spleen, which comprises a quarter of the body’s lymphoid mass and half of the body’s monocytes and B lymphocytes. Therefore, the spleen is an important organ that helps fight infection, through its involvement with filtration, phagocytosis, and opsonization of bacteria in the blood. Filtration of blood involves removal of antibodies, intracellular materials, and destruction of defective cells. During this filtration process by which debris and foreign particles, unopsonized bacteria, and parasite-containing erythrocytes are removed, iron, erythrocytes, and platelets are sequestered. These sequestered cells can be used for response to bleeding or infection.² The spleen is also capable of extramedullary hematopoiesis, as some hematopoietic stem cells present during the second trimester remain into adult life.^1,2

There are 3 types of asplenia: congenital asplenia, acquired asplenia, and acquired hyposplenia.¹ Congenital asplenia is rare and manifests as a reduced spleen size or absence of the spleen. Therefore, the function of the spleen varies from patient to patient. Acquired hyposplenia is the impairment of splenic function related to inflammatory, rheumatologic, or immunologic disorders. In addition to the disorders themselves, some of the pharmacotherapies used to manage these disorders can directly impair the function of the spleen. Acquired asplenia is the predictable loss of function after infarction or surgical removal of the spleen. Indications for surgical splenectomy include trauma, intractable anemia, or symptomatic splenomegaly. Partial splenectomy is an option in some patients, though the ability of the remaining tissue to protect against infections is unclear. Sickle cell anemia is a common cause of splenic atrophy and eventual asplenia.

Without a functioning spleen to remove debris and bacteria, risk of infection is a major concern.^1,2 B-cell responses which are dependent on T cells occur in the spleen, with formation of IgM and IgG2 antibodies.¹ Without these antibodies to polysaccharide antigens, the body’s response against these is greatly impaired. Furthermore, the body’s ability to mount an immune function against polysaccharide encapsulated bacteria is lost. Within 90 days of splenectomy, the relative risk of infection compared to the general population is 18.1 (95% confidence interval [CI], 14.8 to 22.1) and compared to nonsplenectomized controls is 1.7 (95% CI, 1.5 to 2.1).³ Even after a year of splenectomy, the risk of infection is 2.5 compared to the general population (95% CI, 2.2 to 2.8). Infections caused by encapsulated bacteria such as Streptococcus pneumonia,Neisseria meningitidis, and haemophilus influenzatype b (Hib) are of particular concern, and the case-fatality rate of patients with S pneumoniaewho develop sepsis is 50% to 80%.²

Prevention of infections

The prevention of severe infection in hospitalized asplenic patients can be achieved with antibiotic or vaccination prophylaxis.¹ Because the risk of infection is high within the first 3 months of splenectomy, it is ideal to vaccinate against certain bacteria at least 2 weeks before the procedure, if possible. Two guidelines – the 2013 Infectious Diseases Society of America clinical practice guideline for vaccination of the immunocompromised host⁴ and British Committee for Standards in Haematology/Oncology Task Force update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen⁵ – agree on the necessity of pneumococcal, haemophilus influenza type B, and meningococcal vaccination for asplenic and hyposplenic patients. All other routine vaccinations are likely effective in this patient population. ⁶ A summary of the recommendations for administration of these vaccines are summarized in the Table below.

Table. Summary of vaccination recommendations for asplenic and hyposplenic individuals.¹

^a Hiberix (haemophilus influenzae type b conjugate vaccine) should only be given after primary series with PedvaxBID or ActHIB, and not as a first dose.

^b Trumenba (meningococcal group B vaccine) is not recommended.

Abbreviations: IM, intramuscular; SC, subcutaneous.

Pneumococcal vaccination

If the pneumococcal vaccination cannot be administered prior to the splenectomy, then administration should be delayed until functional antibody response returns, at least 14 days after the procedure.^4,5,7 Patients who are receiving chemotherapy or radiation should wait at least 3 months before immunization. Most patients require revaccination after 5 years; however, patients with sickle-cell disease or lymphoproliferative disorders may require antibody measurement and earlier revaccination, due to more rapidly declining levels in these patient groups.⁵

PCV13 is Food and Drug Administration approved for adults >50 years, but the Advisory Committee on Immunization Practices recommends its administration in adults ≥19 years with certain medical conditions including functional or anatomic asplenia.^8,9 Adults ≥19 years who have not received PCV13 or PPSV23 previously should start with one dose of PCV13, followed by one dose of PPSV23 after 8 weeks. If patients have already received one or more doses of PPSV23 previously, then one dose of PCV13 should be given at least 1 year after receiving the last PPSV23 dose.⁹ Once those individuals reach age 65, an additional single dose of PPSV23 should be given as per the usual schedule, as long as 5 years have elapsed from the previous dose. Revaccination at this point is not necessary.⁸

PCV13 can be safely given at the same time as inactivated influenza vaccine, but there are no data relating to other vaccinations.¹⁰ The PPSV23 vaccine is not recommended for American Indians or Alaskan natives who do not reside in a region with known risk of invasive disease. PPSV23 should also not be given at the same time as zoster vaccine (Zostavax) due to loss of Zostavax immune response. These should be given at least 4 weeks apart. ¹¹

Haemophilus influenza type b vaccination

Vaccination against Hib is recommended in patients with asplenia or hyposplenia.¹² Limited data on timing of vaccination are available, however. ¹³ Some experts recommend vaccinating 14 days or more before the splenectomy, and to administer a dose even if previously vaccinated. Revaccination is not necessary in these patients.^5,13

Meningococcal vaccination

There are 2 types of meningococcal vaccines that have different uses in this population.¹⁴Menomune is the quadrivalent meningococcal polysaccharide vaccine (MPSV4), and is recommended only for adults >55 years. The meningococcal conjugate vaccine (MCV4; [Menactra, Menveo]), has a substantial decline in antibodies after 3 to 5 years, and a single dose of this vaccine is considered inadequate for patients with asplenia. If chosen, a 2-dose series should be given 2 months apart, plus a booster dose every 5 years. Even if patients received the initial series with MPSV4, revaccination with MCV4 every 5 years is recommended for adults with anatomic or functional asplenia. Revaccination with MPSV4 is no longer recommended, even if patients received the initial series.¹⁵ MPSV4 and MCV4 may be administered at the same time as other vaccines at a different anatomic site. However, in asplenic patients, MCV4 should be administered at least 4 weeks after completion of the PCV13 series.

Precautions and Contraindications

All vaccinations are contraindicated if the patient previously experienced a severe allergic reaction such as anaphylaxis upon administration of the vaccine or a component.¹⁰ In patients who are experiencing symptoms of moderate or severe acute illness regardless of the presence of a fever, consideration of the individual’s risks and benefits should be given when deciding whether to give the vaccination.

Certain vaccines are manufactured with a diphtheria or tetanus conjugates as the protein carrier.¹¹ MPSV4 and MCV4 are contraindicated in patients who have had a reaction to diphtheria or tetanus toxoid.¹⁵ PCV13 is also contraindicated in patients who have had a severe reaction to a diphtheria toxoid-containing vaccine.¹¹ Adverse events with the Hib vaccine are mild, uncommon, and usually resolve within 12 to 24 hours of administration.¹²Some vaccinations contain latex in the vial stoppers (ActHib, PedvaxHIB, Menomune).^11,13

Conclusion

Acquired asplenia or hyposplenia increases an individual’s susceptibility to infections with encapsulated bacteria such as S pneumonia, H influenza, and N meningitidis. Therefore, prophylactic measures with immunizations are necessary for this population, and exceptions to the typical dosing schedules for these vaccines are made for individuals with asplenia or hyposplenia. In addition to these recommendations, influenza vaccine should be given annually as usual.

References

1. Gilsdorf JR. Infections in asplenic patients. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8 ^th ed. Philadelphia, PA: Saunders; 2015. https://www.clinicalkey.com. Accessed January 23, 2015.

2. Henry PH, Longo DL. Enlargement of lymph nodes and spleen. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine. 18^th ed. New York, NY: McGraw-Hill; 2012. http://accesspharmacy.mhmedical.com/content.aspx?bookid =331&Sectionid=40726786. Accessed January 23, 2015.

3. Thomsen RW, Schoonen WM, Farkas DK, et al. Risk for hospital contact with infection in patients with splenectomy: a population-based cohort study. Ann Intern Med.2009;151(8):546-555.

4. Rubin LG, Levin MJ, Ljungman P, et al; Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis.2014;58(3):309-318.

5. Davies JM, Barnes R, Milligan D; British Committee for Standards in Haematology. Working Party of the Haematology/Oncology Task Force. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med.2002;2(5):440-443.

6. General recommendations on immunization — recommendations of the Advisory Committee on Immunization Practices (ACIP). National Center for Immunization and Respiratory Diseases. MMWR Recomm Rep. 2011;60(2):1-64.

7. Webb CW, Crowell K. Which vaccinations are indicated after splenectomy? J Fam Pract.2006;55(8):711-712.

8. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61(40):816-819.

9. Pneumococcal disease. In: Atkinson W, Hamborsky J, Stanton A, Wolfe C, eds.Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 12^th ed. Washington DC: Public Health Foundation; 2012. http://www.cdc.gov/vaccines/pubs/pinkbook/pneumo.html. Accessed January 23, 2015.

10. Vaccine recommendations of the ACIP. Centers for Disease Control and Prevention website. http://www.cdc.gov/vaccines/hcp/acip-recs/index.html. Updated September 19, 2014. Accessed January 23, 2015.

11. Facts and Comparisons eAnswers [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; 2014. http://online.factsandcomparisons.com/index.aspx. Accessed January 23, 2015.

12. Haemophilus influenzae type b. In: Atkinson W, Hamborsky J, Stanton A, Wolfe C, eds.Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 12^th ed. Washington DC: Public Health Foundation; 2012. http://www.cdc.gov/vaccines/pubs/pinkbook/hib.html. Accessed January 23, 2015.

13. Briere EC, Rubin L, Moro PL, Cohn A, Clark T, Messonnier N; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC. Prevention and control of haemophilus influenzae type b disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2014;63(RR-01):1-14.

14. Meningococcal disease. In: Atkinson W, Hamborsky J, Stanton A, Wolfe C, eds.Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 12^th ed. Washington DC: Public Health Foundation; 2012. http://www.cdc.gov/vaccines/pubs/pinkbook/mening.html. Accessed January 23, 2015.

15. Cohn AC, MacNeil JR, Clark TA, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-2):1-28.

February 2015

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