November 2011 FAQs
November 2011 FAQs
Updated guidelines for chronic obstructive lung disease: what are the current recommendations?
Updated guidelines for chronic obstructive lung disease: what are the current recommendations?
Chronic obstructive pulmonary disorder (COPD) is the leading cause of morbidity and mortality worldwide.1 In the United States, COPD is the fourth leading cause of death and is associated with an estimated $49.9 billion of economic costs.2,3 Characterized by an airflow limitation that is progressive and not fully reversible, COPD is associated with an abnormal inflammatory response of the lung to noxious particles or gases. 1 Symptoms include chronic progressive dyspnea, cough, and sputum production. The appropriate management of COPD is critical, as exacerbations of COPD have been associated with an increase risk of mortality.4
In August 2011, the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS) jointly published a clinical practice guideline on the diagnosis and management of stable COPD as an update to a previous guideline published in 2007.5 The guideline panel included representatives from each of the 4 collaborating organizations. Members weighed recommendations in light of new literature published since the release of the 2007 guidelines, specifically focusing on patient outcomes (eg, exacerbations, hospitalizations, mortality, health-related quality of life, and dyspnea). The goal of the update was to discuss specific questions related to stable COPD and to expand, clarify, and reaffirm the recommendations made in 2007. However, these practice guidelines were not the only COPD guidelines recently updated.
In 2010, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published an update to their 2006 guidelines for the diagnosis, management, and prevention of COPD.1 The 2010 update reviewed 182 articles published from July 2009 to June 2010, and 16 new papers were included in the update. In light of these recent updates, it is imperative to understand the consensus when it comes to managing COPD to optimize patient care. This comparison focuses on the similarities and differences in the medication management of stable COPD between the 2 guidelines.
The Evaluation of Guideline Recommendations
The ACP graded the literature for the clinical guidelines as either strong or weak. Recommendations were considered strong if the benefits clearly outweighed the risks or if the risks clearly outweighed benefits.5 Recommendations were considered weak if the benefits were finely balanced with the risks. Quality of evidence was then assigned to the recommendation as either moderate-quality or low-quality evidence. In contrast, the GOLD group assigned their recommendations using an A to D grading system.1 Grade A recommendations were supported by randomized, controlled trials (RCTs) and a rich body of data. Grade B recommendations were supported by RCTs and a limited body of data. Grade C recommendations were supported by nonrandomized trials and observational data. Finally, grade D recommendations were supported by panel consensus judgment.
The goals of COPD treatment are to manage symptoms, reduce long-term function decline, prevent and treat exacerbations, reduce hospitalizations, improve quality of life, and decrease mortality. Both the ACP and the GOLD guidelines have remarked that inhaled therapy, with appropriate education and proper use, is an effective treatment route for patients with COPD.1,5 However, there are multiple options for management including inhaled versus systemic therapy and single versus combination therapy. Both guidelines attempt to provide evidence-based recommendations with regard to pharmacological treatment of stable COPD.
Emphasis on Staging and Treatment
Both the ACP and GOLD guidelines place heavy emphasis on the staging of COPD for determining treatment with inhaled β-agonists, anticholinergics, and/or corticosteroids.1,5 COPD staging is dependent on three factors: the forced expiratory volume over 1 second (FEV1)/forced vital capacity (FVC) <0.7; FEV1 itself; and respiratory symptoms.1
In asymptomatic COPD patients, the 2010 ACP guidelines reaffirmed the 2007 guidelines. It recommends against treatment in these individuals to prevent future respiratory symptoms or decline in lung function.5 The ACP and GOLD guidelines both recommend the use of a short-acting inhaled bronchodilator (β-agonists or anticholinergics) as needed in patients with few or intermittent symptoms.1,5 However, as symptoms become more persistent the recommendations are based on the patient's FEV1.
In its review, ACP found limited, conflicting evidence that inhaled therapies including long-acting bronchodilators, corticosteroids, or a combination of the two produced clinically significant improvements in mean FEV1 when compared to placebo in patients with less severe COPD. As a result, their recommendation for treatment with bronchodilators (inhaled long-acting β-agonists and anticholinergics) was graded as weak for patients with respiratory symptoms and an FEV1 between 60% and 80%. However, a strong recommendation was made for combination of inhaled bronchodilator and corticosteroid therapy in patients with respiratory symptoms and an FEV1 <60%, as these patients were enrolled in most of the clinical trials, and therefore, considered to derive the most benefit from such therapy.
GOLD also found strong evidence that current COPD medications do not prevent the long-term decline in lung function (Evidence A and B) and stated that there was limited evidence that regular treatment with inhaled therapy could decrease the rate of decline of lung function (Evidence B).1 As a result, GOLD also recommended the addition of long-acting bronchodilators based on FEV1. Patient considered having moderate COPD, defined as an FEV1 between 50% and 80% should be started on a long-acting bronchodilator. The addition of inhaled corticosteroids to the regimen is recommended in patients with an FEV1 <50% (Evidence A).
With no new studies included for the guideline update with regards to monotherapy, ACP reaffirmed its recommendation for monotherapy with inhaled, long-acting β-agonists or long-acting anticholinergics (strong recommendation, moderate quality evidence).5 Both drugs have been shown to decrease exacerbations and statistically improve quality of life when compared to placebo and short-acting agents. These benefits are also seen with long-acting corticosteroids, but their side effect profile, which includes oropharyngeal candidiasis, dysphonia, osteoporosis, cataracts, dermal thinning, and adrenal insufficiency and crisis, makes these unfavorable first-line agents.
The GOLD guidelines do not differ from ACP guidelines in that they also recommended initial monotherapy with a bronchodilator. Bronchodilators are initially recommended for stable COPD patients with an FEV1 between 50% and 80% (Evidence A).1 Similar to the updated ACP guideline, it does not differentiate between the 2 bronchodilators (long acting β-agonists or anticholinergics) due to insufficient evidence.
Despite the symptomatic improvements associated with β-agonist therapy, ACP guidelines recognize the mortality controversy surrounding these drugs. Previous studies did not find any difference in pulmonary-related mortality between long-acting β-agonists and other inhaled monotherapies. 5 However, a meta-analysis by Salpeter et al is described in the guidelines which identified an increased risk of pulmonary-related mortality with the use of long-acting β-agonists and a decreased risk with long-acting anticholinergics when compared to placebo. This controversy has not manifested itself in the current updated guidelines as both inhaled long-acting bronchodilators are recommended as first-line therapy for symptomatic COPD patients with an FEV1<60% (strong recommendation, moderate quality of evidence).
The POET-COPD Study
In the debate of which bronchodilator should be first-line for monotherapy-long-acting β-agonists versus anticholinergics-evidence exists that shows long-acting anticholinergics as superior to long-acting β-agonists. Neither guideline includes the Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) study by Vogelmeier et al comparing tiotropium to salmeterol for the prevention of exacerbations of COPD in nearly 7400 patients. This study was published in March 2011 after the release of the guidelines.6 It was a 1-year, randomized, double-blind, double-dummy, parallel-group trial that compared the effect of 18 mcg of tiotropium once daily with 50 mcg of salmeterol twice daily. It measured the incidence of moderate or severe exacerbations in patients with moderate-to-very severe COPD and a history of exacerbations in the previous year. The primary endpoint was the time to exacerbation of COPD. Tiotropium significantly increased the time to first exacerbation of COPD (187 days vs. 145 days, hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.77-0.90, p<0.001) and the time to first severe exacerbation (HR 0.72, 95% CI 0.61-0.85, p<0.001) and significantly decreased the annual rate of exacerbations (HR 0.83, 95% CI 0.77-0.90, p<0.001) compared to salmeterol. It is highly likely that the results of this study will be included in future guidelines for COPD and will result in long-acting inhaled anticholinergics being identified as a first-line bronchodilator and β-agonists, such as salmeterol, being second.
In 2007, the ACP guidelines reached the conclusion that combination therapy with an inhaled bronchodilator and corticosteroid did not consistently demonstrate benefits over monotherapy (weak recommendation, moderate-quality evidence).5 The update contained 9 new trials that provide conflicting information concerning the benefit of using combination therapy over monotherapy for exacerbations, hospitalization, quality of life, and mortality. While some trials showed clinically significant symptomatic improvement, decreased exacerbations, and decreased mortality in patients with an FEV1<60%, others did not. Some studies showed an increase risk of experiencing adverse effects with combination therapy while others did not. Because of the lack of evidence, no specific combination therapy is highlighted, and the current ACP guidelines only weakly recommend the use of combination therapy over monotherapy.
The GOLD guidelines have a different stance on combination therapy than the recently updated ACP guidelines.1 As mentioned previously, patients with an FEV1 between 50% and 80% are recommended to start a long-acting bronchodilator. However, once the FEV1 deteriorates to between 30% and 50%, the addition of inhaled corticosteroids is recommended in patients with repeated exacerbations. GOLD found strong evidence that inhaled corticosteroid combined with a long-acting β-agonist was more effective than the individual components alone in reducing exacerbations, improving lung function, and enhancing health status (Evidence A). It also noted that triple therapy with inhaled β-agonist, anticholinergic, and corticosteroid appears to provide additional benefits than just an inhaled β-agonist and corticosteroid alone.
The updated ACP guidelines have not changed practice significantly when compared to the GOLD guidelines. For all patients, stratification based on the stage of COPD is the first step in determining pharmacological therapy. Despite new literature, the consensus remains that patients with an FEV 1 > 60% require therapy with only a short-acting bronchodilator as needed. When patients' FEV1 deteriorate to less than 60%, the addition of a long-acting bronchodilator (with a possible preference for a long-acting anticholinergic) improves patient outcomes. However, in patients who continue to deteriorate with significant symptoms and exacerbations, the addition of a second agent, usually a corticosteroid, is warranted.
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: Updated 2010. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Published December 2010. Accessed September 10, 2011.
2. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2010 Factbook Fiscal Year 2010. Bethesda, MD: National Heart, Lung, and Blood Institute; 2010. http:// http://www.nhlbi.nih.gov/about/factbook/FactBook_2010.pdf. Accessed September 10, 2011.
3. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2009 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: National Heart, Lung, and Blood Institute; 2009.
4. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-931
5. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society . Ann Intern Med. 2011 155(3):179-191.
6. Vogelmeier C, Hederer B, Glaaab T, Schmidt H, Rutten-van Molken MP, Beeh KM, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103.
Written By :Tammy Nguyen, PharmD
Fluzone Intradermal-what is its place in therapy?
Fluzone Intradermal-what is its place in therapy?
Seasonal influenza is associated with significant morbidity and mortality in the United States.1 With approximately 200,000 hospitalizations and 30,000 deaths from the 25 to 50 million annual cases, influenza is the greatest cause of vaccine-preventable mortality. Yearly vaccination is the primary means by which influenza can be prevented and has historically been administered by either the intramuscular (IM) or intranasal routes. Vaccination helps prevent hospitalization and death, and decreases physician and emergency room visits, otitis media in children, and missed days of school and work due to influenza. The Centers for Disease Control and Prevention (CDC) recommend that all persons aged ≥6 months receive an annual influenza vaccine.1,2
The Healthy People 2020 initiative, released by a federal interagency workgroup, which includes the US Department of Health and Human Services, aims to improve the nation's health by providing evidence-based 10-year objectives.3 One objective of the initiative is to increase the percentage of children and adults who are vaccinated annually against seasonal influenza. Vaccination rates in 2008 for healthy adults aged 18 to 64, high-risk adults aged 18 to 64, and institutionalized adults aged 18 and older were 25%, 39%, and 62%, respectively. These are well below the Healthy People 2020 goals of 80% for healthy adults and 90% for high-risk and institutionalized adults. Reasons for non-vaccination include misconceptions about the safety and efficacy of vaccines as well as misconceptions about influenza itself.4 Approximately 20% of patients who decline vaccination do so because of a fear of needles or dislike of injections.
Fluzone Intradermal was approved in May 2011 as the first intradermal (ID) vaccine in the United States.2 Like the traditional IM preparation, it is a trivalent inactivated vaccine (TIV), which contains hemagglutinin (HA) of the 3 influenza virus strains likely to be circulating during the influenza season.2,5 For the 2011-2012 season, all inactivated influenza vaccines are formulated to contain HA of A/California/07/2009 X-179A (H1N1), A/Victoria/210/2009 X-187 (H3N2), and B/Brisbane/60/2008. Fluzone Intradermal is approved for use in persons aged 18 to 64 years and is supplied as a single-dose, preservative-free, prefilled syringe containing 9 mcg HA of each strain per 0.1 mL dose. In comparison, all adult IM vaccines (except for Fluzone High-Dose) contain 15 mcg HA of each strain per 0.5 mL dose. Fluzone Intradermal uses a microinjection system with a 0.06-inch needle; the IM adult vaccines have a needle 1 to 1.5 inches in length. Current CDC recommendations give no preference to either the IM or ID formulations.2
A phase 2 multicenter, randomized, partially blinded, noninferiority study tested the safety and immunogenicity of a single dose of TIV administered IM or ID.6 A total of 1592 patients aged 18 to 64 were enrolled and stratified into 18- to 49-year-old and 50- to 64-year-old groups. Patients were then randomized to receive either a 3 mcg ID dose administered by the Mantoux method, a 6 mcg or 9 mcg ID dose administered using the Fluzone Intradermal microinjection system, or a 15 mcg IM dose. Only data from the 9 mcg ID and 15 mcg IM groups are discussed here. The primary endpoint of the study was the anti-HA antibody geometric mean titers (GMT) for each strain of influenza at 21 days post-vaccination. Noninferiority with respect to GMT was defined by a value of <log101.5 for the upper boundary of the 95% confidence interval (CI) of the difference between the 15 mcg IM group and the 9 mcg ID group in the per protocol analysis. Superiority was evaluated if noninferiority was found. Secondary endpoints were seroconversion rates and seroprotection rates. Local and systemic adverse events within 30 minutes of injection, solicited adverse events for 7 days following injection, unsolicited adverse events for 21 days following injection, and serious adverse events for 6 months following injection were monitored. Solicited adverse events included injection site pain, itching, erythema, swelling, fever, headache, malaise, and myalgia.
The 9 mcg dose of Fluzone Intradermal was found to be noninferior to 15 mcg IM with respect to GMT for all strains tested with post-vaccination GMT values for the 9 mcg ID and 15 mcg IM groups of 116 and 121 for the A/H1N1 strain, 615 and 593 for the A/H3N2 strain, and 83 and 87 for the B strain, respectively.6 More than 95% of patients in all groups achieved seroconversion, defined as a GMT titer ≥1:40 post-vaccination or a 4-fold increase from baseline. Rates of seroprotection, defined as the proportion of patients with a GMT titer ≥1:40 post-vaccination, were noninferior with values for the 9 mcg ID and 15 mcg IM groups of 81% and 85.3% for the A/H1N1 strain, 99.5% and 99.7% for the A/H3N2 strain, and 76.2% and 81.4% for the B strain, respectively. Superiority of the ID route was not shown for any strain compared to the IM route. Geometric mean titer response and seroprotection rates were significantly greater for patients in the 18- to 49-year-old strata than for those 50- to 64-years-old for each vaccine strain.
All injection site reactions were more common with 9 mcg ID versus the IM group including erythema (74% vs. 3%), swelling (27% vs. 1.3%), pain, and itching.6 These reactions generally resolved within 7 days and were mild or moderate in nature. For pain associated with injection, the 9 mcg ID group reported a mean score of 17.31 while the 15 mcg IM group reported a score of 10.52 on a scale with 0 indicating no pain and 100 indicating maximal pain; however, the 9 mcg ID group reported less pain at the site of injection during the 7 days following administration than subjects in the IM group (42.7% vs. 54%). There were 191unsolicited adverse events reported by the 9 mcg ID group and 104 by the 15 mcg IM group within 21 days of vaccination; headache, upper respiratory infection symptoms, and diarrhea were most common. The only serious adverse event related to study participation (exacerbation of multiple sclerosis) occurred in a patient in the 9 mcg ID group.
A phase 3 multicenter, randomized, open-label noninferiority study, upon which the approval of Fluzone Intradermal was based, found similar results. 5 Though the results of the study are not published, limited immunogenicity and safety data are reported in the product labeling. Patients aged 18 to 64 years were included in the study; 2581 received 9 mcg of Fluzone Intradermal and 1287 received 15 mcg Fluzone IM. Noninferiority with respect to GMT was defined by a value of <1.5 for the upper bound of the 95% CI of the ratio of the 15 mcg IM group to the 9 mcg ID group. The 9 mcg dose of Fluzone Intradermal was shown to be noninferior to 15 mcg IM with respect to GMT for all strains tested with GMT ratios of 0.92 (95% CI 0.85 to 1.01) for the A/H1N1 strain, 0.94 (95% CI 0.85 to 1.03) for the A/H3N2 strain, and 1.24 (95% CI 1.15 to 1.33) for the B strain. Noninferiority with respect to seroconversion was defined by a value of <10% for the upper boundary of the 95% CI of the difference in seroconversion rates between groups at 28 days. The 9 mcg ID dose was found to be noninferior with respect to seroconversion for the A/H1N1 and A/H3N2 strains with differences of -0.69% (95% CI -3.97 to 2.56) and -0.55% (95% CI -3.49 to 2.31) respectively, but not for the B strain with a difference of 7.99% (95% CI 4.64 to 11.31).
The safety analysis in the phase 3 trial included 2855 patients in the 9 mcg Fluzone Intradermal and 1421 patients in the 15 mcg Fluzone IM groups. 5 All injection site reactions except pain were more common in the 9 mcg ID group, including erythema (76.4% vs. 13.2%), induration (58.4% vs. 10%), swelling (56.8% vs. 8.4%), pruritis (46.9% vs. 9.3%), and ecchymosis (9.3% vs. 6.2%). Injection site pain was experienced by 51% of patients in the 9 mcg ID group and 53.7% of patients in the 15 mcg IM group. Forty-nine percent of patients in the 9 mcg ID group versus 9% in the 15 mcg IM group had injection site reactions that persisted past day 3. Systemic adverse events within 7 days of vaccination, serious adverse events within 28 days, and serious adverse events within 6 months were similar between the groups.
Despite a greater proportion of patients experiencing injection site reactions with Fluzone Intradermal, patients have generally found the product acceptable. In the phase 2 study, 73% of patients in the 9 mcg ID group thought the injection was similarly or less painful than IM administration with 50% describing it as less painful.6 Additionally, 98% of patients reported they would be willing to have another vaccine administered using the same microinjection system.
Administration of the vaccine by the ID route may take advantage of the immunological activity of the skin.4,7 The dermis contains specialized antigen-presenting cells that capture and transport antigens to lymph nodes, leading to humoral and cellular immune responses. Using the ID route may lead to improved immunogenicity compared to IM administration with smaller amounts of antigen needed.6 In the event of a shortage, this may help ensure availability of sufficient vaccine supply.
Additionally, while the traditional Mantoux method for ID injection requires healthcare providers with specialized training to reliably administer a medication into the dermis, the microinjection system used with Fluzone Intradermal helps ensure reliable and correct placement of the needle and delivery of medication without specialized training.4,6 In the phase 2 study of Fluzone Intradermal, the microinjection system was reportedly easy to use and reliable in delivering medication into the dermis.6 Importantly, immunizing pharmacists do not need any additional training to administer Fluzone Intradermal.8 The list price for Fluzone Intradermal is reported to be $15.50 per single-dose syringe.9 This is comparable to the price of the IM formulation, which ranges from $7.83 to $13.60 per dose and the intranasal formulation which is $19.70 per dose.10
Fluzone Intradermal is licensed for all patients aged 18 to 64 years and is included as an option in current CDC influenza recommendations. Given the noninferior efficacy of the ID influenza vaccine and increased rates of adverse effects related the site of injection, the ID formulation should not generally be recommended over the IM formulation. Nonetheless, patients have found the product acceptable, and the injection system is reportedly easy to use. With no additional training needed for providers and cost comparable to the IM formulation, Fluzone Intradermal has the potential for widespread availability and may be a good option for increasing vaccination rates. Overall, Fluzone Intradermal is an appropriate alternative to the traditional IM formulation and should be available for patients and providers who prefer the ID route due to a fear of needles or an aversion to the IM or intranasal routes.
- Njoku JC, Hermsen ED. Influenza. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. http://www.accesspharmacy.com/Content.aspx?searchStr=influenza&aid=8002170 . Accessed October 11, 2011.
- Centers for Disease Control and Prevention. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2011;60(33):1128-1132.
- U.S. Department of Health and Human Services. Healthy People 2020: Immunization and Infectious Diseases. http://www.healthypeople.gov/2020/topicsobjectives2020/overview.aspx?topicid=23 . Accessed October 11, 2011.
- Falsey AR. New emerging technologies and the intradermal route: the novel way to immunize against influenza. Vaccine. 2010;28 Suppl 4:D24-D32.
- Fluzone [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2011.
- Frenck RW, Belshe R, Brady R, et al. Comparison of the immunogenicity and safety of a split-virion, inactivated, trivalent influenza vaccine (Fluzone) administered by intradermal and intramuscular route in healthy adults. Vaccine. 2011;29(34):5666-5674.
- Reygrobellet C, Viala-Danten M, Meunier J, Weber F, Nguyen VH. Perception and acceptance of intradermal influenza vaccination: patient reported outcomes from phase 3 clinical trials. Hum Vaccine. 2010;6(4):336-345.
- Foster S, Rothholz M. Intradermal Influenza Administration With Fluzone ID. American Pharmacists Association Pharmacist Immunization Center. http://www.pharmacist.com/AM/CM/ContentDisplay.cfm?ContentFileID=6656 . Accessed October 11, 2011.
- Mitchell D. Microinjection Flu Vaccine Product Approved by FDA. American Academy of Family Physicians News Now. http://www.aafp.org/online/en/home/publications/news/news-now/health-of-the-public/20110512intradermalfluvacc.html . Accessed October 11, 2011.
- Centers for Disease Control and Prevention. CDC Vaccine Price List. http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm. Accessed October 11, 2011.
Written By :Matthew Brew, PharmD candidate, class of 2012
What is the role of telaprevir and boceprevir in the treatment of chronic hepatitic C infection?
What is the role of telaprevir and boceprevir in the treatment of chronic hepatitic C infection?
New recommendations from the American Association for the Study of Liver Diseases
Hepatitis is an inflammation of the liver that may be caused by a variety of toxic or infectious agents such as viruses. Hepatitis B and C are examples of viral causes of liver inflammation.1 The hepatitis C virus (HCV) is a single-stranded ribonucleic acid (RNA) virus. Overall, an estimated 3.2 million individuals are infected with chronic HCV in the United States. Individuals at increased risk of HCV infection include human immunodeficiency virus (HIV)-infected individuals, children born to HCV-positive mothers, patients on chronic hemodialysis, current or former injection drug users, patients who received clotting factors prior to 1987 or those who were given blood transfusions or solid organ transplants before July 1992, and individuals with known exposure such as healthcare workers who sustain a needlestick injury from an infected patient or patients who receive transfusions or transplants from an infected individual. Although a small percentage of patients (15% to 25%) can clear HCV from their bodies and not develop chronic infection, the majority of patients (75% to 85%) become chronically infected with HCV.
Hepatitis C infection is transmitted primarily through large or repeated percutaneous exposures to infectious blood.2 These exposures can occur through injection drug use, needlestick injuries, perinatal transmission, and receipt of infected blood, blood products, or organs. The virus is infrequently transmitted through sexual contact or the sharing of personal items contaminated with HCV-infected blood (e.g, toothbrushes or razors). The signs and symptoms of acute HCV infection are usually mild if symptoms occur at all. Initial symptoms include fever, fatigue, jaundice, abdominal pain, nausea, and vomiting; these occur in 20% to 30% of newly infected individuals with a usual onset of 4 to 12 weeks from the initial exposure. The majority of patients chronically infected with HCV are asymptomatic; however, the disease may become severe leading to eventual cirrhosis and liver cancer. Approximately 8,000 to 10,000 deaths are attributed to chronic HCV infection in the United States annually.
Interferons in combination with ribavirin have long been considered the mainstay of therapy for HCV infection.3 Telaprevir and boceprevir, NS3/4A serine protease inhibitors, were approved in May 2011 and represent a new class of drugs to treat HCV.4 These agents inhibit the replication of HCV genotype 1 and have been effective in improving sustained virologic response (SVR) in both treatment-naïve and treatment-experienced patients.5
Boceprevir has been evaluated in 2 randomized, multicenter, phase III trials (RESPOND-2 and SPRINT-2).6,7 Both trials compared the addition of boceprevir or placebo to standard therapy (pegylated interferon alfa-2b plus ribavirin). All patients in the phase III studies received standard therapy for 4 weeks as a lead-in (to assess responsiveness to interferon) followed by addition of boceprevir or placebo to standard therapy. Traditional 48-week therapy (including the lead-in phase) was compared to "response-guided" therapy as follows:
- Response-guided investigational regimens: boceprevir 800 mg 3 times daily plus pegylated interferon alfa-2b plus ribavirin for 24 (SPRINT-2) or 36 weeks (RESPOND-2); subsequent therapy based on HCV RNA levels at various timepoints (patients not required to complete 48 weeks of treatment)
- 48-week investigational regimen: boceprevir plus standard therapy for 44 weeks
- 48-week regimen (control group): standard therapy plus placebo for 44 weeks
The primary outcome measure was SVR. The RESPOND-2 trial enrolled patients with chronic genotype 1 HCV who were nonresponders or relapsers to prior pegylated interferon plus ribavirin therapy.6 The addition of boceprevir 800 mg 3 times daily to pegylated interferon alfa-2b plus ribavirin was associated with improved SVR (p<0.001 for both boceprevir groups [response-guided and 48-week regimen] vs. control) and reduced the rate of relapse (p value not reported) compared to standard therapy. No significant differences were found between boceprevir-containing regimens; however, the primary statistical comparison was to assess each boceprevir regimen compared to the standard therapy.
The SPRINT-2 trial enrolled previously untreated patients with HCV genotype 1.7 Results were analyzed separately for black and nonblack patients due to differences seen in SVR. Results revealed that rates of SVR were significantly improved with boceprevir in both cohorts compared to standard therapy. Rates of SVR among nonblack patients were 40% with standard therapy, 67% with boceprevir response-guided therapy (p<0.001 vs. standard therapy), and 68% with the 48-week boceprevir-containing regimen (p<0.001 vs. standard therapy). Rates of SVR were lower among black patients; however, addition of boceprevir to response-guided standard therapy (42%, p=0.04 vs. standard therapy) or combination of boceprevir plus standard therapy for 44 weeks (53%, p=0.004 vs. standard therapy) significantly improved rates compared to standard therapy (23%).
A prior phase II trial, SPRINT-1 demonstrated superior efficacy of boceprevir added to pegylated interferon alfa-2b plus ribavirin compared to standard therapy alone in treatment-naïve patients with HCV.8 There is no published experience with boceprevir in combination with pegylated interferon alfa-2a at this time.
Telaprevir has also been evaluated in treatment-naïve patients with chronic HCV as well as those who have failed to achieve an SVR with pegylated interferon in combination with ribavirin.9 REALIZE was a phase III, randomized, double-blind, placebo-controlled multicenter trial that evaluated the addition of telaprevir 750 mg every 8 hours to pegylated interferon alfa-2a plus ribavirin compared to standard therapy alone in patients who had no response or partial response to previous therapy or relapse after initial response. Forty-eight week treatment regimens included:
- Triple therapy for 12 weeks followed by standard therapy for 36 weeks
- Standard therapy for 4 weeks followed by triple therapy for 12 weeks followed by standard therapy for 32 weeks (lead-in)
- Standard therapy for 48 weeks (control group)
Rates of SVR were 83% (triple therapy), 88% (lead-in), and 24% (control group), respectively, among patients who had a previous relapse; 59%, 54%, and 15%, respectively for previous partial responders; and 29%, 33%, and 5%, respectively for previous nonresponders (p<0.001 for all comparisons to standard therapy). The lead-in phase did not offer any benefit. The PROVE-3 was a randomized, double-blind, placebo-controlled multicenter phase II trial also conducted in previously treated patients.10 In this study, telaprevir was given as a loading dose (1125 mg) followed by 750 mg every 8 hours in various combinations with standard therapy. As in REALIZE, SVR rates were significantly improved among telaprevir recipients (24% to 53%) compared to 14% with standard therapy (all p values <0.05).
The major phase III trials involving telaprevir for treatment-naïve patients are ILLUMINATE and ADVANCE.11,12 ILLUMINATE, an open-label study, has not been published, but has been summarized in the prescribing information.11 The main outcome was SVR rates among patients treated with telaprevir in combination with standard therapy who achieved an extended rapid virologic response (eRVR). Triple therapy was given for 12 weeks followed by 24 or 48 weeks of standard therapy. The trial was designed to assess noninferiority of the 24-week regimen to the 48-week regimen. The overall SVR rate was 74%. Rates of 92% (24-week regimen) and 90% (48-week regimen) were seen for patients who had an eRVR; therefore, noninferiority was established.
ADVANCE was a randomized, double-blind, placebo-controlled trial that investigated the addition of telaprevir 750 mg every 8 hours to standard therapy. 12 There were 3 regimens:
- Triple therapy for 12 weeks followed by standard therapy for 12 or 36 weeks (based on response)
- Triple therapy for 8 weeks followed by standard therapy for 12 or 36 weeks (based on response)
- Standard therapy for 48 weeks.
The SVR was significantly higher among telaprevir recipients (p<0.001 for both groups vs. standard therapy). Based on HCV viral assessments and achievement of eRVR (extended rapid virologic response), 58% of telaprevir recipients were eligible for 24 weeks of treatment instead of 48 weeks.
Two phase II trials (PROVE-1 and PROVE-2) found the addition of telaprevir to be more effective than standard therapy in terms of achieving an SVR. 13,14 These trials used a telaprevir loading dose (1250 mg) followed by 750 mg every 8 hours in various regimens. The loading dose is not currently indicated. The aforementioned telaprevir trials all involved standard therapy with pegylated interferon alfa-2a plus ribavirin.
At this time, there are no published comparisons of boceprevir and telaprevir.
Key features of the 2011 update
In October 2011, the American Association for the Study of Liver Diseases (AASLD) published an update on the treatment of genotype 1 HCV.5 In general, boceprevir or telaprevir, in combination with peginterferon alfa and ribavirin are optimal treatments for genotype 1 HCV; however, neither should be used as single therapy. The guidelines do not address when triple-drug therapy is preferred or what treatment is recommended in specific patient populations. Below is a summary of additional recommendations.
- After a 4-week lead-in phase of ribavirin and peginterferon alfa, boceprevir should be administered at a dose of 800 mg 3 times daily with food, in combination with the other agents, for 24 to 44 weeks.
- Patients without cirrhosis and undetectable HCV RNA levels at weeks 8 and 24 may be treated with boceprevir-based triple-drug therapy for a total of 28 weeks.
- Boceprevir-based triple-drug therapy should be stopped when the HCV RNA level is >100 international units/mL at week 12 or detectable at week 24.
- Telaprevir 750 mg 3 times daily with food should be administered with peginterferon alfa and ribavirin for 12 weeks followed by 12 to 36 weeks of only peginterferon alfa and ribavirin.
- Patients without cirrhosis and undetectable HCV RNA levels at weeks 4 and 12 may be treated with telaprevir-based triple-drug therapy for a total of 24 weeks.
- Triple therapy in patients with cirrhosis, with either boceprevir or telaprevir, should be administered for 48 weeks.
- Telaprevir-based triple-drug therapy should be stopped if the HCV RNA level is >1000 international units at treatment weeks 4 or 12 or detectable at week 24.
- Partial responders with a prior course of therapy may be re-treated with triple therapy with either boceprevir or telaprevir.
- Re-treatment with telaprevir may be considered in combination with standard therapy for nonresponders.
- Patients who have relapsed or had partial response may use response-guided therapy with either boceprevir or telaprevir; however, this is not recommended for patients that have not responded.
- Due to the chance of developing antiviral resistance, therapy should be stopped in patients treated with boceprevir-based triple therapy who have detectable HCV RNA levels >100 international units at week 12 and in patients treated with telaprevir-based triple therapy who have HCV RNA levels >1000 international units at weeks 4 or 12.
- The ribavirin dose should be reduced in patients on triple therapy that develop anemia.
- HCV RNA levels should be closely monitored; patients who fail one protease inhibitor should not be re-treated with the other.
The 2011 AASLD guidelines provide specific guidelines for use of boceprevir ad telaprevir; however, one agent is not recommended over the other. The following factors should be considered when choosing a protease inhibitor for HCV:11, 15,16
- Adverse effects: anemia and dysgeusia with boceprevir; rash (sometimes severe), pruritis, and gastrointestinal effects with telaprevir
- Pill burden: boceprevir 800 mg (four 200 mg capsules) 3 times daily versus telaprevir 750 mg (two 375 mg tablets) 3 times daily
- Cost: boceprevir ($5656/month) versus telaprevir ($21,085/month); however, the duration of therapy for telaprevir is shorter
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