Single Pill Combinations Versus Generics: Prescribing Practices in a New Healthcare Era

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1 Activity Code FM285

2 Single Pill Combinations Versus Generics: Prescribing Practices in a New Healthcare Era Monica Gandhi MD, MPH Clinic Director, Ward 86 HIV Clinic, SFGH/UCSF

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Review the role of single pill combinations (SPCs) in HIV treatment and the advantages and disadvantages of available SPCs Assess how the availability of generics may change cost-benefit considerations for SPCs in HIV treatment

4 Outline The problem of adherence Does co-formulating the pills help? Current single pill combinations (SPCs) Pros and cons Anticipated SPCs for HIV SPCs, healthcare reform and generics

5 Case 52 yo AA man with HIV CD4 257, viral load 17,000 copies/ml, marginally housed, depression, and polysubstance use. Presents to SFGH with PNA. Pt originally diagnosed w/ HIV in 05 and has had trouble adhering to ARVs in past. After treatment for PNA, ID Consult Service called for ARV recommendations. Virus W.T., HLA-B5701 negative, Cr 1.0, LFTs WNL; team concerned about adherence

6 Which ART regimen would you start given the pt s problems with adherence? A. TDF/FTC/EFV B. TDF/FTC + darunavir/ritonavir C. TDF/FTC + atazanavir/ritonavir D. TDF/FTC + raltegravir E. TDF/FTC/EVG/cobicistat F. ABC/3TC + dolutegravir 14% 14% 14% 14% 14% 14% 14% G. TDF/FTC + dolutegravir A. B. C. D. E. F. G. 8

7 Case (continued) The patient was prescribed multi-pill ART 2 months ago but hasn t taken regularly, because taking out lots of pills in the shelter just announces to the world that I have AIDS. Pt states he would take medications regularly if he could just take one pill once a day. Not on concomitant meds, but has h/o HTN and pt says he wants one pill so they will think this is for my blood pressure

8 Adherence Nonadherence has been labeled America s other drug problem National Council on Patient Information and Education: statistics on medicine use and compliance. utrx.org/

9 In era of universal ART in U.S., adherence is key HIV Infection ART is recommended for all HIVpositive individuals for individual and community-level benefits DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available at: March 27, 2012; last updated 5/1/14

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11 CDC vital statistics Vital Signs: HIV Prevention Through Care and Treatment United States, MMWR December 2, 2011 / 60(47); Medical Monitoring Project (MMP) 3 surveillance datasets. Adherence

12 The Clinical Problem Multiple adherence barriers Combination ART- Major benefits for individual and community, but requires lifelong adherence to multicomponent therapy Depression Race/ethnicity Alcohol/substance use Younger age Pill fatigue Side effects Stigma

13 A new era

14 Which is your preferred SPC for HIV? A. TDF/FTC/efavirenz B. TDF/FTC/rilpivirine C. TDF/FTC/ elvitegravir/ cobicistat D. I am still waiting for my favorite SPC for HIV 25% 25% 25% 25% A. B. C. D. 8

15 Era of many options Nucleoside and nucleotide RTIs Zidovudine, AZT Abacavir, ABC Lamivudine, 3TC Didanosine, ddi Stavudine, d4t Tenofovir, TFV Emtricitabine, FTC AZT/3TC AZT/3TC/ABC 3TC/ABC TDF/FTC CCR5 receptor blocker Maraviroc Integrase inhibitor Raltegravir Elvitegravir Dolutegravir NNRTI s: Delavirdine (DLV) Nevirapine, NVP Efavirenz, EFV Etravirine Rilpivirine Fusion inhibitors: Enfuvirtide, ENF or T20 Combination (1 pill once daily) EFV/FTC/TDF RPV/FTC/TDF ELV/cobicistat/FTC/TDF Protease inhibitors: Indinavir, IDV Saquinavir, SQV Nelfinavir, NFV Amprenavir, APV Atazanavir, ATZ Fosamprenavir, FPV Lopinavir/ritonavir Tipranavir Darunavir red combination agents

16 HIV = SPC dream state? Need for multiple pills Can t be started sequentially; must be simultaneous Stigma, depression can make multiple pill-taking difficult Mistakes in taking one pill and not another can lead to resistance Near perfect adherence counseled

17 What s the evidence in HIV? Don t have much data comparing SPCs to free components Meta-analysis of 19 RCTs (n=6321) showed modestly better adherence with once daily versus BID (+2.55%, p <0.002); no difference in virologic outcomes Better adherence and virologic suppression rates with lower pill burden Parienti CID 2010; Nachega AB CID 2014 Favors twice daily Favors once daily

18 Few studies in HIV REACH cohort Unannounced pill counts in marginally housed patients on TDF/FTC/EFV: mean adherence to SPC 86% versus 73% (p=0.001) compared to historical controls Higher rates of virologic suppression (69% v. 46%, p 0.02) mediated by adherence Treatment simplification trials Suppression maintained, happy patients Bangsberg AIDS 2010; Dejesus JAIDS 2009; Hodder AIDS Patient Care STDs 2010; Airoldi Patient Preference Adher 2010

19 3 retrospective observational studies,?confounding by indication Study design N Comparison Commercially insured database (Sax P, PLOS ONE 2012) Medicaid patients (Cohen CJ, BMJ Open, 2013) VA cohort (Rao, 53 rd ICAAC, 2013) 7,073 SPCs versus 3 pills per day 7,381 SPCS versus 2 pills per day 15,600 SPCS versus 2 pills per day h Adherence i Healthcare costs i Rate of hospitalization

20 Which SPCs are available? TFV/FTC/efavirenz, approved 2006 TFV/FTC/rilpivirine, approved 2011 TFV/FTC/elvitegravir/ cobicistat, approved 2012 Soon? ABC/3TC/dolutegravir (Filed to FDA 10/22/13)

21 Pros and cons of each PROS Long track record of safety and effectiveness TDF/FTC/EFV CONS Potentially teratogenic (don t worry about this) Neuropsychiatric effects Raises lipid levels Rash To ameliorate side effects, often dosed at bedtime; food increases absorption, which may increase adverse effects

22 PROS Lower rate of CNS and rash events than EFV More favorable lipid effects Pregnancy class B TDF/FTC/RPV CONS Higher failure with pre-therapy HIV-1 RNA levels >100,000 (also CD4 <200 adherence <95%) Needs solid meal (390 kcal + 12g fat studied, protein shake i absorption ~50%) Needs acid for absorption (no PPIs; space antacids, H2 blockers) Caution with drugs that prolong QT

23 PROS Lower rate of CNS and rash events than EFV More favorable lipid effects Pregnancy class B TDF/FTC/EVG/COBI CONS Cobi inhibits tubular secretion of creatinine, h serum Cr mg/dl (mean 0.14), early, reversible Approved only if GFR > 70 ml/min Cross resistance with RAL CYP3A4 inhibitor drug-drug interactions (statins, rifamycins, anticonvulsants, etc.) Take with food (studied w/ 373kcal, 20% fat) Separate from cation-containing antacids by 2 hours (Mg, Al, Ca)

24 Why can t you co-administer elvitegravir with cationcontaining antacids? A. Reduces gastric absorption of medication B. Efflux transporter in gut ph-dependent C. Metal chelation of drug in gut (Integrase inhibitors bind to Mg 2+ at catalytic site of integrase) D. Increase transit time of medication in gut 25% 25% 25% 25% A. B. C. D. 8

25 Next anticipated SPC Dolutegravir approved 8/12/13 for use in HIVinfected adults and children > 12 weighing 40kg Five major trials investigating its use in naïve and experienced patients SINGLE: Walmsley S. NEJM 2013 SPRING-2: Raffi F. et al. Lancet 2013 (48 wks) and Lancet ID (96 wks) SAILING: Cahn P. Lancet 2013 (48 wks) and IAS 2013 (96 wks) VIKING : Eron JJ. JID 2013, Nichols G CID 2014 FLAMINGO: Clotet B. Lancet 2014

26 Which were the 3 dolutegravir trials conducted in treatment naïve patients? A. VIKING, SPRING-2, SINGLE B. FLAMINGO, SPRING-2, SINGLE C. SAILING, SPRING-2, SINGLE D. I cannot keep these trial names straight, but I heard the drug works 25% 25% 25% 25% A. B. C. D. 8

27 Study Patient population Main outcome Dose SINGLE 1 Treatment naïve (ABC/3TC + DTG vs TDF/FTC/EFV) DTG regimen superior to EFV, driven mainly by more discontinuations with EFV 50mg once daily SPRING-2 2,3 Treatment-naïve (TDF/FTC or ABC/3TC with either DTG or RAL) DTG regimen non-inferior to RAL-based regimens 50mg once daily FLAMINGO 4 Treatment naïve (TDF/FTC or ABC/3TC with either DTG or DRV/r) DTG regimen superior to DRV/r, driven mainly by more discontinuations or f/u loss with DRV/r; more virologic response with DTG in viral loads >100,000 copies/ml group 50mg once daily SAILING 5,6 ART-experienced, INSTI-naïve patients with at least 2-class resistance: DTG vs RAL with OBR DTG regimen superior to RAL, driven by more discontinuations, virologic failures and treatment-emergent resistance with RAL 50mg once daily VIKING-3 7,8 LATTE (Phase IIB) 9 Patients with resistance to 2 or more ART classes, including INSTI. DTG vs optimized Treatment naïve GSK744 (dolutegravir analog with long half-life- 40 hours) + rilpivirine; Induction with 3 doses of NRTIs, switch to 744 +RPV vs 2 NRTIs + EFV. DTG regimen superior to optimized regimen with failures most prominent (76%) in patients with the Q148H/R +2 other mutations 82% of 744+RPV and 71% of EFV + NRTIs HIV-1 RNA <50 (ITT 93% 744+RPV and 94% EFV + NRTIs <50); Similar response rate across all 3 doses of 744; 1 subject with low 744 and RPV concentrations emerged INI and NNRTI mutations 50mg po twice daily 744 oral dose 10mg, 30mg, 60mg 1 Walmsley S. NEJM 2013; 2 Raffi F. Lancet 2013; 3 Raffi F. Lancet ID 2013; 4 Clotet B. Lancet 2014; 5 Cahn P. Lancet 2013; 6 Cahn P. IAS 2013; 7 Eron J.J. JID 2013; 8 Nichols G. CID 2014; 9 Margolis D. CROI 2014 (91LB)

28 What data does a company need to show to get a SPC approved? A. That the free drugs can actually be put into the same pill B. Phase I clinical trial data that the SPC is safe C. Phase III clinical trial data that the SPC is equivalent to the free components in patients D. Pharmacokinetic bioequivalence data that the SPC gives same general PK parameters as free components 25% 25% 25% 25% A. B. C. D. 8

29 Bioequivalence data for SPC 62 patients received DTG/ABC/3TC SPC vs DTG and ABC/3TC in single-dose open label randomized 2-period cross over study (also showed no significant effects of food) Weller S. JAIDS May 4, 2014

30 ABC/3TC + DOLUTEGRAVIR PROS Superior to efavirenz and DRV/r regimens in SINGLE, FLAMINGO (driven by d/c s in non-dol arm); non-inferior to raltegravirbased regimens in SPRING-2, superior in SAILING Well tolerated No food restrictions ABC/3TC backbone can be used in mild renal insufficiency (GFR >50 ml/min) Pregnancy class B Seems to have high genetic barrier to resistance Retains activity against some RAL, EVGresistance viruses October 22, 2013: SPC filed with FDA for approval CONS Inhibits creatinine secretion (mean rise Cr 0.11mg/dL) Abacavir needs HLA-B5701 testing Separate from Mg, Al, Ca-containing antacids by 2 hours Limited clinical experience (8/12/13) increase dose with concomitant rifampin, efavirenz; don't give with etravirine unless PIs present; no dose adjustments with rilpivirine

31 What is the next likely SPC to be developed? A. TAF/FTC/ELV/Cobi B. ATV/Cobi/TDF/FTC C. DRV/Cobi/TDF/FTC D. Dolutegravir/TDF/ FTC 25% 25% 25% 25% A. B. C. D. 8

32 TAF/FTC/ELV/Cobi Tenofovir alafenemide fumarate (TAF) Phase II study - Similar virologic efficacy, smaller decrease in egfr and smaller decrease in bone mineral density at 48 weeks with FTC/ELV/COBI Sax P. 53 rd ICAAC, Sept 2013, A1464d

33 Patients achieving a human immunodeficiency virus type 1 (HIV-1) RNA load of < 50 copies/ml through week 48 of the study, according to missing-equals-failure intention-totreat analysis. Week 48 results of atazanavir/ritonavir vs atazanavir/cobicistat Gallant J E et al. J Infect Dis. 2013;208:32-39

34 Darunavir/cobicistat

35 Kakuda T. IAS 2013 PIs co-formulated with cobicistat Data to date paves the way for eventual TDF/FTC/PI (ATV or DRV)/COBI single pill combinations Darunavir/cobicistat submitted to European Medicines Agency for approval 10/15/13 Atazanavir/cobicistat submitted to FDA April 2-14

36 Sign me up! or What did one cost-effectiveness study estimate as the cost-savings of switching TDF/FTC/EFV to 3 generic drugs? A. $5 million per year B. $10 million per year C. $100 million per year D. $1 billion per year 25% 25% 25% 25% A. B. C. D. 8

37 Cost considerations generic era and ACA Changing TDF/FTC/EFV SPC to a 3-pill regimen of generic EFV, generic 3TC and branded TDF would save almost a billion dollars per year, with a relatively small reduction in treatment efficacy Areas of uncertainty Walensky. Ann Intern Med 2013

38 Cost section, DHHS guidelines New cost section, DHHS guidelines ARVs $10,000/yr in resource-rich settings Branded combinations likely to cost patient more in co-pays, may be prohibitive Prior authorizations may help costs, but more likely to reduce prescribing Save money in reduced lab monitoring DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available at: 5/1/14

39 Follow-up on case You start an SPC in your marginally-housed patient and he is able to take it with him in the morning and adhere daily to the meds His Section 8 housing comes through and he moves into place with access to food, stabilized CD4 406 and viral load undetectable 6 months and thereafter You are patient s favorite provider!

40 Key clinical points HIV-1 is now a chronic controllable condition, requiring lifelong daily adherence to a combination of antiretroviral medications Inadequate adherence leads to HIV-1 resistance in individuals and ongoing transmission (including of drug-resistant virus) in communities Single pill combinations improve adherence in other chronic disease states Three SPCs currently marketed for HIV-1 infection, each with unique benefits/limitations, others in development Initial considerations are whether TDF/FTC is right for your patient, whether you want a PI, renal function Consider also drug resistance, HIV-1 RNA level and CD4 cell count, potency, durability of response, tolerability, food issues, drug-drug interactions, access and cost

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42 Activity Code FM285