WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

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1 18th Expert Committee on the Selection and Use of Essential Medicines 1 (21 to 25 March 2011) Section Antiretrovirals -- Raltegravir (Adults) WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION 1. Summary statement Inclusion of the tablet formulation of raltegravir 400mg is proposed for treatment of multi-drug resistant HIV among adults living with HIV/AIDS. The principal reasons for requesting this inclusion are as follows: 1. Adults living with multi-drug resistant HIV in resource-limited settings presently have limited options for their infection. 2. WHO Guidelines recommend raltegravir for third-line antiretroviral therapy (ART). 3. Treatment of HIV will be improved with wider availability of this tablet. 2. Name of the focal point in WHO submitting or supporting the application Marco Vitoria, WHO/HTM/HIV/ATC 3. Name of the organization(s) consulted and/or supporting the application applicable 4. International Nonproprietary Name (INN, generic name) of the medicine Raltegravir 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Raltegravir 400 mg tablet for adult patients. 6. International availability - sources, if possible manufacturers Merck Sharp & Dohme Ltd (Manufactured in Netherlands) 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group This medication is proposed for the Antiretrovirals category (6.4.2). Since raltegravir (RAL) has a novel mechanism of action, it inhibits the integrase enzyme in HIV, we propose including it in a new category: Integrase inhibitors ( ) 8. Information supporting the public health relevance 8.1 Epidemiological information on disease burden As of December 2008, 95% of the world s 33.4 million people living with HIV/AIDS (PLHIV) were in low and middle income countries (1). In 2008 there were 2.7 million new HIV infections and two million AIDS-related deaths. (2) (1).

2 In the end of 2009 there were approximately 5.25 million people in low and middle income countries on antiretroviral therapy (36% of those in need of therapy). (3). Resistance to ART may emerge due to inappropriate prescribing of ART (monotherapy or dual therapy), treatment interruptions due to suboptimal patient adherence, poor patient retention on ART, or ART supply shortages or stock-outs at unacceptably high levels (4). Years gained due to antiretroviral therapy can be wiped away without effective treatment of drug-resistant HIV. Therefore, adding the antiretrovirals recommended in the 2010 WHO Antiretroviral Therapy guidelines is critical. 8.2 Assessment of current use The WHO does not collect statistics on the number of persons on raltegravir. 8.3 Target population HIV-infected adults who have failed WHO-recommended first and second-line regimens. 9. Treatment details 9.1 Reference to existing WHO and other clinical guidelines The 2010 WHO adult antiretroviral therapy guidelines make the following recommendations for third-line regimens: 1. National programmes should develop policies for third-line therapy that consider funding, sustainability, and the provision of equitable access to ART. (Conditional recommendation, low quality of evidence) 2. Third-line regimens should include new drugs likely to have anti-hiv activity, such as integrase inhibitors and second-generation NNRTIs and PIs. (Conditional recommendation, low quality of evidence) 3. Patients on a failing second-line regimen with no new ARV options should continue with a tolerated regimen. (Conditional recommendation, very low quality of evidence) The 2010 IAS-USA guidelines recommend three active drugs for HIV resistant to protease inhibitors and non nucleoside reverse transcriptase inhibitors (5). These guidelines recommend the use of new classes of agents (integrase or entry inhibitors) in this scenario. The 2009 DHHS guidelines recommend a goal viral load of < 50 cp/ml in persons with multidrug resistant HIV(1). No recommendation on use of particular agents were made since there is remarkable heterogeneity in first and second line antiretroviral therapy regimens in the USA, and use of third-line regimens are therefore highly individualized. 9.2 Dosage regimens and duration Raltegravir must always be given in combination with other antiretrovirals. ART-experienced adults: RAL 400mg twice daily without regard to food. Hepatic impairment: Dosage adjustment is not needed in patients with mild to moderate hepatic impairment (Child-Pugh score A or B). Pharmacokinetics of raltegravir have not been studied in patients with severe hepatic impairment (Child-Pugh score C). 2

3 Renal impairment: Dosage adjustment is not needed in patients with renal impairment. 9.3 Need for special diagnostic or treatment facilities and skills needed 10. Summary of comparative effectiveness in a variety of clinical settings: 10.1 Identification of clinical evidence Search strategy Pubmed Search "MK 0518" [Substance Name] 278 By title: 5 By abstract: 6 By article: 4* The critical outcomes of interest were viral suppression (< 50 copies/ml and/or < 400 copies/ml), deaths, new AIDS-defining conditions (6), and adverse events causing treatment cessation. Wikktop et al. (7) was excluded because this study used viral load reduction rather than viral suppression as their efficacy outcome. Cooper et al. (8) was excluded because this study focused on RAL resistance mutations that developed during follow-up and on efficacy subanalyses of the Steigbigel et al. publication (9). The four studies reviewed in this application for third-line use of raltegravir are as follows: 1. Gatell JM, Katlama C, Grinsztejn B, et al. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. J Acquir Immune Defic Syndr Apr 1;53(4): (10) 2. Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drugresistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis Feb 15;50(4): (11) 3. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med Jul 24;359(4): (9) 4. Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet Apr 14;369(9569): (12) 3

4 Study summaries for RAL 400mg twice daily can be found in Annex 1 and 2. The data indicate that RAL suppresses multidrug resistant HIV in adults living with HIV. It is also well tolerated with % of adults on RAL experiencing an adverse event causing RAL discontinuation after 96 weeks of follow-up (11,10) Summary of available estimates of comparative effectiveness Studies comparing the effect of RAL to other antiretrovirals on multi-drug resistant HIV were not found. Studies comparing the effect of RAL to other antiretrovirals in antiretroviral-naïve adults are available, however this comparison is outside of WHO s medical indication for RAL (i.e. use in third-line regimens). 11. Summary of comparative evidence on safety: 11.1 Estimate of total patient exposure to date There are no sources which indicate total exposure to RAL Description of adverse effects/reactions The most common adverse events were abdominal distension, diarrhea, nausea, vomiting, fatigue, pyrexia, and headache (11). Please see appendix three for a table describing the adverse events seen after 96 weeks of follow up in patients on placebo and RAL Identification of variation in safety due to health systems and patient factors No clinically significant differences in safety have been identified due to differences in health systems and patient factors Summary of comparative safety against comparators Please see appendix three for a table describing the adverse events seen after 96 weeks of follow up in patients on placebo and RAL. 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group*: 12.1 Range of costs of the proposed medicine Raltegravir pricing USD Price/Year (for RAL 400 Source mg B.I.D.) MSF (13) 1113 WHO Global Price Reporting 1117 Mechanism (14) Management Sciences for 1169 Health (15) 12.2 Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained) No cost-effectiveness analyses for use of RAL were identified in the MEDLINE search. 13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) Raltegravir is registered with the Food and Drug Administration in the United States (Merck Sharp & Dohme Corporation). Raltegravir is registered with the European Medicines Agency (Merck Sharp & Dohme Corporation). 4

5 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) Raltegravir is available in the United States Pharmacopoeia. Raltegravir is not available in the International Pharmacopoeia. The status of raltegravir in the British pharmacopoeia is unknown, as there was no publicly available version of it available online. 15. Proposed (new/adapted) text for the WHO Model Formulary *e the AHFS Drug Information book was used as a reference for this section (32). Dosage forms: 400mg tablet Description: Raltegravir is an inhibitor of HIV s integrase enzyme. Uses: Treatment of HIV in combination with at least two other antiretrovirals in third-line therapy. Contraindications: Hypersensitivity to RAL or to any of the excipients. Precautions: Increased serum creatine kinase concentrations have been observed in patients receiving RAL. Myopathy and rhabdomyolysis have been reported rarely, although the relationship to RAL is unknown. Therefore, RAL should be used with caution in patients at increased risk of myopathy or rhabdomyolysis. Doses: Raltegravir 400mg BID in combination with at least two other antiretrovirals in thid-line therapy. Adverse effects: The most common adverse events reported were insomnia, headache, nausea, asthenia, and fatigue. Pregnancy: Safety of RAL in pregnant women has not been established. Drug Interactions Concomitant use with drugs that are strong inducers of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 may result in decreased plasma concerntrations of raltegravir. Concomitant use with drugs that are strong inhibitors of UGT 1A1 may result in increased plasma concentrations of raltegravir. Rifampicin is a strong inducer of UGT 1A1. Rifabutin is a weaker inducer and should be considered in this scenario, although both rifamycins have potential to decrease RAL concentrations. If rifampicin is the only available anti-tuberculosis medication available, increasing RAL to 800mg BID should be considered in order to maintain an adequate RAL area under the curve (16). Dosage adjustment of RAL does not appear to be necessary when given with ritonavir boosted atazanvir. Etravirine and efavirenz both decrease serum concentrations of RAL, however the clinical importance is unknown. 5

6 Annex 1: Summary of selected studies for raltegravir Author (Year) Grinsztejn et al. (2007) Gatell et al. (2010) Steigbigel et al. (2008) Steigbigel et al. (2010) Methods/design Participants VL < 50 cp/ml VL < 400 cp/ml Adverse events Losses to follow up Double-blind, randomised, dose-ranging, 24- week study comparing RAL 200mg BID, 400mg BID. 600mg BID, and placebo BID. This is the 96- week follow-up data from the Grinsztejn et al. study Double-blind, randomised 48- week study comparing RAL 400mg BID to placebo This is the 96- week follow-up data from the earlier Steigbigel et al. study Non-pregnant HIV-seropositive patients 18 years of age were eligible if they had plasma HIV-1 RNA levels 5000 copies/ml and CD4+ T-cell (CD4) counts 50 cells/mm3 on stable ART for more than 3 months and were infected with HIV-1 with documented genotypic and phenotypic resistance to at least 1 NNRTI, 1 NRTI, and 1 PI. Of the 179 participants, 45 were randomised to RAL 400mg BID and 45 were randomised to placebo BID. 44 were randomised to RAL 200mg BID and 45 were randomised to RAL 600 mg BID. This is a follow-up of the Grinsztejn et al. study. Since only 6 patients in the placebo group completed more than 24 weeks, their data were not presented as a comparator group. Of the 133 participants randomised to all RAL groups 94, (71%) entered the open-label phase, during which participants in other study arms were eligible to receive RAL 400mg BID as part of an open label extension. 86 (65%) completed at least 96 weeks of follow up. HIV-infected patients 16 years of age or older were eligible if they had HIV-1 RNA levels of more than 1000 cp/ml while receiving ART, with documented resistance to 1 drug in each of following classes: NNRTI, NRTI, and PI). Of the 699 participants, 462 were randomised to RAL 400mg BID and 237 were randomised to placebo BID. Of the 462 originally randomised to RAL 400mg BID, 302 remained in the study. Of the 237 randomised to placebo, 67 remained in the study. 6 13% of placebo and 56% of RAL reached this level of viral suppression after 24 weeks. This threshold of suppression was achieved in 55% of participants after 48 weeks, and in 48% of participants after 96 weeks. 33% of placebo and 63% of RAL reached this level of viral suppression after 48 weeks. 26% of placebo and 57% of RAL reached this level of viral suppression after 96 weeks. 16% of particpants on placebo 71% of RAL reached this level of viral suppression after 24 weeks. This threshold of suppression was achieved in 68% of participants after 48 weeks, and in 55% of participants after 96 weeks. 37% of placebo 73% of RAL reached this level of viral suppression after 48 weeks. One individual on placebo discontinued due to lipoatrophy. No treatment limiting adverse events in RAL 400mg BID arm. After 96 weeks of RAL exposure, 6 of 133 participants discontinued RAL due to an adverse event. 2 of 45 placebo discontinued to an adverse event 6 of 462 participants discontinued RAL due to an adverse event. 1 of 237 participants discontinued placebo due to an adverse event. 17 of the 462 RAL discontinued due to an adverse event. 12 of the 237 placebo discontinued due to an adverse event None. 5 of 45 participants on RAL 400mg BID discontinued due to to lack of efficacy (LOE). 27 of 45 partipants on placebo discontinued due to LOE, one discontinued due to an adverse event. This was an open-label observational study. 35% of the 86 on RAL 400mg BID after the randomised 24-week trial did not complete the 96 weeks of follow-up. 24 of the 462 participants (5%) on RAL discontinued during the study period. 15 of the 237 participants (6%) on placebo discontinued during the study period 70 of the 302 (15%) RAL discontinued the study during follow up. 41 of the 237 participants (17.3%) on placebo discontinued the study during follow up

7 Annex 2: Evidence review for raltegravir Author(s): Amitabh Suthar Bibliography: Gatell (2010), Grinsztejn (2007), Steigbigel (2008), Steigbigel (2010) Publications Comparison Follow up N % with VL < 50 cp/ml, RAL % with VL < 50 cp/ml, Placebo % with VL < 400 cp/ml, RAL % with VL < 400 cp/ml, placebo Deaths/Personyears on RAL (Rate/100 PY) Death/Personyears on placebo (Rate/100 PY) AE/Persons exposed to RAL (Rate/100 PY)* AE/Persons exposed to placebo (Rate/100 PY)* Steigbigel et al. CID Weeks % 26% 13/824 (1.58) 7/269 (2.60) 17/462 (1.60) 12/237 (2.60) Steigbigel et al. NEJM 2008 Steigbigel et al. NEJM Weeks % 33% 73% 37% 10/462 6/237 6/462 1/ Weeks % 35% 78% 42% Gatell et al. JAIDS Weeks % 55% 6/133 2/45 Gatell et al. JAIDS Weeks % 68% Grinsztejn et al. Lancet Weeks 90 56% 13% 71% 16% * AE represents adverse drug events causing treatment cessation 7

8 Appendix 3. Clinical adverse events after 96 weeks of follow up (11) Variable Raltegravir and OBT (n = 462) Placebo and OBT (n = 237) Duration on therapy, mean weeks Person years at risk Clinical adverse events Any 92.9 (52.1) 88.6 (78.0) Drug-related 58.4 (32.8) 58.6 (51.6) Serious 25.3 (14.2) 22.4 (19.7) Serious drug-related 2.8 (1.6) 3.8 (3.3) Deaths 2.8 (1.6) 3.0 (2.6) Requiring discontinuation of treatment 3.7 (2.1) 5.1 (4.5) Drug-related adverse events (incidence 2%) Abdominal distension 2.2 (1.2) 1.7 (1.5) Diarrhea 3.2 (1.8) 5.1 (4.5) Nausea 4.1 (2.3) 4.6 (4.1) Vomiting 1.5 (0.8) 2.1 (1.9) Fatigue 3.2 (1.8) 0.8 (0.7) Pyrexia 0.9 (0.5) 2.5 (2.2) Headache 4.8 (2.7) 5.1 (4.5) Data are percentages of patients with adverse events. Data in parentheses are cases/100 person-years at risk. OBT, optimized background therapy. 8

9 Bibliography 1. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents [Internet]. [cited 2010 Nov 8];Available from: 2. UNAIDS 2009 AIDS Epidemic Update [Internet]. [cited 2009 Nov 30];Available from: 3. WHO Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector [Internet]. [cited 2010 Nov 8];Available from: 4. Hong SY, Jonas A, Dumeni E, Badi A, Pereko D, Blom A, et al. Population-Based Monitoring of HIV Drug Resistance in Namibia With Early Warning Indicators. J Acquir Immune Defic Syndr Dec 1;55(4): Thompson MA, Aberg JA, Cahn P, Montaner JSG, Rizzardini G, Telenti A, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA Jul 21;304(3): Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults [Internet]. [cited 2010 Nov 8];Available from: 7. Wittkop L, Breilh D, Da Silva D, Duffau P, Mercié P, Raymond I, et al. Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort. J. Antimicrob. Chemother Jun;63(6): Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N. Engl. J. Med Jul 24;359(4): Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med Jul 24;359(4): Gatell JM, Katlama C, Grinsztejn B, Eron JJ, Lazzarin A, Vittecoq D, et al. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. J. Acquir. Immune Defic. Syndr Apr 1;53(4): Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin. Infect. Dis Feb 15;50(4): Grinsztejn B, Nguyen B, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet Apr 14;369(9569):

10 13. Untangling the Web of Antiretroviral Price Reductions [Internet]. [cited 2010 Nov 24];Available from: WHO Global price reporting mechanism [Internet]. [cited 2010 Nov 24];Available from: ERC - International Drug Price Indicator Guide [Internet]. [cited 2010 Nov 24];Available from: Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, et al. Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir. Antimicrob. Agents Chemother Jul 1;53(7):